Seo-Young Song

Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients

AbstractBackgroundStatins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer.nMethodsPatients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000xa0mg/m2 on days 1, 8, and 15 plus simvastatin 40xa0mg once daily) or GP (gemcitabine 1,000xa0mg/m2 on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP).ResultsBetween December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4xa0months (95xa0% CI 0.7–4.1xa0months) and 3.6xa0months (95xa0% CI 3.1–4.1xa0months) in the GS and GP arms, respectively (Pxa0=xa00.903). The overall disease control rate was 39.7xa0% (95xa0% CI 12.2–33.8xa0%) and 57.1xa0% (95xa0% CI 19.8–44.2xa0%) in the GS and GP arms, respectively (Pxa0=xa00.09). The 1-year expected survival rates were similar (27.7 and 31.7xa0% in the GS and GP arms, respectively; Pxa0=xa00.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis.ConclusionsAdding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.

Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition.

Smad7, an inhibitory Smad, acts as a key regulator forming autoinhibitory feedback loop in transforming growth factor-beta (TGF-β) signaling. However, a growing body of evidences suggests that Smad7 is capable of apoptotic function. In the present study, we have demonstrated a proapoptotic function of Smad7 as a negative regulator of survival protein heme oxygenase-1 (HO-1). The HO-1 protein level was elevated in cisplatin-resistant A549 human lung cancer cells and blockade of HO-1 activation sensitized the cells to apoptosis. Interestingly, overexpression of Smad7 decreased HO-1 gene expression and its enzymatic activity. Notably, Smad7 reduced Akt activity and infection with adenovirus expressing a constitutively active form of the Akt reversed the inhibitory effects of Smad7 to HO-1, indicating a negative action mechanism of Smad7 to Akt-HO-1-linked survival pathway. Consistently, Smad7 sensitized A549 cells to cisplatin-induced apoptosis and these effects were dependent on HO-1 and Akt inhibition. Based on these findings, we suggest that targeting Smad7 may be an efficient strategy for overcoming drug-resistance in cancer therapy.

Vasogenic edema in striatum following ingestion of glufosinate-containing herbicide

Glufosinate-ammonium (GLA) is a broad-spectrum herbicide used worldwide. We report a patient who attempted suicide by ingesting a liquid herbicide containing GLA. A diffusion-weighted MRI showed cytotoxic edema in the hippocampus as well as vasogenic edema in the striata. To our knowledge, vasogenic edema caused by GLA-containing herbicide involving the striatum has not been reported in association with cytotoxic edema in the hippocampus. We assume that this herbicide affected the central nervous system via different mechanisms to produce both cytotoxic and vasogenic edema in the same patient.

Attenuated FOLFIRINOX in the salvage treatment of gemcitabine-refractory advanced pancreatic cancer: a phase II study

BackgroundCombination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemotherapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second-line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine-refractory advanced pancreatic cancer.MethodsA multicenter phase II prospective open-label, single-arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19xa0years or older were eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65xa0mg/m2, irinotecan 135xa0mg/m2, and leucovorin 400xa0mg/m2 injected intravenously on day 1 and 5-fluorouracil 2000xa0mg/m2 continuously infused intravenously over 46xa0h on days 1–2, repeated every 2xa0weeks. The primary endpoint was progression-free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression-free survival using the Kaplan–Meier methods.ResultsWe enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6-month and 1-year overall survival rates were 59.0% and 15.4%, respectively. Median progression-free survival and overall survival were 3.8xa0months (95% confidence interval [CI] 1.5–6.0xa0months) and 8.5xa0months (95% CI 5.6–11.4xa0months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment-related death attributable to septic shock occurred.ConclusionAttenuated FOLFIRINOX may be promising as a second-line therapy for gemcitabine-refractory pancreatic cancer.

1593PDIFFERENTIAL EXPRESSION OF MICRORNAS AND THEIR TARGET GENES IN NON-SMALL-CELL LUNG CANCER

ABSTRACT Aim: MicroRNAs (miRNAs) are single-stranded RNA species that constitute a class of noncoding RNAs that are emerging as key regulators of gene expression. Because each miRNA can regulate multiple genes, miRNAs are attractive markers for studies of coordinated gene expression. We investigated miRNA expression profiling using a massively parallel sequencing technique to compare non-small-cell lung cancer tissue (NSCLC) and normal lung tissue. Methods: Lung cancer tissue and normal lung tissue were obtained from nine NSCLC patients. RNA isolated from these samples was processed using RNA sequencing (RNA Seq) and the HiSeq 2000 system. Differentially expressed miRNAs and mRNAs were analyzed using a t-test. We selected target pairs that showed a negative correlation among significantly differentially expressed miRNAs and their putative target mRNAs using miRBase Targets. Results: The differences in the expression levels of 222 miRNAs and 1,597 genes were statistically significant, as indicated by an absolute fold change ≥1.5 and p Conclusions: There were significantly differentially expressed miRNAs and mRNAs between lung cancer and normal tissue. Further investigation of miRNAs and their target genes is warranted to better understand NSCLC. Disclosure: All authors have declared no conflicts of interest.