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1.  Vertebral carcinomatosis eleven years after advanced gastric cancer resection: A case report 
Oncology Letters  2014;9(3):1403-1405.
Bone metastasis is an uncommon event in advanced gastric cancer patients and bone metastases are rarely detected as isolated lesions. However, eleven years after treatment for locally advanced gastric cancer, including total gastrectomy followed by adjuvant chemotherapy, a 49-year-old female was admitted to the IX Division of General Surgery of the Second University of Naples (Naples, Italy) exhibiting severe progressive neurological symptoms. Magnetic resonance imaging indicated vertebral abnormalities, with evidence of marrow infiltration in several vertebral bodies; however, a contrast-enhanced computed tomography scan did not detect disease progression to other sites. Biopsy of the soft tissue at the level of the second lumbar vertebra (L2) revealed a metastatic lesion derived from gastric mucinous adenocarcinoma. The patient was initially treated with radiotherapy directed to the L2–L4 vertebral bodies to control the pain. Subsequently, systemic chemotherapy according to a FOLFOX-4 (leucovorin, fluorouracil and oxaliplatin) regimen commenced. However, after eight cycles, pulmonary progression of the disease occurred. Thus, palliative care was administered and the patient succumbed one month later. The late relapse of gastric cancer in the current patient may be associated with the theory of tumour dormancy.
doi:10.3892/ol.2014.2822
PMCID: PMC4315078  PMID: 25663920
vertebral metastases; gastric cancer; tumour dormancy
2.  CD26-positive/CD326-negative circulating cancer cells as prognostic markers for colorectal cancer recurrence 
Oncology Letters  2014;9(2):542-550.
The present study evaluated the presence and clinical relevance of a cluster of differentiation (CD)26+/CD326− subset of circulating tumor cells (CTCs) in pre- and post-operative blood samples of colorectal cancer patients, who had undergone curative or palliative intervention, in order to find a novel prognostic factor for patient management and follow-up. In total, 80 colorectal cancer patients, along with 25 healthy volunteers were included. The easily transferable methodology of flow cytometry, along with multiparametric antibody staining were used to selectively evaluate CD26+/CD326− CTCs in the peripheral blood samples of colorectal cancer patients. The multiparametric selection allowed any enrichment methods to be avoided thus rendering the whole procedure suitable for clinical routine. The presence of CD26+/CD326− cells was higher in advanced Dukes’ stages and was significantly associated with poor survival and high recurrence rates. Relapsing and non-surviving patients showed the highest number of CD26+/CD326− CTCs. High pre-operative levels of CD26+/CD326− CTCs correctly predicted tumor relapse in 44.4% of the cases, while 69% of post-operative CD26+/CD326− CTC-positive patients experienced cancer recurrence, with a test accuracy of 88.8%. By contrast, post-operative CD26+/CD326− CTC-negative patients showed an increase in the three-year progression-free survival rate of 86%, along with a reduced risk of tumor relapse of >90%. In conclusion, CD26+/CD326− CTCs are an independent prognostic factor for tumor recurrence rate in multivariate analysis, suggesting that their evaluation could be an additional factor for colorectal cancer recurrence risk evaluation in patient management.
doi:10.3892/ol.2014.2749
PMCID: PMC4301532  PMID: 25624884
cluster of differentiation 26; circulating tumor cell; patient management; colorectal cancer; flow cytometry
3.  Clinical management of advanced gastric cancer: The role of new molecular drugs 
World Journal of Gastroenterology : WJG  2014;20(40):14537-14558.
Gastric cancer is the fourth most common malignant neoplasm and the second leading cause of death for cancer in Western countries with more than 20000 new cases yearly diagnosed in the United States. Surgery represents the main approach for this disease but, notwithstanding the advances in surgical techniques, we observed a minimal improvement in terms of overall survival with a significant increasing of relapsing disease rates. Despite the development of new drugs has significantly improved the effectiveness of chemotherapy, the prognosis of patients with unresectable or metastatic gastric adenocarcinoma remains poor. Recently, several molecular target agents have been investigated; in particular, trastuzumab represents the first target molecule showing improvements in overall survival in human epithelial growth factor 2-positive gastric cancer patients. New molecules targeting vascular epithelial growth factor, mammalian target of rapamycin, and anti hepatocyte growth factor-c-Met pathway are also under investigation, with interesting results. Anyway, it seems necessary to select more accurately the population to treat with new agents by the identification of new biomarkers in order to optimize the results. In this paper we review the actual “scenario” of targeted treatments, also focusing on the new agents in development for gastric cancer and gastro-esophageal carcinoma, discussing their efficacy and potential applications in clinical practice.
doi:10.3748/wjg.v20.i40.14537
PMCID: PMC4209522  PMID: 25356019
Advanced gastric cancer; Gastrointestinal cancer; Targeted therapy; Monoclonal antibodies; Tyrosine-kinase inhibitor; Gastric cancer
4.  Treatment of gastric cancer 
The authors focused on the current surgical treatment of resectable gastric cancer, and significance of peri- and post-operative chemo or chemoradiation. Gastric cancer is the 4th most commonly diagnosed cancer and the second leading cause of cancer death worldwide. Surgery remains the only curative therapy, while perioperative and adjuvant chemotherapy, as well as chemoradiation, can improve outcome of resectable gastric cancer with extended lymph node dissection. More than half of radically resected gastric cancer patients relapse locally or with distant metastases, or receive the diagnosis of gastric cancer when tumor is disseminated; therefore, median survival rarely exceeds 12 mo, and 5-years survival is less than 10%. Cisplatin and fluoropyrimidine-based chemotherapy, with addition of trastuzumab in human epidermal growth factor receptor 2 positive patients, is the widely used treatment in stage IV patients fit for chemotherapy. Recent evidence supports the use of second-line chemotherapy after progression in patients with good performance status
doi:10.3748/wjg.v20.i7.1635
PMCID: PMC3930964  PMID: 24587643
Gastric cancer; Surgery; Radiotherapy; Adjuvant chemotherapy; Palliative chemotherapy; Chemoradiation
5.  Prospective Validation of Candidate SNPs of VEGF/VEGFR Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab 
PLoS ONE  2013;8(7):e66774.
Purpose
The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included.
Experimental design
To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing.
Results
Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05–1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95–1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082–1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14).
Conclusion
This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.
doi:10.1371/journal.pone.0066774
PMCID: PMC3701556  PMID: 23861747
6.  Critical appraisal of the use of regorafenib in the management of colorectal cancer 
The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients.
doi:10.2147/CMAR.S34281
PMCID: PMC3628528  PMID: 23610528
colorectal cancer; angiogenesis; regorafenib
7.  Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy 
BMC Cancer  2012;12:482.
Background
Data on efficacy of bevacizumab (B) beyond first-line taxane -including regimen (BT) as first-line treatment are lacking. Although preclinical results that anti-angiogenic agents combined with hormonal therapy (HT) could be active, no clinical data exist about combination of maintenance Bevacizumab (mBev) with HT.
Methods
Thirty-five patients who experienced a response after first-line BT, were given mBev at the dose of 15 mg/kg every 3 weeks. Among 30 pts with hormonal receptor-positive metastatic breast cancer (MBC), 20 (66.6%) received HT with mBev (mHTBev). Objective of the study was the outcome and safety of mBev and in two groups of patients receiving HT or not.
Results
Complete response and partial response was achieved/maintained in 4 (11.4%) and 13 (37.1%) patients, respectively (overall response rate: 48.5%). Clinical benefit was obtained on 23 patients (65.7%). Median of mBev PFS and clinical benefit were 6.8 months (95% CI: 0.8-12.7) and 17.1 months (95% CI :12.2-21.9), respectively. Median PFS of patients who received mHTBev was longer than mBev without HT (13 months and 4.1 months, respectively, p = 0.05). The most common severe toxicities were proteinuria (11.4%) and hypertension (8.5%). No additional toxicity was observed with HTBev.
Conclusion
Maintenance bevacizumab with or without anti-hormonal therapy in patients with hormone receptor positive breast cancer is tolerable and associated with long-term clinical outcome; these results encourage the strategy of prolonging bevacizumab until progression in combination with anti-hormonal agents.
doi:10.1186/1471-2407-12-482
PMCID: PMC3488474  PMID: 23083011
Maintenance Bevacizumab; Antiangiogenic agents; HER2 negative metastatic breast cancer
8.  Persistent left superior vena cava: A possible contraindication to chemotherapy and total parenteral nutrition in cancer patients 
Oncology Letters  2012;4(4):759-762.
Persistent left superior vena cava (PLSVC) is the most common thoracic venous anomaly. Awareness of this condition may be useful when placement of left-side transvenous subclavian or internal jugular catheters is required. This anomaly may be detected only by chest radiograph following placement of the catheter. The primary endpoints of this study were to analyze the prevalence of PLSVC, measurement of its diameters and the outcome of cancer patients with this anomaly undergoing placement of a long term catheter for nutrition and chemotherapy at the Department of Surgery, of the Second University of Naples, Naples, Italy. A total of 600 consecutive adult patients with hematological or solid tumors admitted to our surgery department for implantation of a central venous catheter (CVC) were considered. The CVC was routinely implanted in the left internal jugular vein under ultrasound guidance. Four cases of PLSVC (0.6% of patients) were observed and confirmed using cine magnetic resonance imaging (MRI). In all cases, the CVC was not removed. Three patients underwent chemotherapy and one patient was subjected to total parenteral nutrition. In the three patients undergoing chemotherapy, dynamic ECG and echocardiography were performed at the end of the treatment. No disturbances of the cardiac rhythm or thrombosis were detected, and heart ejection fraction (EF) was not affected. In conclusion, although PLSVC may be a risky condition, no complications occurred in our study. Thus, PLSVC should not be regarded as a strict contraindication to infusion of chemotherapy or hyperosmolar nutritional solutions. However, further research is needed to confirm our data.
doi:10.3892/ol.2012.808
PMCID: PMC3506673  PMID: 23205097
central venous catheter; persistent left superior vena cava; cancer patients
9.  Antitumor Activity of Sorafenib in Human Cancer Cell Lines with Acquired Resistance to EGFR and VEGFR Tyrosine Kinase Inhibitors 
PLoS ONE  2011;6(12):e28841.
Treatment of non small cell lung cancer (NSCLC) and colorectal cancer (CRC) have substantially changed in the last years with the introduction of epidermal growth factor receptor (EGFR) inhibitors in the clinical practice. The understanding of mechanisms which regulate cells sensitivity to these drugs is necessary for their optimal use.
An in vitro model of acquired resistance to two tyrosine kinase inhibitors (TKI) targeting the EGFR, erlotinib and gefitinib, and to a TKI targeting EGFR and VEGFR, vandetanib, was developed by continuously treating the human NSCLC cell line CALU-3 and the human CRC cell line HCT116 with escalating doses of each drug. MTT, western blot analysis, migration, invasion and anchorage-independent colony forming assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in sensitive, wild type (WT) and TKI-resistant CALU-3 and HCT116 cell lines.
As compared to WT CALU-3 and HCT116 human cancer cells, TKI-resistant cell lines showed a significant increase in the levels of activated, phosphorylated AKT, MAPK, and of survivin. Considering the role of RAS and RAF as downstream signals of both the EGFR and VEGFR pathways, we treated resistant cells with sorafenib, an inhibitor of C-RAF, B-RAF, c-KIT, FLT-3, RET, VEGFR-2, VEGFR-3, and PDGFR-β. Sorafenib reduced the activation of MEK and MAPK and caused an inhibition of cell proliferation, invasion, migration, anchorage-independent growth in vitro and of tumor growth in vivo of all TKI-resistant CALU-3 and HCT116 cell lines.
These data suggest that resistance to EGFR inhibitors is predominantly driven by the RAS/RAF/MAPK pathway and can be overcame by treatment with sorafenib.
doi:10.1371/journal.pone.0028841
PMCID: PMC3235154  PMID: 22174910
10.  Hepatoid carcinoma colliding with a liposarcoma of the left colon serosa presenting as an abdominal mass 
Background
Hepatoid adenocarcinoma (HAC) is a peculiar type of extrahepatic adenocarcinoma generally characterized by adenocarcinomatous and hepatocellular carcinoma (HCC)-like foci. Stomach is the most frequent site where hepatoid adenocarcinoma occurs, although it has been described in many other organs. On the other side, liposarcoma is a rare, malignant tumor that develops from fat cells.
Case presentation
We describe here a case of hepatoid carcinoma in collision with a liposarcoma of the left colon serosa in a 71-year-old man. It presented as an abdominal mass involving several organs, falsely mimicking metastatic colonic adenocarcinoma. Recognition of this entity was evident on microscopic evaluation following surgery. The patient had an objective response following liposomal antracycline chemotherapy, with a 3-year overall survival.
Conclusion
To our knowledge, this is the first case of a hepatoid tumor colliding with a liposarcoma of the left colon serosa reported to date.
doi:10.1186/1477-7819-5-42
PMCID: PMC1866233  PMID: 17448253

Results 1-10 (10)