Yu- Lin

Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis

BACKGROUND Major adjuvant treatments for pancreatic adenocarcinoma include fluorouracil, gemcitabine, chemoradiation, and chemoradiation plus fluorouracil or gemcitabine. Since the optimum regimen remains inconclusive, we aimed to compare these treatments in terms of overall survival after tumour resection and in terms of grade 3-4 toxic effects with a systematic review and random-effects Bayesian network meta-analysis. METHODS We searched PubMed, trial registries, and related reviews and abstracts for randomised controlled trials comparing the above five treatments with each other or observation alone before April 30, 2013. We estimated relative hazard ratios (HRs) for death and relative odds ratios (ORs) for toxic effects among different therapies by combining HRs for death and survival durations and ORs for toxic effects of included trials. We assessed the effects of prognostic factors on survival benefits of adjuvant therapies with meta-regression. FINDINGS Ten eligible articles reporting nine trials were included. Compared with observation, the HRs for death were 0·62 (95% credible interval 0·42-0·88) for fluorouracil, 0·68 (0·44-1·07) for gemcitabine, 0·91 (0·55-1·46) for chemoradiation, 0·54 (0·15-1·80) for chemoradiation plus fluorouracil, and 0·44 (0·10-1·81) for chemoradiation plus gemcitabine. The proportion of patients with positive lymph nodes was inversely associated with the survival benefit of adjuvant treatments. After adjustment for this factor, fluorouracil (HR 0·65, 0·49-0·84) and gemcitabine (0·59, 0·41-0·83) improved survival compared with observation, whereas chemoradiation resulted in worse survival than fluorouracil (1·69, 1·12-2·54) or gemcitabine (1·86, 1·04-3·23). Chemoradiation plus gemcitabine was ranked the most toxic, with significantly higher haematological toxic effects than second-ranked chemoradiation plus fluorouracil (OR 13·33, 1·01-169·36). INTERPRETATION Chemotherapy with fluorouracil or gemcitabine is the optimum adjuvant treatment for pancreatic adenocarcinoma and reduces mortality after surgery by about a third. Chemoradiation plus chemotherapy is less effective in prolonging survival and is more toxic than chemotherapy. FUNDING None.

A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer

Background:PEP02, also known as MM-398, is a novel nanoliposomal irinotecan that has improved pharmacokinetics and tumour bio-distribution of the free drug. This phase 2 study evaluated PEP02 monotherapy as second-line treatment for pancreatic cancer.Methods:Patients who had metastatic pancreatic adenocarcinoma, Karnofsky performance status ⩾70, and had progressed following gemcitabine-based therapy were eligible. Intravenous injection of PEP02 120 mg m−2 was given every 3 weeks. Simon 2-stage design was used. The primary objective was 3-month survival rate (OS3-month).Results:A total of 40 patients were enrolled. The most common severe adverse events included neutropenia, abdominal pain, asthenia, and diarrhoea. Three patients (7.5%) achieved an objective response, with an additional 17 (42.5%) demonstrating stable disease for a minimum of two cycles. Ten (31.3%) of 32 patients with an elevated baseline CA19-9 had a >50% biomarker decline. The study met its primary end point with an OS3-month of 75%, with median progression-free survival and overall survival of 2.4 and 5.2 months, respectively.Conclusion:PEP02 demonstrates moderate antitumour activity with a manageable side effect profile for metastatic, gemcitabine-refractory pancreatic cancer patients. Given the limited treatment options available to this patient population, a phase 3 trial of PEP02 (MM-398), referred to as NAPOLI-1, is currently underway.

MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib. Acquired resistance to EGFR‐TKIs develops after prolonged treatments. The study was prompt to explore effective strategies against resistance to EGFR‐TKIs. We established gefitinib resistant PC‐9 cells which harbor EGFR exon 19 deletion. Known mechanisms for intrinsic or acquired EGFR‐TKI resistance, including KRAS mutation, HER2 mutation, EGFR T790M mutation and MET gene amplification, were studied, and we did not observe any known mechanisms for intrinsic or acquired resistance to EGFR‐TKIs in the resistant cells. In the parental PC‐9 cells, labeled as PC‐9/wt, gefitinib completely inhibited EGF‐induced phosphorylation of EGFR, AKT and ERK. Gefitinib inhibited EGFR phosphorylation, but was unable to block EGF‐induced phosphorylation of ERK in resistant cells, labeled as PC‐9/gef cells, including PC‐9/gefB4, PC‐9/gefE3, and PC‐9/gefE7 subclones. We detected NRAS Q61K mutation in the PC‐9/gef cells but not the PC‐9/wt cells. MEK inhibitors, either AZD6244 or CI1040, inhibited ERK phosphorylation and sensitized gefitinib‐induced cytotoxicity in PC‐9/gef cells. Whereas MEK inhibitors or gefitinib alone did not activate caspases in PC‐9/gef cells, combination of gefitinib and AZD6244 or CI1040 induced apoptosis. Our in vivo studies showed that gefitinib inhibited growth of PC‐9/wt xenografts but not PC‐9/gef xenografts. Furthermore, combination of a MEK inhibitor and gefitinib inhibited growth of both PC‐9/wt xenografts and PC‐9/gefB4 xenografts. To conclude, persistent activation of ERK pathway contributes to the acquired gefitinib‐resistance. Combined treatment of gefitinib and MEK inhibitors may be therapeutically useful for acquired gefitinib‐resistance lung adenocarcinoma cells harboring EGFR mutations.

Traditional serrated adenoma has two pathways of neoplastic progression that are distinct from the sessile serrated pathway of colorectal carcinogenesis

Traditional serrated adenoma is one type of colorectal serrated neoplasm and a precursor of colorectal cancer. We evaluated the pathologic and molecular features of 60 traditional serrated adenomas with cytologic dysplasia and/or invasive carcinoma. On the basis of morphological features, 16 cases (27%) were categorized as traditional serrated adenoma with serrated dysplasia and 25 cases (42%) as traditional serrated adenoma with conventional adenomatous dysplasia. In addition, 19 cases (31%) showed an overall tubulovillous adenomatous structure but with focal serrated feature. Traditional serrated adenoma with serrated dysplasia had a significantly higher frequency of BRAF mutation than traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature (P=0.006), whereas traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature had higher frequencies of KRAS mutation than traditional serrated adenoma with serrated dysplasia (P<0.0001). Only traditional serrated adenoma with serrated dysplasia showed sessile serrated adenoma-like lesions at the periphery (n=3) and developed invasive carcinomas when the lesions were <15 mm in size. Abnormal nuclear accumulation of β-catenin was detected in traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature but not in traditional serrated adenoma with serrated dysplasia. The frequency of the positive CpG island methylator phenotype was similar among the three dysplastic subtypes, and immunostaining of four mismatch repair proteins in the nucleus was retained in all traditional serrated adenomas and associated invasive malignancies. Traditional serrated adenoma-associated adenocarcinomas (n=28) displayed distinctive morphological features: oval cell nuclei, serrated glands, infiltrating borders, rare occurrences of necrosis and mucinous differentiation. Overexpression of p53 was detected only in high-grade dysplasia and invasive adenocarcinoma. Our findings indicate that traditional serrated adenoma is a heterogeneous neoplasm with two pathways of neoplastic progression, which are distinct from the sessile serrated pathway of colorectal carcinogenesis.

Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer.

Introduction: Germline Bcl-2-like protein 11 (BIM) deletion polymorphism in Asian is a poor predictive factor for treatment outcomes to tyrosine kinase inhibitors (TKIs) in malignancies. We explored the impact of BIM deletion polymorphism on treatment outcome of advanced non–small-cell lung cancer (NSCLC). Methods: We prospectively collected tissue samples, blood, and clinical data from two cohorts of advanced NSCLC patients. BIM deletion polymorphism was correlated with overall survival (OS) and progression-free survival (PFS) to epidermal growth factor receptor (EGFR) TKIs and chemotherapy treatment. Results: BIM deletion polymorphism was detected in blood of 16.2% (33 of 204) patients. The PFS to first-line EGFR-TKIs in 153 patients were 8.6 and 4.6 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.004). Among 120 patients who received chemotherapies, the PFS to chemotherapies were 5.6 and 3.5 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.050). The OS of all 204 patients was 24.8 and 16.8 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.005). Multivariate analyses suggested that BIM deletion polymorphism was an independent predictor for shorter PFS to EGFR-TKIs (hazard ratio [HR] 2.15, p = 0.002), PFS to chemotherapy (HR 2.40, p = 0.016), and OS (HR 1.65, p = 0.039). Conclusions: BIM deletion polymorphism predicts shorter PFS to EGFR-TKIs and OS in advanced NSCLC.

KRAS Mutation Is a Predictor of Oxaliplatin Sensitivity in Colon Cancer Cells

Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1G13D and SW480G12V) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels, and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1G13D and SW480G12V), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation.

Prognostic Factors in Extrapulmonary Small Cell Carcinomas

Background: Extrapulmonary small cell carcinoma (EPSCC) is a heterogeneous group of cancers. The clinicopathological features of EPSCC remain poorly defined. Patients and Methods: Patients with the clinicopathological features of EPSCC, treated at three major medical centers in Taiwan, were included. Histologic and clinical diagnoses, smoking history, staging, clinical course and treatment outcome were reviewed and analyzed. Results: A total of 90 patients, treated between 1995 and 2005, were eligible for analysis. Forty-nine patients had limited disease and 41 extensive disease. Ten, 18, 17 and 45 patients received no treatment, local treatment, chemotherapy alone or combined modality treatment, respectively; the median survival for these four groups was 1.1, 13.8, 6.7 and 24.9 months. The origin of cancer was head and neck in 17, gastrointestinal in 27, genitourinary in 10, gynecologic in 27 and unknown in 9 patients; the median survival time was 34.2, 6.4, 9.1, 23.7 and 9.2 months, respectively. Ten out of 90 patients were long-term survivors, and 9 of them had tumors of head-and-neck and gynecologic origin. There was no statistically significant difference in survival between smokers and non-smokers. Factors associated with survival in univariate analysis included age ≤60, female gender, limited disease, head-and-neck and gynecologic origin, as well as combined modality treatment. However, in multivariate analysis, only female gender, limited disease and combined modality treatment were independent predictors of survival. Conclusions: Female gender, limited disease and combined modality treatment are favorable prognostic factors for patients with EPSCC. Prolonged survival is more likely in patients with tumors of head-and-neck and gynecologic origin.

Aberrant expression of annexin A10 is closely related to gastric phenotype in serrated pathway to colorectal carcinoma.

Annexin A10 (ANXA10) is a member of the ANX family that is normally expressed in gastric mucosa. ANXA10 was recently observed to be upregulated in sessile serrated adenoma, a precursor to microsatellite-unstable colorectal cancer. We investigated the use of ANXA10 in diagnosing colorectal carcinoma. In an immunohistochemical analysis, the intensity and quantity of ANXA10, MUC5AC, MUC6 and CDX2 in 123 colorectal carcinomas were graded. We determined the molecular status of BRAF and KRAS mutations, as well as the microsatellite instability status and the CpG island methylator phenotype in all colorectal carcinomas, and subcategorized into four molecular subgroups according to the molecular derangements. Nuclear ANXA10 staining was present in 36 colorectal carcinomas, exhibiting a strong significant association with the BRAF mutation status (P<0.0001) and positive CpG island methylator phenotype (P<0.0001), and a borderline significant association with high levels of microsatellite instability (P=0.072). The ANXA10-positive colorectal carcinomas were frequently positive for MUC5AC and MUC6, and were associated with absent or reduced CDX2 expression (all P<0.0001). According to a classification and regression tree analysis, ANXA10 is a superior marker for the molecular subtyping of colorectal carcinomas and represents a specific marker for colorectal cancers of the serrated pathway. Our results indicated that ANXA10 expression is implicated in gastric programming in serrated-pathway-associated colorectal carcinoma. ANXA10-positive colorectal carcinoma is highly associated with the molecular features of the serrated neoplasia pathway.

Induction chemotherapy with gemcitabine, oxaliplatin, and 5-fluorouracil/leucovorin followed by concomitant chemoradiotherapy in patients with locally advanced pancreatic cancer: a Taiwan cooperative oncology group phase II study.

PURPOSE To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS Chemonaïve patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m2) infusion at a fixed dose rate (10 mg/m2/min), followed by 85 mg/m2 oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m2) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m2 gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected for surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity. RESULTS Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2-42.5%) and 70% (95% CI, 44.4-99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8-12.8) months and 14.5 (95% CI, 11.9-17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. Neutropenia was the most common Grade 3-4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18%). CONCLUSION Three months of triplet ICT followed by gemcitabine-based CCRT is feasible, moderately active, and associated with encouraging survival in patients with LAPC.

Disseminated microvascular pulmonary tumor embolism from non-small cell lung cancer leading to pulmonary hypertension followed by sudden cardiac arrest

Disseminated microvascular pulmonary tumor embolism (DMPTE) is extremely rare and invariably fatal. Typical symptoms and signs of DMPTE include shortness of breath and inadequate oxygenation. Here we demonstrate a patient with unexplained progressive pulmonary hypertension followed by sudden cardiac arrest, who finally diagnosed of DMPTE pathologically under veno-arterial extracorporeal membrane oxygenation (VA-ECMO) system support. A 59-year-old gentleman was diagnosed of advanced non-small cell lung cancer with clinical stage of T3N2M1 in February 2008. His disease had been controlled well for two years under first-line clinical trial and salvage pemetrexed treatment. In early January 2010, he suffered from dyspnea on exertion gradually, although cancer progression was not proven by computed tomography (CT) scan. Transthoracic echocardiography also revealed normal heart size and function. However, he was sent to emergency room (ER) one month later due to dyspnea where pulmonary hypertension was discovered by repeated echocardiography. Follow-up CT scan was shown neither evidences of tumor progression nor pulmonary thromboembolic event in all major pulmonary vessels. Unfortunately, he was found to be unconscious suddenly at ER during urination and diagnosed as pulse-less electrical activity. Cardiopulmonary resuscitation (CPR) was initiated immediately and he was sent to intensive care unit with VA-ECMO system under the impression of cardiovascular system dysfunction. He passed away 10 days after intensive treatment. A necropsy was performed after we received the inform consent from his family. DMPTE was confirmed by pathologists. Currently, diagnosis of DMPTE is challenging and treatment is limited although advances of modern medicine. DMPTE should be kept in mind if cancer patients have dyspnea, inadequate oxygen saturation and unexplained pulmonary hypertension during their disease courses that unexpected serious consequences, like sudden cardiac arrest, may happen.