Genexol-PM is a novel Cremophor EL (CrEL)-free polymeric micelle formulation of paclitaxel (Taxol). This multicenter phase II study was designed to evaluate the efficacy and safety of the combination ...of Genexol-PM and cisplatin for the treatment of advanced non-small-cell lung cancer (NSCLC).
Patients with advanced NSCLC received Genexol-PM 230 mg/m2 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle as first-line therapy. Intrapatient dose escalation of Genexol-PM to 300 mg/m2 was carried out from the second cycle if the prespecified toxic effects were not observed after the first cycle.
Sixty-nine patients were enrolled in this study. Overall response rate was 37.7%. The median time to progression was 5.8 months and the median survival period was 21.7 months. The major non-hematologic toxic effects included grade 3 peripheral sensory neuropathy (13.0%) and grade 3/4 arthralgia (7.3%). Four patients (5.8%) experienced grade 3/4 hypersensitivity reactions. The major hematological toxic effects were grade 3/4 neutropenia (29.0% and 17.4%, respectively).
Genexol-PM plus cisplatin combination chemotherapy showed significant antitumor activity. The use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel compared with the CrEL-based formulation without significant increased toxicity.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
ZnO-nanowire gas sensors were fabricated by a selective growth of nanowires on patterned Au catalysts thus forming nanowire air bridges or ‘
nanobridges’ between two Pt pillar electrodes. The gas ...sensing properties of nanobridge gas sensors were demonstrated using a diluted NO
2. The response, as a function of temperature, was highest at 225
°C and was linearly increased with the concentration of NO
2 in the range of 0.5–3
ppm and then showed a sign of saturation. Our sensor showed higher response compared with different types of sensors including ZnO nanocrystals, Sn- and In-doped ZnO thin film, or ZnO nanowires. The enhanced response was attributed to the additional modulation of the sensor resistance due to potential barrier at nanowire/nanowire junctions as well as the surface depletion region of each nanowire. Also nanobridge structure enabled fast recovery behavior because desorbed gas molecules can be easily swept away from the surface of ZnO nanowire without re-adsorption.
The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
...Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21-activated kinase 4 (PAK4) in prostate ...cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer.
Background
The aim of this study was to identify clinical predictors of malignancy and surgical strategies for pancreatic solid pseudopapillary neoplasm (SPN) by analysis of surgical outcomes at a ...single institution.
Methods
All patients who underwent surgery for SPN between 1995 and 2010 were identified. Histopathology slides of all patients were reviewed by a specialized pathologist and the neoplasms were classified according to the criteria of the World Health Organization 2010.
Results
Of the 106 patients identified, 85 (80·2 per cent) were female, and the median age was 36 (range 10–65) years. Median tumour size was 4·5 (range 1·0–15·0) cm. Some 17 patients (16·0 per cent) were classified as having a high‐grade malignant SPN. Tumour size of at least 5 cm was associated with high‐grade malignant potential (P = 0·022). Although lymph nodes were removed from 40 patients (37·7 per cent), there were no nodal metastases. A total of five patients underwent en bloc resection of adjacent structures, including two with portal vein involvement. After a median follow‐up of 56·9 months, two patients with high‐grade malignant SPN had evidence of tumour recurrence in the lymph nodes and liver.
Conclusion
SPN with a diameter of 5 cm or more is associated with a high‐grade malignant phenotype. Complete surgical removal is associated with low recurrence rates.
Tumour size matters
Recent researches revealed that class III β-tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in head and neck squamous cell carcinoma (HNSCC) is not defined yet. We analyzed ...the significance of TUBB3 expression along with p53 and ERCC1 in locally advanced HNSCC patients receiving cisplatin-based induction chemotherapy.
Retrospective review of medical records at Seoul National University Hospital between 1998 and 2007 was carried out. Immunohistochemical stain of TUBB3, p53, and ERCC1 was done in paraffin-embedded tumor tissue. We assessed response to treatment, progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS).
Eighty-five patients with oropharyngeal, hypopharyngeal, and laryngeal cancers received induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (n=55), or 5-FU, cisplatin, and docetaxel (Taxotere) (n=30). Eighty-three received definitive treatment after induction chemotherapy, where 62 received radiotherapy and 21 received surgery. TUBB3-positive patients showed lower response rate than TUBB3-negative patients (69% versus 88%, P=0.039). Shorter median PFS was observed in TUBB3-positive group (12 versus 47 months, P=0.001). Shorter median OS was observed in TUBB-positive group not reaching statistical significance (30 versus 59 months, P=0.072). TUBB3 status significantly influenced CSS (35 months versus not reached, P=0.017). Positive p53 status was related to poorer OS and CSS. ERCC1 showed no influence on chemotherapy response, PFS, OS, and CSS.
TUBB3 is a predictive and prognostic marker along with well-known p53 in HNSCC patients receiving cisplatin-based induction chemotherapy. Clinical impact of ERCC1 is not evident in this setting.
In this paper, we introduce a new partial transmit sequence (PTS) orthogonal frequency division multiplexing (OFDM) scheme with low computational complexity. In the proposed scheme, 2/sup n/-point ...inverse fast Fourier transform (IFFT) is divided into two parts. An input symbol sequence is partially transformed using the first l stages of IFFT into an intermediate signal sequence and the intermediate signal sequence is partitioned into a number of intermediate signal subsequences. Then, the remaining n-l stages of IFFT are applied to each of the intermediate signal subsequences and the resulting signal subsequences are summed after being multiplied by each member of a set of W rotating vectors to yield W distinct OFDM signal sequences. The one with the lowest peak to average power ratio (PAPR) among these OFDM signal sequences is selected for transmission. The new PTS OFDM scheme reduces the computational complexity while it shows almost the same performance of PAPR reduction as that of the conventional PTS OFDM scheme.
Extranodal natural killer/T-cell lymphoma (NKTCL) is a clinically heterogeneous disease with a poor prognosis, requiring risk-stratified management in affected patients. Recently, tumor ...microenvironment including regulatory T cells (Tregs) has been implicated as a prognostic marker in certain types of lymphoma.
We collected 64 NKTCL cases and numerically quantified the amount of tumor-infiltrating FOXP3-positive Tregs by automated slide scanning and image analysis program after immunohistochemical staining using anti-FOXP3 antibody.
Patients were able to be classified into two end groups by their level of Tregs. Twenty-eight (44%) patients had Tregs <50/0.40 mm2, while 36 (56%) had Tregs ≥50/0.40 mm2 within the tumor. The decreased number of Tregs (<50/0.40 mm2) was more common in patients with poor performance status or in those presented in non-upper aerodigestive tract. However, the level of Tregs was not associated with other prognostic factors, including stage, lactate dehydrogenase level, International Prognostic Index, and NKTCL Prognostic Index. Importantly, patients with increased numbers of Tregs (≥50/0.40 mm2) showed prolonged overall and progression-free survival (P = 0.0005 and P = 0.0079, respectively). The number of FOXP3-positive Tregs was an independent prognostic factor (P = 0.001) by multivariate analysis.
Increased quantity of tumor-infiltrating Tregs predicted improved clinical outcome in NKTCL patients.
Background: Many patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy.
Patients and methods: This was ...single-institutional, phase II study. The primary end point was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Patients with relapsed or refractory NTCL were eligible. They received the chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone and it was repeated every 3 weeks.
Results: Thirty-two patients were enrolled and 15 patients had achieved partial remission (PR) or complete remission (CR) after the front-line chemotherapy. The International Prognostic Index scores were 0–1 in thirteen, 2 in five, 3 in five, and 4–5 in nine patients. Twelve and two patients achieved CR and PR, respectively. Median OS and TTF of all patients were 8.2 and 3.7 months, respectively. Non-hematologic toxic effects were well tolerated, but grade 3/4 leukopenia occurred in 11.7% of all cycles. Four patients developed febrile neutropenia and one patient died due to pneumonia.
Conclusions: This chemotherapy regimen was moderately effective for relapsed/refractory extranodal NTCL, nasal type. Toxic effects were moderate, but caution should be exercised to prevent severe infection.
PDF
