Chest wall resection effective for recurrent mesothelioma

Salvage chest wall resection could lengthen survival in patients with isolated chest wall recurrence of malignant pleural mesothelioma, research indicates.

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Erlotinib ‘dose-to-rash’ strategy effective in advanced NSCLC

Erlotinib as first-line therapy in patients with advanced non-small-cell lung cancer is equivalent to chemotherapy with regard to overall survival, an “all-comers” phase II trial has shown.

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Establishment of a bortezomib-resistant Chinese human multiple myeloma cell line: MMLAL

Background: A new human myeloma cell line, MMLAL, was established from the myelomatous pleural effusion of a 73-year-old Chinese patient suffering from symptomatic International stage III IgG/lambda myeloma. After a brief period of complete remission, he developed aggressive systemic relapse complicated by malignant pleural effusion with exclusive plasma cell infiltration. His disease remained chemo-refractory, and died six months after relapse. Methods: Purified mononuclear cells from the pleural effusion of the patient were cultured in the presence of IL-6. Continually growing cells were characterized by morphological, immunophenotypic, cytogenetic, fluorescence in situ hybridization (FISH) and TP53 mutation analyses. Cell proliferation was measured and compared with other myeloma cell lines by cell counting at day 3, 6, 9, and 12. Drug resistance against bortezomib, a proteasome inhibitor approved as a frontline chemotherapy for eligible myeloma patients, was evaluated and compared with other myeloma cell lines by MTT assay. Results: Immunophenotypic analysis of the myeloma cells confirmed strong expression of plasma cell markers CD38 and CD138 but not T-cell or natural killer-cell marker CD56. Cytogenetic analysis of the myeloma cells showed a hypodiploid composite karyotype including loss of chromosome 13 and 17 or deletion of the short arm of chromosome 17, i.e. del(17p), in the form of isochromosome 17q10. FISH confirmed a hypodiploid karyotype with TP53 deletion but absence of t(4;14). Sequencing analysis of the TP53 gene indicated absence of mutation. Cell counting revealed that the maximum viable cell density was about 2.5 X 106 cells/ml. Upon bortezomib treatment, MTT assay reported an IC50 of 72.17nM, suggesting a strong bortezomib resistance. Conclusion: A hypodiploid with loss of chromosome 13 and loss or del(17p) human myeloma cell line, MMLAL, was established from the pleural effusion of a Chinese myeloma patient.

via Cancer Cell International

Cetuximab fails in second-line combination for recurrent NSCLC

Results from a phase III trial indicate that cetuximab should not be given alongside chemotherapy in patients with recurrent non-small-cell lung cancer after platinum-based therapy.

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Low sodium levels linked to poor targeted therapy outcomes in RCC

Low serum sodium levels in patients receiving targeted therapy for metastatic renal cell carcinoma (mRCC) may signal a poor outcome, study findings indicate.

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Early tumor shrinkage predicts targeted therapy efficacy in RCC

Early tumor shrinkage in patients with metastatic renal cell carcinoma following vascular endothelial growth factor-targeted therapy may herald good long-term survival, research shows.

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Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines

Background: MET is a receptor tyrosine kinase that is activated by the ligand HGF and this pathway promotes cell survival, migration, and motility. In accordance with its oncogenic role, MET is constitutively active, mutated, or over-expressed in many cancers. Corollary to its impact, inhibition of MET kinase activity causes reduction of the downstream signaling and demise of cells. In myeloma, a B-cell plasma malignancy, MET is neither mutated nor over-expressed, however, HGF is increased in plasma or serum obtained from myeloma patients and this was associated with poor prognosis. The small-molecule, amuvatinib, inhibits MET receptor tyrosine kinase. Based on this background, we hypothesized that targeting the HGF/MET signaling pathway is a rational approach to myeloma therapy and that myeloma cells would be sensitive to amuvatinib. Methods: Expression of MET and HGF mRNAs in normal versus malignant plasma cells was compared during disease progression. Cell death and growth as well as MET signaling pathway were assessed in amuvatinib treated primary myeloma cells and cell lines. Results: There was a progressive increase in the transcript levels of HGF (but not MET) from normal plasma cells to refractory malignant plasma cells. Amuvatinib readily inhibited MET phosphorylation in primary CD138+ cells from myeloma patients and in concordance, increased cell death. A 48-hr amuvatinib treatment in high HGF-expressing myeloma cell line, U266, resulted in growth inhibition. Levels of cytotoxicity were time-dependent; at 24, 48, and 72 h, amuvatinib (25 muM) resulted in 28%, 40%, and 55% cell death. Consistent with these data, there was an amuvatinib-mediated decrease in MET phosphorylation in the cell line. Amuvatinib at concentrations of 5, 10, or 25 muM readily inhibited HGF-dependent MET, AKT, ERK and GSK-3-beta phosphorylation. MET-mediated effects were not observed in myeloma cell line that has low MET and/or HGF expression. Conclusions: These data suggest that at the cellular level MET/HGF pathway inclines with myeloma disease progression. Amuvatinib, a small molecule MET kinase inhibitor, is effective in inducing growth inhibition and cell death in myeloma cell lines as well as primary malignant plasma cells. These cytostatic and cytotoxic effects were associated with an impact on MET/HGF pathway.

via Journal of Hematology & Oncology

Expression of MACC1 and c-Met in human gastric cancer and its clinical significance

Background: Recent studies have suggested that the metastasis-associated colon cancer1 (MACC1) gene can promote tumor proliferation, invasion and metastasis through an upregulation of c-Met expression. However, its role in gastric cancer is controversial. Our study investigated expression of MACC1 and c-Met in gastric cancer, as well as correlated this with clinicopathological parameters. Methods: Expressions of MACC1 and c-Met protein in a sample of 98 gastric carcinoma and adjacent nontumorous tissues were detected by immunohistochemistry. Their relationships and correlations with clinicopathological features were analyzed. Results: The positive rates of MACC1 and c-Met protein in primary tumors were 61.22% and 59.18%, respectively. A significant correlation was found between expression of MACC1 and c-Met (P<0.05). Expression of the MACC1 protein in gastric cancer tissue was correlated with lymph node metastasis(chi2 = 10.555,P = 0.001), peritoneal metastasis (chi2 = 5.694, P = 0.017), and hepatic metastasis (chi2 = 4.540,P = 0.033), but not with age, gender, tumor size, location, clinical stage or the distant metastases (P>0.05). Conclusion: The positive rate of MACC1 protein expression was related to the protein expression of c-Met. Both had a correlation with the presence of peritoneal metastasis, lymph node metastasis and hepatic metastasis, all of which contribute to a poor prognosis for gastric cancer patients.

via Cancer Cell International

Meta-analysis of the efficacy of pancreatoduodenectomy with extended lymphadenectomy in the treatment of pancreatic cancer

Background: The purpose of this meta-analysis is to compare the efficacy of pancreatoduodenectomy (PD) with extended lymphadenectomy (PD/ELND) versus standard PD in the treatment of pancreatic cancer, with the hope of providing evidence for clinical practice. Methods: The retrieval of relevant literature published before September 2012 was carried out on PubMed, Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) by computer. Information was extracted according to Cochrane systematic review methods, and analyzed using software Stata 11.0. Results: Five prospective randomized controlled trials (RCTs) were included in this meta-analysis of 555 cases (278 in the PD/ELND group and 277 in the standard PD group). The PD/ELND group showed a significantly lower 3-year survival rate (relative risk (RR) = 1.46, 95% confidence interval (CI) 1.03 to approximately 2.06, P = 0.034), prolonged operative time (weighted mean difference WMD = -1.03, 95% CI -1.96 to approximately -0.10, P = 0.029) and higher incidence of postoperative complications (RR = 0.56, 95% CI 0.42 to approximately 0.77, P = 0.000) by comparing with standard PD group. Besides, no significant difference was observed in the 1-year survival rate (RR = 0.87, 95% CI 0.60 to approximately 1.25, P = 0.69), 5-year survival rate (RR = 1.04, 95% CI 0.68 to approximately 1.58, P = 0.854), postoperative mortality (RR = 1.14, 95% CI 0.43 to approximately 3.00, P = 0.789), length of stay (WMD = -0.32, 95% CI -2.57 to approximately 1.94 , P = 0.784) and the amount of blood transfusions (WMD = -0.14, 95% CI -0.36 to approximately 0.08, P = 0.213). Conclusions: PD/ELND does not have an advantage over standard PD in the survival rate for patients with pancreatic cancer, but does increase operative time and incidences of postoperative complications.

via World Journal of Surgical Oncology

Pemetrexed, paclitaxel regimens equally effective in NSCLC

PointBreak trial results suggest that pemetrexed- and paclitaxel-based chemotherapy offer comparable survival outcomes and tolerability for patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) but with differing toxicity profiles.

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Novel multi-kinase inhibitor shows early promise in NSCLC

Researchers have reported promising early data on an investigational drug that targets two tyrosine kinase receptors that drive invasive growth and drug resistance in non-small-cell lung cancer.

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Fact or fiction - identifying the elusive multiple myeloma stem cell

: Multiple Myeloma (MM) is a debilitating disease of proliferating and malignant plasma cells that is currently incurable. The ability of monoclonal recurrence of disease suggests it might arise from a stem cell-like population capable of self-renewal. The difficulty to isolate the cancer stem-like cell in MM has introduced confusion toward this hypothesis. However, recent evidence has suggested that MM originates from the B cell lineage with memory-B cell like features, allowing for self-renewal of the progenitor-like status and differentiation to a monoclonal plasma cell population. Furthermore, this tumor-initiating cell uses signaling pathways and microenvironment similar to the hematopoietic stem cell, though hijacking these mechanisms to create and favor a more tumorigenic environment. The bone marrow niche allows for pertinent evasion, either through avoiding immunosurveillance or through direct interaction with the stroma, inducing quiescence and thus drug resistance. Understanding the interaction of the MM stem cell to the microenvironment and the mechanisms utilized by various stem cell-like populations to allow persistence and therapy-resistance can enable for better targeting of this cell population and potential eradication of the disease.

via Journal of Hematology & Oncology

Sialyl Lewis X as a predictor of skip N2 metastasis in clinical stage IA non-small cell lung cancer

Background: Radical segmentectomy has been performed for small-sized non-small cell lung cancer (NSCLC). However, underestimation of mediastinal lymph node metastasis in the absence of hilar or interlobar metastasis (skip N2) affects surgical strategy. Our aim was to investigate preoperative and intraoperative predictors of skip N2 in clinical stage (c-stage) IA NSCLC. Methods: From 1998 to 2011, 279 patients (155 men and 124 women) with c-stage IA NSCLC (230 pN0, 17 pN1, 12 skip N2, 20 non-skip N2) underwent systematic lobectomy (R0 resection) at our institute. We compared preoperative serum concentrations of carcinoembryonic antigen, cytokeratin 19 fragment, sialyl Lewis X (SLX), and pre- and intraoperative clinicopathological features of pN0 and skip N2 patients. Receiver operator characteristic (ROC) curve analysis was performed to distinguish between the two patient groups. Results: The 5-year survival rate of skip N2 patients was 78.6%, higher than that of non-skip N2 patients (44.9%), and not significantly different than that of pN0 (86.7%) or pN1 patients (82.4%). The mean serum SLX concentration in skip N2 patients (28.0 U/ml) was elevated compared to that in pN0 patients (22.9 U/ml). In ROC analysis of SLX, the area under the curve was 0.710, and the optimal cut-off value was 21.4 U/ml (sensitivity, 91.7%; specificity, 51.7%). In multivariate analysis, SLX was an independent predictor of skip N2 in patients with c-stage IA NSCLC (odds ratio, 9.43; p = 0.006). Conclusions: Skip N2 metastasis is common in patients with c-stage IA NSCLC with high serum SLX, and lobectomy with complete dissection of hilar and mediastinal lymph nodes should remain the standard surgical procedure for these cases.

via World Journal of Surgical Oncology

Training advised to plug lung cancer care gaps

Guideline-consistent care for patients with suspected lung cancer with mediastinal lymphadenopathy without distant metastases varies by region and physician characteristics, say researchers.

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STAT inhibitors for cancer therapy

Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds.

via Journal of Hematology & Oncology

The mitochondrial C16069T polymorphism, not mitochondrial D310 (D-loop) mononucleotide sequence variations, is associated with bladder cancer

Background: Bladder cancer is a relatively common and potentially life-threatening neoplasm that ranks ninth in terms of worldwide cancer incidence. The aim of this study was to determine deletions and sequence variations in the mitochondrial displacement loop (D-loop) region from the blood specimens and tumoral tissues of patients with bladder cancer, compared to adjacent non-tumoral tissues. Methods: The DNA from blood, tumoral tissues and adjacent non-tumoral tissues of twenty-six patients with bladder cancer and DNA from blood of 504 healthy controls from different ethnicities were investigated to determine sequence variation in the mitochondrial D-loop region using multiplex polymerase chain reaction (PCR), DNA sequencing and southern blotting analysis. Results: From a total of 110 variations, 48 were reported as new mutations. No deletions were detected in tumoral tissues, adjacent non-tumoral tissues and blood samples from patients. Although the polymorphisms at loci 16189, 16261 and 16311 were not significantly correlated with bladder cancer, the C16069T variation was significantly present in patient samples compared to control samples (p < 0.05). Interestingly, there was no significant difference (p > 0.05) of C variations, including C7TC6, C8TC6, C9TC6 and C10TC6, in D310 mitochondrial DNA between patients and control samples. Conclusion: Our study suggests that 16069 mitochondrial DNA D-Loop mutations may play a significant role in the etiology of bladder cancer and facilitate the definition of carcinogenesis-related mutations in human cancer.

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Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma

Background: The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model. Methods: NOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 x 200 mug) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively. Results: The anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated. Conclusions: The anti-CCR7 antibody exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies.

via Journal of Hematology & Oncology

Role of the Hypoxia-inducible factor-1 alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells

The initiation and progression of various solid tumors, including pancreatic carcinoma, are driven by a population of cells with stem cell properties, namely cancer stem cells (CSCs). Like their normal counterparts, CSCs are also believed to rely on their own microenvironment termed niches to sustain the population. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a major actor in the cell survival response to hypoxia. Recently, several researchers proposed that non-stem cancer cells can convert to stem-like cells to maintain equilibrium. The present study focuses on whether non-stem pancreatic cancer cells can convert to stem-like cells and the role of HIF-1alpha and autophagy in modulating this conversation. The non-stem pancreatic cancer cells and pancreatic cancer stem-like cells were separated by magnetic sorting column. Intermittent hypoxia enhanced stem-like properties of non-stem pancreatic cancer cells and stimulated the levels of HIF-1alpha, LC3-II and Beclin. Enhanced autophagy was associated with the elevated level of HIF-1alpha. The conversation of non-stem pancreatic cancer cells into pancreatic cancer stem-like cells was induced by HIF-1alpha and autophagy. This novel finding may indicate the specific role of HIF-1alpha and autophagy in promoting the dynamic equilibrium between CSCs and non-CSCs. Also, it emphasizes the importance of developing therapeutic strategies targeting cancer stem cells as well as the microenvironmental influence on the tumor.

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Lung cancer is costliest cancer in European Union

The total cost of cancer care across the European Union was an estimated € 126 billion in 2009, with lung cancer having the highest cost, at 15% of the total.

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Investigational c-Met inhibitor shows early promise in NSCLC

A first-in-class drug that inhibits c-Met, a receptor tyrosine kinase, has demonstrated good tolerability when combined with erlotinib in the treatment of Japanese patients with advanced/metastatic non-small-cell lung cancer.

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Clinicians ‘nihilistic’ toward lung cancer patients

Clinicians tend to view their lung cancer patients more negatively than patients with other solid tumors, study findings indicate.

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Four-drug regimen shows first-line efficacy in advanced NSCLC

A four-drug combination of cetuximab, bevacizumab, carboplatin, and paclitaxel is effective and has acceptable safety as a first-line treatment for advanced non-small-cell lung cancer, US researchers report.

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Diagnosis and treatment of solid pseudopapillary tumor of the pancreas: experience of one single institution from Turkey

Background: Solid pseudopapillary neoplasia (SPN) of the pancreas is an extremely rare epithelial tumor of low malignant potential. SPN accounts for less than 1 % to 2 % of exocrine pancreatic tumors. The aim of this study is to report our experience with SPN of the pancreas. It includes a summary of the current literature to provide a reference for the management of this rare clinical entity. Methods: A retrospective analysis was performed of all patients diagnosed and treated for SPN in our hospital over the past 15 years (1998 to 2013). A database of the characteristics of these patients was developed, including age, gender, tumor location and size, treatment, and histopathological and immunohistochemical features. Results: During this time period, 255 patients with pancreatic malignancy (which does not include ampulla vateri, distal choledocal and duodenal tumor) were admitted to our department, only 10 of whom were diagnosed as having SPN (2.5 %). Nine patients were women (90 %) and one patient was a man (10 %). Their median age was 38.8 years (range 18 to 71). The most common symptoms were abdominal pain and dullness. Seven patients (70 %) presented with abdominal pain or abdominal dullness and three patient (30 %) were asymptomatic with the diagnosis made by an incidental finding on routine examination. Abdominal computed tomography and/or magnetic resonance imaging showed the typical features of solid pseudopapillary neoplasm in six (60 %) of the patients. Four patients underwent distal pancreatectomy with splenectomy, one patient underwent a total mass excision, and one patient underwent total pancreatic resection. Two required extended distal pancreatectomy with splenectomy. Two underwent spleen-preserving distal pancreatectomy. Conclusions: SPN is a rare neoplasm that primarily affects young women. The prognosis is favorable even in the presence of distant metastasis. Although surgical resection is generally curative, a close follow-up is advised in order to diagnose a local recurrence or distant metastasis and choose the proper therapeutic option for the patient.

via World Journal of Surgical Oncology

Prognostic and predictive value of Phospho-p44/42 and pAKT in HER2-positive locally advanced breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy

Background: To evaluate the predictive and prognostic value of various molecular factors associated with the Ras/MAPK and PI3K/Akt signaling pathways in HER2-positive locally advanced breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy (NAC). Methods: A total of 113 patients were recruited in this retrospective study. Core needle biopsies and excision samples were assessed through immunohistochemistry for various biomarkers, including IGF-1R, Phospho-p44/42, Ki67, pAKT, PTEN, p27, and cyclinD1. The changes in these biomarkers after NAC and their predictive and prognostic values were investigated. Results: Significant decreases in Ki67, Phospho-p44/42, and pAKT expression were observed after treatment (30.7% vs. 18.1%, 36.4% vs. 18.9%, and 35.1% vs. 16.4%, respectively). The decreases in Phospho-p44/42, pAKT, and Ki67 expression were strongly associated with the response to anthracycline treatment (P = 0.027, P = 0.031, and P = 0.008, respectively). In a multivariate survival analysis, Phospho-p44/42 expression after neoadjuvant chemotherapy and lymph node status were significant independent prognostic factors of both relapse-free survival and overall survival. Conclusions: Reductions in Ki-67, Phospho-p44/42, and pAKT expression are related to the clinical response to anthracycline-based NAC in HER2-positive breast cancer patients. High pAKT expression prior to NAC had a better clinical response. Phospho-p44/42 expression and lymph node status after NAC could be useful for determining relapse-free survival and overall survival.

via World Journal of Surgical Oncology

Endobronchial ultrasound has edge for lung cancer staging

Endobronchial ultrasound-guided transbronchial needle aspiration is a better primary procedure than endoscopic ultrasound-guided fine needle aspiration for staging non-small-cell lung cancer, study results suggest.

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Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis

Background: With the wide application of targeted drug therapies, the relevance of prognostic and predictive markers in patient selection has become increasingly important. Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer. However, there are currently no predictive or prognostic biomarkers for bevacizumab. Several clinical studies have evaluated bevacizumab-induced hypertension in patients with metastatic colorectal cancer. This meta-analysis was performed to better determine the association of bevacizumab-induced hypertension with outcome in patients with metastatic colorectal cancer, and to assess whether bevacizumab-induced hypertension can be used as a prognostic factor in these patients. Methods: We performed a systematic review and meta-analysis on seven published studies to investigate the relationship between hypertension and outcome of patients with metastatic colorectal cancer treated with bevacizumab. Our primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Hazard ratios (HRs) for PFS and OS were extracted from each trial, and the log of the relative risk ratio (RR) was estimated for ORR. Results: The occurrence of bevacizumab-induced hypertension in patients was highly associated with improvements in PFS (HR = 0.57, 95% CI: 0.46--0.72; P <0.001), OS (HR = 0.50; 95% CI: 0.37--0.68; P <0.001), and ORR (RR = 1.57, 95% CI: 1.07--2.30, P <0.05), as compared to patients without hypertension. Conclusions: Bevacizumab-induced hypertension may represent a prognostic factor in patients with metastatic colorectal cancer.

via World Journal of Surgical Oncology

A specific miRNA signature promotes radioresistance of human cervical cancer cells

Background: The mechanisms responsible for cervical cancer radioresistance are still largely unexplored. The present study aimed to identify miRNAs associated with radioresistance of cervical cancer cells. Methods: The radioresistant cervical cancer cell variants were established by repeated selection with irradiation. The miRNA profiles of radioresistant cells and their corresponding controls were analyzed and compared using microarray. Differentially expressed miRNAs were confirmed by quantitative real-time PCR. Cervical cancer cells were transfected with miRNA-specific mimics or inhibitors. Radiosensitivity of cervical cancer cells were determined using colony-forming assay. Results: Among the differentially expressed miRNAs, 20 miRNAs showed the similar pattern of alteration (14 miRNAs were overexpressed whilst 6 were suppressed) in all three radioresistant cervical cancer cell variants compared to their controls. A miRNA signature consisting of 4 miRNAs (miR-630, miR-1246, miR-1290 and miR-3138) exhibited more than 5 folds of increase in radioresistant cells. Subsequent analysis revealed that these four miRNAs could be up-regulated in cervical cancer cells by radiation treatment in both time-dependent and dose-dependent manners. Ectopic expression of each of these 4 miRNAs can dramatically increase the survival fraction of irradiated cervical cancer cells. Moreover, inhibition of miR-630, one miRNA of the specific signature, could reverse radioresistance of cervical cancer cells. Conclusions: The present study indicated that miRNA is involved in radioresistance of human cervical cancer cells and that a specific miRNA signature consisting of miR-630, miR-1246, miR-1290 and miR-3138 could promote radioresistance of cervical cancer cells.

via Cancer Cell International

Intraperitoneal dedifferentiated liposarcoma showing MDM2 amplification: case report

Background: Liposarcoma is the most common type of soft tissue sarcoma (STS). It is divided into five groups according to histological pattern: well-differentiated, myxoid, round cell, pleomorphic, and dedifferentiated. Dedifferentiated liposarcoma most commonly occurs in the retroperitoneum, while an intraperitoneal location is extremely rare. Only seven cases have been reported in literature. Many pathologists recognize that a large number of intra-abdominal poorly differentiated sarcomas are dedifferentiated liposarcomas. We report a case initially diagnosed as undifferentiated sarcoma that was reclassified as intraperitoneal dedifferentiated liposarcoma showing an amplification of theMDM2 gene.Case presentationA 59-year-old woman with abdominal pain and constipation was referred to the Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy, in November 2012.Onphysical examination, a very large firm mass was palpable in the meso-hypogastrium.Computed tomography (CT) scan showed a heterogeneous density mass (measuring 10 x 19 cm) that was contiguous with the mesentery and compressed the third part of the duodenum and jejunum.At laparotomy, a large mass occupying the entire abdomen was found, adhering to the first jejunal loop and involving the mesentery. Surgical removal of the tumor along with a jejunal resection was performed because the first jejunal loop was firmly attached to the tumor.Macroscopic examination showed a solid, whitish, cerebroid, and myxoid mass, with variable hemorrhage and cystic degeneration, measuring 26 x 19 x 5 cm.Microscopic examination revealed two main different morphologic patterns: areas with spindle cells in a myxoid matrix and areas with pleomorphic cells. The case was initially diagnosed as undifferentiated pleomorphic sarcoma. Histological review showed areas of well-differentiated liposarcoma.Fluorescencein situ hybridization (FISH) analysis was performed and demonstrated an amplification of the MDM2 gene. Definitive diagnosis was intraperitoneal dedifferentiated liposarcoma.No adjuvant therapy was given, but 5 months after laparotomy, the patient presented with a locoregional recurrence and chemotherapy with high-dose ifosfamide was started. Conclusions: No guidelines are available for the management of intraperitoneal dedifferentiated liposarcoma. We report this case to permit the collection of a larger number of cases to improve understanding and management of this tumor. Moreover, this study strongly suggests that poorly differentiated sarcomas should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component and, if possible, FISH analysis.

via World Journal of Surgical Oncology

Should level V be included in lateral neck dissection in treating papillary thyroid carcinoma?

Background: The study was designed to explore the regular patterns of level V lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC), and to indicate whether level V should be included in the management of lateral neck dissection when treating PTC. Methods: This retrospective study consisted of 330 patients diagnosed with PTC from January 1994 to July 2009 who underwent an operation that included therapeutic lateral neck dissection (levels II to V). The patterns of lateral neck LNM were analyzed and the relevant risk factors of level V LNM were analyzed with univariate and multivariate analysis, respectively. Results: All the patients underwent lateral neck dissection at levels II to V. The predominant site of metastasis was level III (247/330 (74.8 %)), followed by level IV (233/330 (70.6 %)), and level II (215/330 (65.3 %)). Simultaneous multilevel involvement (level II, III, and IV) of lymphatic metastases presented in 46.1 % (152/330) of the cases. Level V showed 28.8 % (95/330) of nodal metastasis. Multivariate analysis showed that level V LNM was significantly associated with location (whole thyroid), gross extrathyroidal extension and simultaneous multilevel involvement (level II, III and IV). (P <0.05). Conclusions: Due to relatively high rate of level V involvement and its correlation with location (whole thyroid), gross extrathyroidal extension and multilevel involvement, we consider that it may be more rational to include level V in the therapeutic lateral neck dissection when treating PTC, especially for those who have any one of these three independent risk factors.

via World Journal of Surgical Oncology

Smoking reduces nasopharyngeal cancer survival

Both current and former smoking have a significant impact on the prognosis of patients with nasopharyngeal carcinoma, Chinese researchers caution.

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Functional tongue reconstruction with the anterolateral thigh flap

Background: A retrospective study was conducted to evaluate the advantages of anterolateral thigh (ALT) flap in tongue reconstruction.MethodFrom September 2008 to February 2012, patients receiving ALT flap tongue reconstruction were included in the study. Patients undergoing ALT flap were compared with those undergoing similar surgery with radial forearm flap (RFF). The medical records of the included patients were reviewed, and a questionnaire was used to assess acceptability of the surgery. Results: All flaps (both ALT and RFF) were successful In the ALT group, most patients were satisfied with the appearance of the reconstructed tongue and the intelligibility of their speech, and there were fewer complications with this technique compared with the RFF. Conclusion: The ALT flap is an ideal method for tongue reconstruction. The thickness and volume of the ALT flap can be adjusted based on the individual extent of the defect, and it can not only provide bulk but also ensure mobility, and it has other advantages also, including a long pedicle and low donor site morbidity.

via World Journal of Surgical Oncology

Cancer seeding contributes to intestinal anastomotic dehiscence

Background: Surgical wounds in cancer patients have a relatively high dehiscence rate. Although colon cancer resections are performed so as to include macroscopically non-involved tissues, some cancer cells can be present in the line of transection. The local healing process may facilitate proliferation of these localized cancer cells and the high cytokine concentration within the healing wound may also attract cancer cells from distant sites to migrate into the wound area. The growing tumor cells may then stretch the wound, hampering its contraction process. Methods: The aim of the study was to monitor and compare, using immunohistochemical methods, the healing process of intestinal anastomosis in both normal rats and in rats with disseminated cancer (the CC531 colon cancer model). Results: There was a significantly higher rate of anastomotic dehiscence in the group of rats with disseminated cancer, than in the group of normal rats. There were no significant differences between the two groups in the levels of mononuclear wound infiltration or of formation of connective tissue or new vessels. All anastomotic wounds in animals with disseminated cancer had abundant infiltrates of both migrating and proliferating cancer cells. Conclusions: We confirmed that the environment of a healing wound attracts cancer cells. Migration of cancer cells to the wound and centrifugal cancer proliferation may adversely affect the healing process and cause wound disruption.

via World Journal of Surgical Oncology

Clinicopathological risk factors for recurrence after neoadjuvant chemotherapy and radical hysterectomy in cervical cancer

Background: Cervical cancer is one of the common gynecological malignancies with a high recurrence rate after surgery. This study aimed to analyze the clinicopathological risk factors for recurrence after the surgical treatment of cervical cancer and provide the basis for the prevention of recurrence and an improvement of prognosis. Methods: A total of 424 cervical cancer cases between 1 January 1998 and 31 December 2011 undergoing surgical treatment were studied retrospectively, of which 23 cases had recurrences. Relevant recurrence risk factors were evaluated by univariate and multivariate analyses between recurrence group and non-recurrence group. Results: Using univariate analysis, tumor differentiation, clinical stage, pelvic lymph node metastasis, postoperative radiotherapy and postoperative chemotherapy were related to recurrence of cervical cancer. Multivariate COX model analysis revealed that pelvic lymph node metastasis and postoperative chemotherapy had an impact on recurrence rate. Moderately and highly differentiated tumor, advanced clinical stage, and positive pelvic lymph nodes indicated a high recurrence rate of cervical cancer. Postoperative chemotherapy and radiotherapy can effectively reduce the recurrence rate. Conclusions: In conclusion, cervical lymph node metastasis and postoperative chemotherapy are two independent factors for recurrence of cervical cancer after radical surgery.

via World Journal of Surgical Oncology

Urea immunoliposome inhibits human vascular endothelial cell proliferation for hemangioma treatment

Background: Urea injection has been used in hemangioma treatment as sclerotherapy. It shrinks vascular endothelial cells and induces degeneration, necrosis, and fibrosis. However, this treatment still has disadvantages, such as lacking targeting and difficulty in controlling the urea dosage. Thus, we designed a urea immunoliposome to improve the efficiency of treatment. Methods: The urea liposome was prepared by reverse phase evaporation. Furthermore, the urea immunoliposome was generated by coupling the urea liposome with a vascular endothelial growth factor receptor (VEGFR) monoclonal antibody using the glutaraldehyde cross-linking method. The influence of the urea immunoliposome on cultured human hemangioma vascular endothelial cells was observed preliminarily. Results: Urea immunoliposomes showed typical liposome morphology under a transmission electron microscope, with an encapsulation percentage of 54.4 % and a coupling rate of 36.84 % for anti-VEGFR. Treatment with the urea immunoliposome significantly inhibited the proliferation of hemangioma vascular endothelial cells (HVECs) in a time- and dose-dependent manner. Conclusions: The urea immunoliposome that we developed distinctly and persistently inhibited the proliferation of HVECs and is expected to be used in clinical hemangioma treatment.

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EZH2 expression in invasive lobular carcinoma of the breast

Background: Invasive lobular carcinoma (ILC) is the second most common histologic type of breast cancer, but the prognosis of ILC is still controversial. Enhancer of Zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2), is frequently overexpressed in various cancers. This study evaluated the relationship between clinicopathologic characteristics and EZH2 expression. Methods: We retrospectively reviewed the medical records of 54 patients with ILC and selected 49cases of ILC. Immunohistochemistry for EZH2 was undertaken. Results: We defined ILC as discohesive cells with a linear or nonlinear growth pattern. No statistically significant difference was found for most variables, including multifocality, menstrual status, body mass index, tumor stage (pT), lymph node stage (pN), estrogen receptor, and progesterone receptor. In contrast, nuclear grade was statistically significant and EZH2 expression was associated with high nuclear grade. In total, 80% of nuclear grade 3 cases had an EZH2 score of 4, and 86% of nuclear grade 1 cases had EZH2 scores of 1 and 2. Our cases had a score of 3 for tubule formation and a score of 1 for mitosis, and so the histologic grading consisted of grades 1 (7 cases) and 2 (42 cases) depending on the nuclear grade. Conclusion: Although EZH2 could not predict survival in our study, EZH2 expression was associated with a high nuclear grade. Most ILCs have histologic grade 2 with nuclear grade 2 or 3. Therefore, our opinion is that if ILC is diagnosed by separating the classic type and variants and considering both EZH2 expression and nuclear grade, EZH2 overexpression could help and the Nottingham grading system would be more accurate prognostic factor.

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Aldehyde dehydrogenase 1 expression in primary and metastatic renal cell carcinoma: an immunohistochemistry study

Background: ALDH1 has been shown to be a cancer stem cell marker, and its expression correlates with prognosis in a number of malignancies. We aimed to evaluate to the expression of ALDH1 in a cohort of primary and metastatic RCC specimens, and to correlate expression with pathological outcomes such as tumor stage and grade, and clinical outcomes such as progression free survival. Methods: Three tissue microarrays were constructed from 244 RCC specimens, taken from 1985 to 2006. Samples were stained using an ALDH1 monoclonal antibody and expression was quantified by degree of staining. Membrane and cytoplasm staining were considered separately. A retrospective chart review enabled correlation with clinical outcomes. Results: ALDH1 expression did not vary significantly based on tumor stage (P = 0.6274) or grade (P = 0.1666). ALDH1 showed significantly more membranous expression in clear cell RCC versus other subtypes (P < 0.0001), as well as in the primary setting compared to metastases (P = 0.0216). In terms of progression free survival, no significant differences were seen based on ALDH1 expression levels. In a subanalysis of clear cell tumors, ALDH1 membranous expression was decreased in tumors of higher stage (P = 0.0233). Conclusions: ALDH1 may be useful in characterizing RCC tumors as clear cell subtype. However, unlike in other malignancies, ALDH1 may not be useful in prognosticating renal cancers. The clinical significance of decreased ALDH1 expression in the high stage and metastatic setting remains to be determined in further investigations.

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Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate diverse cellular processes including proliferation, adhesion, survival, and motility. Dysregulated PI3K pathway signaling occurs in one-third of human tumors. Aberrantly activated PI3K signaling also confers sensitivity and resistance to conventional therapies. PI3K has been recognized as an attractive molecular target for novel anti-cancer molecules. In the last few years, several classes of potent and selective small molecule PI3K inhibitors have been developed, and at least fifteen compounds have progressed into clinical trials as new anticancer drugs. Among these, idelalisib has advanced to phase III trials in patients with advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma. In this review, we summarized the major molecules of PI3K signaling pathway, and discussed the preclinical models and clinical trials of potent small-molecule PI3K inhibitors.

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miR-363-5p regulates endothelial cell properties and their communication with hematopoietic precursor cells

Recent findings have shown that the blood vessels of different organs exert an active role in regulating organ function. In detail, the endothelium that aligns the vasculature of most organs is fundamental in maintaining organ homeostasis and in promoting organ recovery following injury. Mechanistically, endothelial cells (EC) of tissues such as the liver, lungs or the bone marrow (BM) have been shown to produce "angiocrine" factors that promote organ recovery and restore normal organ function. Controlled production of angiocrine factors following organ injury is therefore essential to promote organ regeneration and to restore organ function. However, the molecular mechanisms underlying the coordinated production and function of such "angiocrine" factors are largely undisclosed and were the subject of the present study. In detail, we identified for the first time a microRNA (miRNA) expressed by BM EC that regulates the expression of angiocrine genes involved in BM recovery following irradiation. Using a microarray-based approach, we identified several miRNA expressed by irradiated BMEC. After validating the variations in miRNA expression by semi-quantitative PCR, we chose to study further the ones showing consistent variations between experiments, and those predicted to regulate (directly or indirectly) angiogenic and angiocrine factors. Of the mi-RNA that were chosen, miR-363-5p (previously termed miR-363*) was subsequently shown to modulate the expression of numerous EC-specific genes including some angiocrine factors. By luciferase reporter assays, miR-363-5p is shown to regulate the expression of angiocrine factors tissue inhibitor of metalloproteinases-1 (Timp-1) and thrombospondin 3 (THBS3) at post-transcriptional level. Moreover, miR-363-5p reduction using anti-miR is shown to affect EC angiogenic properties (such as the response to angiogenic factors stimulation) and the interaction between EC and hematopoietic precursors (particularly relevant in a BM setting). miR-363-5p reduction resulted in a significant decrease in EC tube formation on matrigel, but increased hematopoietic precursor cells adhesion onto EC, a mechanism that is shown to involve kit ligand-mediated cell adhesion. Taken together, we have identified a miRNA induced by irradiation that regulates angiocrine factors expression on EC and as such modulates EC properties. Further studies on the importance of miR-363-5p on normal BM function and in disease are warranted.

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High expression of astrocyte elevated gene-1 (AEG-1) is associated with progression of cervical intraepithelial neoplasia and unfavorable prognosis in cervical cancer

Background: Astrocyte elevated gene-1(AEG-1) plays an important role in the development and progression of certain types of human cancers. However, the expression dynamics of AEG-1 in cervical cancer and its clinical/ prognostic significance are unclear.MethodIn present study, the methods of tissue microarrays (TMA) and immunohistochemistry (IHC) were utilized to investigate AEG-1 expression in cervical intraepithelial neoplasia (CIN) and cervical cancer. Receiver operating characteristic (ROC) curve analysis, chi2 test, Kaplan-Meier plots, and multivariate Cox regression analysis were used to analyze the data. Results: The expression level of AEG-1 was increased from CIN I to CIN III. High expression of AEG-1 could be observed in 61.1% (55/90) of cervical cancer. Moreover, high expression of AEG-1 correlated with tumor size and lymph node metastasis (all P <0.05). More importantly, high expression of AEG-1 was closely associated with cervical cancer patient shortened survival time as evidenced by univariate and multivariate analysis (P <0.05). Conclusions: Our data suggest for the first time that high expression of AEG-1 is associated significantly with progression of cervical cancer. AEG-1 overexpression, as examined by IHC, has the potential to be used as an immunomarker to predict prognosis of cervical cancer patients.

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Sparing sentinel node biopsy through axillary lymph node fine needle aspiration in primary breast cancers

Background: Axillary lymph node status is an important staging and prognostic factor in breast cancer. This study aimed to evaluate the efficacy of axilla fine needle aspiration cytology (FNAC) in primary breast cancer without a palpable node and even without image characteristics of a metastatic node. Methods: From June 2008 to January 2012, 77 patients met the inclusion criteria of having received a FNAC procedure during the diagnostic protocol of primary breast cancer with the characteristic of impalpable axilla nodes, and of having received axillary surgery after that, according to the guidelines. The patients' characteristics, clinical-pathological features, pre-operative axillary lymph node FNAC findings, surgical lymph node report, and definite pathologic staging were reviewed. Results: The FNAC procedures had a reported sensitivity of 58.82%, specificity of 100%, positive predictive value of 100%, negative predictive value of 72.55%, and accuracy of 80.28%. There were no false positives on FNAC; therefore, the positive likelihood ratio approached infinity. The negative likelihood ratio was 41.18%. Axillary lymph node FNAC is feasible in newly diagnosed breast cancer patients to evaluate metastatic lymph nodes even in those without clinical or ultrasonic evidence of lymphadenopathy. Conclusions: FNAC can be a routine evaluation for most primary breast cancer patients with benefits in expediting treatment. For those patients with positive findings of the axilla, sentinel node biopsy can be avoided.

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CD44 targets Wnt/beta-catenin pathway to mediate the proliferation of K562 cells

Background: Chronic myeloid leukemia is a clonal myeloproliferative disorder disease in which BCR/ABL plays an important role as an oncoprotein and molecular target. Despite the success of targeted therapy using tyrosine kinase inhibitors, CML remains largely incurable, most likely due to the treatment resistance after firstly chemical therapy. So know well the unique molecular pathway of CML is very important. Methods: The expressions of CD44 in different leukemia patients and cell lines were detected by real-time PCR and western blotting. The effects of CD44 on proliferation of K562 cells were determined using the MTT and colony formation assays, and even in a nude mouse transplantation model. Then, the cell cycle changes were detected by flow cytometric analysis and the early apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay. The expressions of the cycles and apoptosis-related proteins p21, Cyclin D1 and Bcl-2 were analyzed by western blot and real-time PCR assay. Finally, the decreased nuclear accumulation of beta-catenin was detected by western blotting and immunefluorescence. Results: Firstly, we showed that CD44 expression was increased in several kinds of leukemia patients and K562 cells. By contrast, the down-regulation of CD44 resulted in decreased proliferation with a G0/G1 arrest of cell cycle in K562 cells according to the MTT assay and the flow cytometric analysis. And no significant induction of both the early and late phases of apoptosis was shown by the annexin V-FITC and PI staining. During this process, p21 and cyclin D1 are the major causes for cell cycle arrest. In addition, we found CD44 down-regulation decreased the expression of beta-catenin and increased the expression of phosphorylated beta-catenin. The instability of Wnt/beta-catenin pathway induced by increased expression of p-beta-catenin resulted in a decreased nuclear accumulation in CD44 silenced K562 cells. In the nude mouse transplantation model, we also found the same results. Conclusions: These results show that K562 cells depend to a greater extent on CD44 for proliferation, and CD44 down-regulation may induce a cell cycle arrest through Wnt/beta-catenin pathway. CD44 blockade may be beneficial in therapy of CML.

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Metachronous, colitis-associated rectal cancer that developed after sporadic adenocarcinoma in an adenoma in a patient with longstanding Crohn's disease: a case report

Background: Colorectal cancer associated with Crohn's disease (CD) is increasing in proportion to the number of patients with CD in Japan. There are two subtypes of colorectal cancer with CD: sporadic cancer and colitis-associated cancer. Early diagnosis of colitis-associated cancer is sometimes difficult; when colorectal cancer is found in patients with CD, both colitis-associated cancer and sporadic cancer should be kept in mind. Here, we describe a case of metachronous, colitis-associated rectal cancer that developed after the complete resection of an adenoma that became a sporadic adenocarcinoma in a patient with longstanding CD. To the best of our knowledge, this is the first report of colitis-associated cancer in a patient with CD after removal of a sporadic cancer.Case presentationWe describe a 51-year old man with CD who had difficulty in defecation. A rectal polyp was detected and a transanal resection of the polyp was performed. A histopathological examination showed an adenoma with sporadic adenocarcinoma. After three years, a follow-up colonoscopy revealed a reddish, elevated lesion in the patient's rectum. A colonoscopic biopsy showed a signet ring cell carcinoma. We performed an abdominoperineal resection of the rectum and a bilateral pelvic lymph node dissection. A histopathological examination revealed a mucinous adenocarcinoma with signet ring cell carcinoma and lymph node metastasis. The patient received adjuvant chemotherapy with oral uracil 224 mg combined with tegafur 100 mg plus leucovorin. No signs of recurrence were noted at a follow-up 18 months after the third surgery and 60 months after the second surgery.

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Expression of hypoxia-related markers in inflammatory myofibroblastic tumors of the head and neck

Background: The etiology of inflammatory myofibroblastic tumors (IMTs) is controversial and the prognosis is unpredictable. Previous studies have not investigated the expression of hypoxia-related markers in IMTs. Methods: Between 2002 and 2012, 12 consecutive patients with histologically proven IMTs were enrolled in the study. Immunohistochemistry was used to detect GLUT-1, HIF-1alpha, PI3K, and p-Akt expression in paraffin-embedded tumor specimens. Associations among GLUT-1, HIF-1alpha, PI3K, and p-Akt protein expression and clinical parameters were investigated. Results: The mean duration of follow-up was 52.1 months (range, 11 to 132 months). Six patients had local recurrence. GLUT-1, HIF-1alpha, PI3K, and p-Akt expression were detected in 41.7%, 50.0%, 33.3%, and 41.7% of patients, respectively. Fisher's exact test revealed significant correlations between recurrence of IMT and PI3K expression (P = 0.01) and p-Akt expression (P = 0.015). Univariate analyses revealed significant correlations between survival and GLUT-1 expression (P = 0.028), PI3K expression (P = 0.006), and p-Akt expression (P = 0.028). Multivariate analysis did not show a significant relationship between survival and GLUT-1, HIF-1alpha, PI3K, or p-Akt. Spearman rank correlation analysis showed significant correlations between HIF-1alpha and PI3K expression (r = 0.707, P = 0.01) and between p-Akt and PI3K expression (r = 0.837, P = 0.001). Conclusions: Although our results are inconclusive owing to the small sample size, they suggest that PI3K and p-Akt expression may play a role in the recurrence of IMTs of the head and neck.

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Expression pattern of the apoptosis-stimulating protein of p53 family in p53+ human breast cancer cell lines

Background: The apoptosis-stimulating protein of p53 (ASPP) family comprises three members, namely, ASPP1, ASPP2, and iASPP. They regulate the promotive effect of p53 on apoptosis. Breast cancer (BC) remains as one of the leading causes of cancer or cancer-related mortality among women. However, the relationship between the ASPP family members and p53, as well as the dissemination and expression pattern of ASPP family members in p53+ BC, has not been elucidated. Our objectives are to detect the expression of ASPP family members in p53+ BC cell lines and determine its significance in tumor cell apoptosis. Methods: The mRNA expression of ASPP family members in five p53+ BC cell lines was detected through RT-PCR and assayed using Quality-one software. The p53 protein expression was detected by immunohistochemistry. Afterward, the apoptosis indices of the five BC cell lines were detected by flow cytometry. Results: The iASPP mRNA was expressed in Bcap-37, MCF-7, and HBL-100. Compared with the human peripheral blood mononuclear cells, significant differences were found in the ASPP1 mRNA in Bcap-37, MDA-MB-231, MCF-7, and HBL-100 (p <0.05), except that in ZR-75-30 (p >0.05). The ASPP2 mRNA was expressed in MDA-MB-231, Bcap-37, and MCF-7, but not in HBL-100 and ZR-75-30. The p53 protein was expressed in five breast cancer cell lines. ZR-75-30 and MDA-MB-231 apoptosis indices were higher than those of other breast cancer cell line and peripheral blood mononuclear cells (p <0.01). Conclusions: The mRNA expression of ASPP family members varied in the five p53+ BC cell lines. The results also verified that the family members have an important function in apoptosis, which was promoted by p53 protein. ZR-75-30 BC showed high apoptosis index, without expression of any ASPP family members, indicating that the pathway of apoptosis in this cell line may be related to other cell transduction pathway. MDA-MB-231, Bcap37, and MCF-7 cell lines all expressed ASPP1/2. However, the apoptosis pathway in MDA-MB-231 is different from those of the other two cell lines. The status of the different cell lines should also be considered when the functions of the ASPP family members are examined.

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The relevance of the intrinsic subtype to the clinicopathological features and biomarkers in Japanese breast cancer patients

Background: Breast cancer is a disease rich in diversity, and it can be categorized into the immunohistochemical intrinsic subtypes : ER/PR + and HER2-, ER/PR + and HER2+, HER2 type, basal-like and unclassified. Methods: In this study, in addition to the clinicopathological features potentially associated with the intrinsic subtypes, protein expression and genetic mutations of key molecules associated with breast cancer prognosis and treatment sensitivity were analyzed. The distribution of subtypes in the patient population and the differences in marker distribution across the subtypes were investigated. Results: The immunohistochemical features of 471 consecutive surgical cases of women with primary breast cancer, treated in a single institution, were examined. There were 306 patients who were ER/PR + HER2- (65%); 41 who were ER/PR + HER2+ (8.7%); 59 with HER2 type immunohistochemistry (12.5%); 37 with basal-like immunohistochemistry (7.9%); and 28 patients whose breast cancer was unclassified (5.9%). There were no significant differences between the subtypes regarding age, menopausal status, disease stage, lymphatic invasion, blood vessel invasion and lymph node metastasis. Statistically significant differences were found for histological type and grade. Regarding protein expression and genetic mutation, significant differences were found in the distribution within each subtype for six out of 12 molecules investigated. Conclusions: This study revealed that subtypes differ not only in their clinical pathological profiles, such as histological types and histological grades, but also in molecular expression. The molecular expression patterns observed for each intrinsic subtype may help the selection of an optimal treatment strategy.

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The effect of preoperative chemoradiotherapy on lymph nodes harvested in TME for rectal cancer

Background: Adequate lymph nodes resection in rectal cancer is important for staging and local control. This retrospective analysis single center study evaluated the effect of neoadjuvant chemoradiation on the number of lymph nodes in rectal carcinoma, considering some clinicopathological parameters. Methods: A total of 111 patients undergone total mesorectal excision for rectal adenocarcinoma from July 2005 to May 2012 in our center were included. No patient underwent any prior pelvic surgery or radiotherapy. Chemoradiotherapy was indicated in patients with rectal cancer stage II or III before chemoradiation. Results: One-hundred and eleven patients were considered. The mean age was 67.6 yrs (range 36 -- 84, SD 10.8). Fifty (45.0%) received neoadjuvant therapy before resection. The mean number of removed lymph nodes was 13.6 (range 0--39, SD 7.3). In the patients who received neoadjuvant therapy the number of nodes detected was lower (11.5, SD 6.5 vs. 15.3, SD 7.5, p = 0.006). 37.4% of patients with preoperative chemoradiotherapy had 12 or more lymph nodes in the specimen compared to the 63.6% of those who had surgery at the first step (p: 0.006).Other factors associated in univariate analysis with lower lymph nodes yield included stage (p 0.005) and grade (p 0.0003) of the tumour. Age, sex, tumor site, type of operation, surgeons and pathologists did not weight upon the number of the removed lymph nodes. Conclusion: In TME surgery for rectal cancer, preoperative CRT results into a reduction of lymph nodes yield in univariate analisys and linear regression.

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Medical–surgical integration ‘boosts neoadjuvant chemotherapy use for bladder cancer’

Research from the USA indicates that a multidisciplinary approach and coordination between medical and surgical oncology services can help optimize the use of neoadjuvant chemotherapy for bladder cancer.

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Extranodal natural killer/T-cell lymphoma involving the gastrointestinal tract: analysis of clinical features and outcomes from the Asia Lymphoma study group

Background: The gastrointestinal (GI) tract is one of the most common extranasal sites in extranodal NK/T-cell lymphoma (ENKTL). However, data regarding ENKTL involving the GI tract are relatively scarce. Thus, we performed a multicenter, multinational retrospective study to analyze clinical features and treatment outcomes of ENKTL involving the GI tract.Patients and methods: Patients with ENKTL involving the GI tract diagnosed in twelve participating centers between 1991 and 2012 were retrospectively analyzed from five Asian countries. Results: The analysis of 81 patients with ENKTL involving the GI tract revealed that more than 60% of patients presented as advanced disease with B symptoms. 55 patients (68%) had GI manifestations including abdominal pain (n = 26, 32%), GI tract bleeding (n = 17, 21%) and bowel perforation (n = 12, 15%). The most common GI site was the small intestine, including the jejunum and ileum (n = 57, 70.3%). There were 34 patients (42%) who received systemic chemotherapy while 33 patients (41%) underwent surgery plus chemotherapy. However, 35 patients (43%) died due to disease progression, and treatment-related mortality including sepsis occurred in 17 patients (21%). Thus, the median overall survival was 7.8 months (95% Confidence interval: 3.9 -- 11.7 months). Patients who could undergo surgery plus chemotherapy showed a trend of better survival than those treated with chemotherapy alone. Conclusion: Overall, the data indicated that ENKTL involving the GI tract has a dismal prognosis despite active treatment including chemotherapy and surgery. Thus, more effective treatment strategies are required for this disease entity.

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Si-RNA mediated knockdown of CELF1 gene suppressed the proliferation of human lung cancer cells

Background: Lung cancer is the leading cause of cancer-related death in the world, with metastasis as the main reason for the mortality. CELF1 is an RNA-binding protein controlling the post-transcriptional regulation of genes related to cell survival. As yet, there is little knowledge of CELF1 expression and biological function in lung cancer. This study investigated the expression levels of CELF1 in lung cancer tissues and the biological function of CELF1 in lung cancer cells. Methods: CELF1 mRNA expression was determined in lung cancer and normal tissues, and the relationship between the expression level of CELF1 and clinicopathological parameters was evaluated. The biological function of CELF1 in A549 and H1299 lung cancer cell lines growth was examined. Results: The expression of CELF1 was higher in human lung cancer tissues compared with the normal lung tissue. Lentiviral-mediated transfection of CELF1 siRNA effectively silenced the expression of CELF1 in both A549 and H1299 cells. Moreover, CELF1 knockdown markedly reduced the survival rate of lung cancer cells. Colony formation assays revealed a reduction in the number and size of lung cancer cell colonies from CELF1 knockdown. Conclusion: These results indicated that CELF1 may have significant roles in the progression of lung cancer, and suggested that siRNA mediated silencing of CELF1 could be an effective tool in lung cancer treatment.

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The relationship between the BRAFV600E mutation in papillary thyroid microcarcinoma and clinicopathologic factors

Background: The BRAFV600E mutation, which accounts for about 60--80% papillary thyroid carcinoma(PTC), has been identifiedas a prognostic marker for risk stratification of PTC patients. However, the BRAFV600E mutation as a prognostic marker in papillary thyroid microcarcinoma (PTMC) is unclear. Methods: We performed a retrospective review of 101 patients who underwent surgery for PTMC. We studied the prevalence of the BRAFV600E mutation. The associations between the BRAFV600E mutation and clinicopathologic characteristics were analyzed. Results: The BRAFV600E mutation was observed in 72 patients (71.3%). There was no statistically significant correlation in age, gender, multifocality, extrathyroidal extension, presence of Hashimoto thyroiditis, and lymph node metastasis between the BRAFV600E mutant group and wild group. Conclusions: The BRAFV600E mutation is not significantly associated with prognostic factors in PTMC.

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Wilms' tumour suppressor gene 1 (WT1) is involved in the carcinogenesis of Lung cancer through interaction with PI3K/Akt pathway

Although studies have shown the oncogene WT1 is overexpressed in lung cancer, there is no data showing the implication of WT1 in lung cancer biology. In the present study, we first demonstrated that isotype C of WT1 was conservely overexpressed in 20 lung cancer patient specimens. Knockdown of WT1 by small interference RNA (siRNA) transfection resulted in a significant inhibition of cell proliferation, induction of cell cycle arrest at G1 phase, and the expression change of BCL-2 family genes in WT1+ A549 cells. Furthermore, we found that DDP treatment could decrease the WT1 mRNA expression level by 5% and 15% at a dose of 1 mug/ml, by 25% and 40% at a dose of 2 mug/ml for 24 and 48 h, respectively. In the mean time, DDP treatment also reduced the PI3K/AKT pathway activity. Further analysis by using siRNA targeting the AKT-1 and the PI3K pathway inhibitor Ly294002 revealed that the AKT-1 siRNA reduced the WT1 expression effectively in A549 cells, and the same result was observed in Ly294002 treated cells, indicating that DDP treatment could down regulate WT1 expression through the PI3K/AKT pathway. Of particular interest, knockdown of WT1 also inhibited the AKT expression effectively, Chip assay further confirmed that WT1 is a transcription factor of AKT-1. We thus concluded that there is a positive feedback loop between WT1 and AKT-1. Taken together, DDP treatment downregulates the WT1 expression through the PI3K/AKT signaling pathway, and there is a feedback between WT1 and AKT-1; WT1 is involved in cellular proliferation in A549 cells, WT1 inhibition in combination with DDP will provide a new light for lung cancer therapy.

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The expression and clinical significance of HERC4 in breast cancer

Background: Increasing evidence suggest that ubiquitin-proteasome system (UPS) plays a key role in tumorigenesis. HERC4 is a recently identified ubiqutin ligase. However, the expression status and biological functions of HERC4 in cancers are not clearly. Methods: We evaluated the HERC4 expression in breast cancer cell lines and breast tumor tissues by quantitative real-time PCR and western blot analysis. To investigate the clinicopathological significance of HERC4, immunohistochemistry analysis for HERC4 was performed on a tissue microarray including 13 benign fibroadenoma, 15 intraductal carcinoma, 120 histologically confirmed invasive ductal carcinoma. Receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off score for positive expression of HERC4, when HERC4 positive expression percentage was above 60%, tumor was defined as "positive". Results: HERC4 was up-regulated in breast cancer cell lines and breast tumor tissues compared to non-tumorigenic cell line and adjacent normal breast tissues. According to ROC analysis, HERC4 positive expression was detected in 1/16 (6.3%) of normal breast tissue, in 3/13 (23.1%) of fibroadenoma, in 6/15(40%) of intraductal carcinoma and 66/120 (55%) of invasive ductal carcinoma. Positive expression of HERC4 was positively correlated with pT status, pN status, clinical stage and histological grade of patients with invasive ductal carcinoma (p < 0.05). Conclusions: Our findings suggest that HERC4 was a significant diagnostic marker for invasive ductal carcinoma of the breast.

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Clinical characteristics and prognosis of primary leiomyosarcoma of the pancreas: a systematic review

Background: Primary pancreatic leiomyosarcoma (PLMS) is rare. The clinical characteristics and prognosis is still not completely understood. The aim of the present study is to identify the clinical characteristics and long-term outcomes of PLMS from the existing reported cases in different scientific literature. Methods: PLMS cases reported in Chinese and English journals were collected and reviewed. Clinical features and long-term outcomes of these cases were summarized and analyzed statistically. Results: A total of 69 cases reported from both Chinese and English journals were included in the present study. An equal incidence in gender was observed. The mean age was 53.9 +/- 14.7 years. The most common symptoms were abdominal mass, abdominal pain, and weight loss. The mean size of the tumor was 11.4 +/- 7.1 cm. The incidence of PLMS between the head and body-tail of the pancreas had a similar pattern. Twenty-five percent of patients had distant metastasis and 19% of patients had adjacent organs/vessels invasion at the time of diagnosis. But lymph node metastasis was documented in only one (1.5%) patient. The median survival time was 48 months. The overall 1-, 3-, 5-, and 10-year survival rates were 66.6%, 51.2%, 43.9%, and 29.3%, respectively. Results from the multivariate analysis showed that non-radical resection (P = 0.000; hazard ratio (HR) 5.128; 95% confidence interval (CI) 2.041-12.987) was the independent adverse prognostic factor. Adjacent organs/vessels invasion (yes) may be considered as an another potential independent adverse prognostic factor (P = 0.071; HR 2.708; 95% CI 0.981-7.474) Conclusions: PLMS is rare without specific clinical features. PLMS is an aggressive tumor and has a poor prognosis. Radical resection can prolong survival time of the patients.

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Pneumococcal pneumonia linked to lung cancer risk

Pneumococcal pneumonia is significantly associated with risk for lung cancer, show findings from a national study in Taiwan.

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Downregulation of the H-2Kd gene by siRNA affects the cytotoxicity of murine LAK cells

To investigate the effect of the H-2Kd gene on the lymphocyte membrane, we constructed a small interfering RNA (siRNA) that targets the H-2Kd gene and compared the cytotoxicity of mouse lymphokine-activated killer (LAK) cells with different H-2Kd expression states. H-2Kd-targeting siRNA was transfected into spleen lymphocytes of BALB/C mice. Flow cytometry (FCM) was then performed to examine the expression of the H-2Kd gene in the transfected and control cells. Additionally, the cytotoxicity of the transfected cells toward the H22 and K562 cell lines was evaluated in vitro using the LDH release assay. H-2Kd-targeting siRNA significantly reduced the expression levels of the target protein, whereas pure transMessenger and non-silencing siRNA did not inhibit H-2Kd expression at the concentrations tested. The cytotoxicity of siRNA-treated LAK cells toward H22 and K562 cells was reduced significantly. The knockdown of H-2Kd gene expression by siRNA may be associated with LAK cell cytotoxicity toward neoplasm cell lines.

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Pancreatic metastases from renal cell carcinoma: a case report and literature review of the clinical and radiological characteristics

Metastatic pancreatic cancer is rare, accounting for approximately 2% of all pancreatic malignancies, and most cases arise from renal cell carcinoma. We report the case of a 63-year-old woman, who presented with a pancreatic tumor detected during her annual health examination. She had undergone left nephrectomy 13 years previously for renal cell carcinoma. Computed tomography (CT) revealed two tumors in the head and body of the pancreas, a hypervascular tumor and a hypovascular tumor with an enhanced rim, respectively. She underwent pylorus-preserving pancreaticoduodenectomy, and metastatic pancreatic tumors arising from the kidney with clustered clear cell carcinoma immunohistochemically positive for CD10 were diagnosed. This report presents the different enhancement features of different lesions on CT scans. Because the enhancement features of lesions have been reported to vary according to the size of the metastatic tumor, a knowledge of the history of renal cell carcinoma is crucial for diagnosis.

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Autophagy contributes to apoptosis in A20 and EL4 lymphoma cells treated with fluvastatin

Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. However, the relationship between apoptosis and autophagy in lymphoma cells exposed to statins remains unclear. The objective of this study was to elucidate the potential involvement of autophagy in fluvastatin-induced cell death of lymphoma cells. We found that fluvastatin treatment enhanced the activation of pro-apoptotic members such as caspase-3 and Bax, but suppressed the activation of anti-apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells. The process was accompanied by increases in numbers of annexin V alone or annexin V/PI double positive cells. Furthermore, both autophagosomes and increases in levels of LC3-II were also observed in fluvastatin-treated lymphoma cells. However, apoptosis in fluvastatin-treated lymphoma cells could be blocked by the addition of 3-methyladenine (3-MA), the specific inhibitor of autophagy. Fluvastatin-induced activation of caspase-3, DNA fragmentation, and activation of LC3-II were blocked by metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggest that autophagy contributes to fluvastatin-induced apoptosis in lymphoma cells, and that these regulating processes require inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP.

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FISH+CD34+CD38- cells detected in newly diagnosed acute myeloid leukemia patients can predict the clinical outcome

Background: In acute myeloid leukemia (AML), the leukemia initiating cells (LICs) or leukemia stem cells (LSCs) is found within the CD34+CD38- cell compartment. The LICs subpopulation survives chemotherapy and is most probable the cause of minimal residual disease (MRD), which in turn is thought to cause relapse. The aim of this study was to determine the prognostic value of the percentage of LICs in blasts at diagnosis.Design and methodsThe percentage of LICs in the blast population was determined at diagnosis using a unique Flow-FISH analysis, which applies fluorescent in situ hybridization (FISH) analysis on flow cytometry sorted cells to distinguish LICs within the CD34+CD38- cell compartment. Fourty-five AML patients with FISH-detectable cytogenetic abnormalities treated with standardized treatment program were retrospectively included in the study. Correlations with overall survival (OS), events-free survival (EFS) and cumulative incidence of relapse (CIR) were evaluated with univariate and multivariate analysis. Results: The percentage of LICs is highly variable in patients with acute myeloid leukemia, ranged from 0.01% to 52.8% (median, 2.1%). High LIC load (>=1%) negatively affected overall survival (2-year OS: 72.57% vs. 16.75%; P = 0.0037) and events-free survival (2-year EFS: 67.23% vs. 16.33%; P = 0.0018), which was due to an increased cumulative incidence of relapse (2-year CIR: 56.7% vs. 18.0%; P = 0.021). By multivariate analysis, high LIC load retained prognostic significance for OS and EFS. Conclusions: In the present study, we established the Flow-FISH protocol as a useful method to distinguish normal and leukemic cells within the CD34+CD38- cell subpopulation. The high percentage of LICs at diagnosis was significantly correlated with increased risk of poor clinical outcome.

via Journal of Hematology & Oncology

MiR-99a may serve as a potential oncogene in pediatric myeloid leukemia

Background: Leukemia is the most common malignant proliferative disease in children. Our previous study found that miR-99a was up-regulated in pediatric primary AML using microRNA expression profiles. Up to date, although there is a certain number of reports on microRNA expression features and functions in pediatric acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), the expression and function of miR-99a in these diseases remain to be investigated. Methods: qRT-PCR was performed to measure the expression level of miR-99a in 88 samples including 68 pediatric acute myeloid leukemia patients, 8 chronic myeloid leukemia patients and 12 pediatric controls. MTT assay, apoptosis assay, dual-luciferase reporter transfection assay and western blot analysis were used to investigate the function of miR-99a. Results: MiR-99a was highly expressed in pediatric-onset AML (M1-M5) and CML, while significantly lowly expressed during complete remission of these diseases. MTT assay indicated that the proliferations of K562 and HL60 cells were significantly promoted by miR-99a, and apoptosis assessment by Annexin V/propidium iodide staining demonstrated that the apoptosis of these cells was inhibited by miR-99a. Additionally, dual-luciferase reporter transfection assay and western blot analysis indicated that miR-99a may target CTDSPL and TRIB2, which are two tumor suppressor genes. Conclusions: This study revealed that miR-99a may play a potential oncogenic role in pediatric myeloid leukemia including AML and CML via regulating tumor suppressors CTDSPL and TRIB2, suggesting that these two leukemias might share some common biological pathways involved in the generation and development of disease and miR-99a could be a common therapeutic target for myeloid leukemias treatment.

via Cancer Cell International

Enhancing bone marrow regeneration by SALL4 protein

Hematopoietic stem cells (HSCs) are widely used in transplantation therapy to treat a variety of blood diseases. The success of hematopoietic recovery is of high importance and closely related to the patient's morbidity and mortality after Hematopoietic stem cell transplantation (HSCT). We have previously shown that SALL4 is a potent stimulator for the expansion of human hematopoietic stem/progenitor cells in vitro. In these studies, we demonstrated that systemic administration with TAT-SALL4B resulted in expediting auto-reconstitution and inducing a 30-fold expansion of endogenous HSCs/HPCs in mice exposed to a high dose of irradiation. Most importantly, TAT-SALL4B treatment markedly prevented death in mice receiving lethal irradiation. Our studies also showed that TAT-SALL4B treatment was able to enhance both the short-term and long-term engraftment of human cord blood (CB) cells in NOD/SCID mice and the mechanism was likely related to the in vivo expansion of donor cells in a recipient. This robust expansion was required for the association of SALL4B with DNA methyltransferase complex, an epigenetic regulator critical in maintaining HSC pools and in normal lineage progression. Our results may provide a useful strategy to enhance hematopoietic recovery and reconstitution in cord blood transplantation with a recombinant TAT-SALL4B fusion protein.

via Journal of Hematology & Oncology

Promoter methylation status of the tumor suppressor gene SOX11 is associated with cell growth and invasion in nasopharyngeal carcinoma

Background: The transcription factor SOX11 is one of members of the SRY box-containing (SOX) family emerging as important transcriptional regulators. In recent years, up-regulation of SOX11 has been detected in various types of solid tumors. In this study, the effects of promoter methylation of the SOX11 gene on SOX11 expression and cell growth and invasion of nasopharyngeal carcinoma were investigated. Methods: In this study,methylation-specific PCR and real time quantitative PCR have been applied to investigate the effect of promoter methylation of the SOX11 gene on SOX11 expression in the nasopharyngeal carcinoma and chronic inflammation tissues. The nasopharyngeal carcinoma cell line (CNE2) was treated with 5-aza-2'-deoxycytidine. The effect of promoter methylation of SOX11 on growth and invasion of nasopharyngeal carcinoma cells was detected with MTT test and Boyden chamber Matrigel invasion assay. Results: No or weak expression of SOX11 mRNA was detected in the nasopharyngeal carcinoma tissues of SOX11 gene promoter methylation. Strong expression of SOX11 mRNA was detected in the nasopharyngeal carcinoma tissues of SOX11 gene promoter unmethylation and chronic inflammation tissues of pharynx nasalis. SOX11 mRNA and protein were re-expressed, SOX11 gene was demethylated, and growth and invasion of cells were inhibited in CNE2 cell line after 5-aza-2'-deoxycytidine treatment. Conclusions: The results of the study indicate that expression of SOX11 mRNA and protein were related to SOX11 gene methylation status. SOX11 gene methylation may be plays a role in growth and invasion of nasopharyngeal carcinoma cells.

via Cancer Cell International

Prognostic significance of XIAP and NF-kappaB expression in esophageal carcinoma with postoperative radiotherapy

Background: X-chromosome-linked IAP (XIAP) and nuclear factor-kappaB (NF-kappaB) are frequently overexpressed and correlate closely with chemoradiotherapy resistance and poor prognosis in many cancers. However, the significance of XIAP and NF-kappaB expression in radiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma (ESCC) are still unknown. The aim of this study was to examine XIAP and NF-kappaB status in ESCC patients undergoing postoperative radiotherapy after radical surgery, and to evaluate their clinical significance. Methods: A total of 78 ESCC patients treated with postoperative radiotherapy after radical surgery were enrolled in this study. We immunohistochemically investigated the expression of XIAP and NF-kappaB in tissues from enrolled patients with specific antibodies. Then, the correlations among XIAP, NF-kappaB expression, clinicopathological features and its prognostic relevance in ESCC were analyzed. Results: The increased expression of XIAP and NF-kappaB in ESCC tissues were clearly correlated with the tumor differentiation and p-TNM stage. Significant positive correlations were found between the expression status of XIAP and NF-kappaB (r = 0.779, P = 0.000). Overexpression of XIAP and NF-kappaB and metastasis were significantly associated with shorter overall survival times in univariate analysis (P < 0.05). Multivariate analysis also confirmed that XIAP expression was an independent prognostic factor (P = 0.005). Conclusions: XIAP and NF-kappaB are intensively expressed in ESCC. The level of XIAP is positively correlated to progression and prognosis of ESCC.

via World Journal of Surgical Oncology

Detection of TP53 dysfunction in chronic lymphocytic leukemia by an in vitro functional assay based on TP53 activation by the non-genotoxic drug Nutlin-3: a proposal for clinical application

Background: TP53 defects, i.e. 17p13 deletion and/or nucleotide mutations, associate with short survival and chemorefractoriness in chronic lymphocytic leukemia (CLL). In this context, since direct sequencing of the TP53 gene does not evaluate TP53 functionality, a functional assessment of TP53 pathway may be of interest to identify high risk CLL. By taking advantage of a training cohort of 100 CLL and a validation cohort of 40 CLL with different patterns of TP53 mutation/deletion by FISH and sequencing, we propose an in-vitro assay in which the modulation of TP53 protein and CDKN1A mRNA were investigated upon 24-hour exposure of CLL cells to Nutlin-3. Methods: The functional assay was set-up on cell lines recapitulating all TP53 genotypes (EHEB, TP53wt/wt; RAJI, TP53mut/wt; MEC-1 and MAVER1, TP53mut/del; HL-60, TP53del/del) and evaluated in two multi-institutional cohorts, purposely enriched in CLL bearing TP53 disruption: a training cohort of 100 cases and a validation cohort of 40 cases, both characterized by FISH and TP53 direct sequencing. Cells were exposed to 10 muM Nutlin-3 for 24 hours; TP53 accumulation was evaluated by Western blotting; TP53 transcriptional activity was determined by quantitative realtime PCR (qRT-PCR) of the TP53 target gene CDKN1A. Results: According to TP53 protein modulation, in the training cohort we identified: i) 63 cases (51 TP53wt/wt, 12 TP53del/wt) with absence of basal TP53 and induction after treatment (normal pattern); ii) 18 cases (3 TP53mut/wt, 15 TP53mut/del) with high basal TP53 without increase after treatment (mutant pattern); iii) 19 cases (5 TP53mut/wt; 3 TP53mut/del; 11 TP53wt/wt) with basal TP53 that increases upon treatment (intermediate pattern). Evaluation of CDKN1A mRNA levels upon Nutlin-3 exposure showed that the 26 TP53 mutated (TP53mut/del or TP53mut/wt) cases had lower induction levels than the majority (57/63) of cases with normal pattern, and 10/12 cases with intermediate pattern without evidence of TP53 derangement by FISH and sequencing. These results were confirmed in the independent validation cohort of 40 cases (13 TP53wt/wt, 3 TP53del/wt, 12 TP53mut/del, 12 TP53mut/wt). Conclusions: The proposed functional assay may integrate the conventional analyses for the identification of TP53 dysregulated CLL.

via Journal of Hematology & Oncology

Total gastrectomy increases the incidence of grade III and IV toxicities in patients with gastric cancer receiving adjuvant TS-1 treatment

Background: We aimed to evaluate the safety and efficacy of TS-1 adjuvant chemotherapy in Taiwanese patients with gastric cancer. Methods: We included in this study patients with locally advanced gastric cancer who received adjuvant TS-1 or 5-fluorouracil chemotherapy after curative surgery and extended lymph node dissection between 1 June 2008 and 31 December 2012 at Chang Gung Memorial Hospital. Patient characteristics, tumor features, safety profiles and compliance with TS-1 treatment were retrospectively analyzed from medical charts. Results: Forty patients received adjuvant chemotherapy with TS-1 and 193 with 5-fluorouracil within the study period. The 1- and 2-year overall survival rates were 90.6 % and 87 % in the TS-1 group and 95.4 % and 86.8 % in the 5-fluorouracil group (P = 0.34). The 1- and 2-year disease-free survival rates were 90.6 % and 74.7 % in the TS-1 group and 88 % and 75.7 % in the 5-fluorouracil group (P = 0.66). In the TS-1 group, tumor recurrence was more frequent in those with >15 metastatic lymph nodes than <=15. Overall, 78.9 %, 74.3 %, 62.1 % and 56 % of patients underwent TS-1 treatment for at least 3, 6, 9 and 12 months, respectively. The most common adverse events of TS-1 were skin hyperpigmentation (55 %), diarrhea (27.5 %), dizziness (27.5 %) and leucopenia (20 %). Severe adverse events (SAEs; grade III or IV toxicity) were diarrhea (7.5 %), stomatitis (7.5 %), leukopenia (5 %), vomiting (2.5 %), anorexia (2.5 %) and dizziness (2.5 %). Patients who underwent total gastrectomy had a significantly greater risk of TS-1-related SAEs than patients who underwent subtotal gastrectomy (40 % versus 8 %, P = 0.014). Conclusions: The incidence of SAEs during TS-1 therapy was more common in Taiwanese patients with gastric cancer who underwent total gastrectomy compared with those who underwent subtotal gastrectomy. Clinicians must be aware of and able to manage these SAEs to maximize patient compliance with adjuvant TS-1.

via World Journal of Surgical Oncology

PI3-kinase inhibition synergistically promoted the anti-tumor effect of lupeol in hepatocellular carcinoma

Background: Lup-20(29)-en-3H-ol (Lupeol), a dietary triterpene, has been shown to possess multiple pharmacological activities including anti-tumor effects Methods: In the current study, we noted that low doses of lupeol (<40muM) promoted the growth of hepatocellular carcinoma (HCC) cells with a significant activation of the PI3-kinase/Akt signaling pathway. We further investigated the combined anti-tumor effect of lupeol and S14161, a newly identified PI3-Kinase inhibitor in vitro and in vivo Results: The results demonstrated that lupeol and S14161 could exert a synergistic antitumor effect resulting in chemo-sensitization of HCC to low doses of lupeol. Using an in vivo HCC model, we further demonstrated that lupeol and S14161 synergistically inhibited tumor growth without any adverse effects on body weight Conclusion: Our studies showed that the activation of PI3-kinase/Akt pathway resulted in the tumor-promoting effect with low doses of lupeol. Combining PI3-kinase inhibitor with lupeol could synergistically augment the anti-tumor effect of lupeol and might be an applicable strategy for HCC therapy.

via Cancer Cell International

FDG-PET parameter predicts locally advanced lung cancer survival

High post-treatment concentrations of a radioactive imaging marker are predictive of worse overall survival from inoperable, locally advanced non-small-cell lung cancer, prospective study findings suggest.

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Factors associated with receipt of adjuvant chemotherapy among married women with breast cancer

Background: Adjuvant chemotherapies are recommended for most women after breast cancer surgery, and can greatly affect the patients' survival. We describe and evaluate possible factors influencing receipt of postoperative adjuvant chemotherapy among breast cancer patients in China. Methods: A total of 1,431 women diagnosed with breast cancer from 1997 to 2005 were enrolled. We reviewed medical records and abstracted information about these patients. Details on social-demographic factors and clinical-pathological characteristics of participants were collected and analyzed. To meet our objectives, the patient's age at diagnosis, comorbidities, menstrual status, rural/urban status, tumor size, lymph node status, distant metastasis, tumor stage and hormone receptor status were estimated. Results: Overall, 936 of these 1,431 patients (65.41%) received adjuvant chemotherapy. Receipt of chemotherapy was significantly associated with age at diagnosis, rural--urban disparities, and lymph node status of patients, though no significant difference was found between the age <50 and age 50 to 64 groups. Moderate association was also observed between hormone receptor status and receipt of adjuvant chemotherapy, though it was still not statistically significant. Conclusions: Our study suggests that age at diagnosis, rural--urban disparities and lymph node status of breast cancer patients are independent predictors for receipt of adjuvant chemotherapy among married Chinese women. Further investigations are warranted, and related public health education needs to be expanded in China.

via World Journal of Surgical Oncology

Toxicity limits benefits of bevacizumab–erlotinib NSCLC maintenance therapy

Two targeted anticancer drugs used together after first-line chemotherapy for advanced stage non-small-cell lung cancer improve progression-free survival, the results of a large, prospective study show.

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DNA methylation signature marks recurrence in early stage lung cancer

An international research team has identified a DNA methylation signature that identifies patients with stage I non-small-cell lung cancer who are at high risk for relapse.

via Med Wire News

STAT3 mutations are frequent in T-cell large granular lymphocytic leukemia with pure red cell aplasia

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder and can cooccur in the context of pure red cell aplasia (PRCA). The aim of the current study was to analyze the signal transducer and activator of transcription 3 (STAT3) mutation status and its clinical significance in T-LGLL. We found STAT3 mutations in 21.4% of patients with T-LGLL. High beta2-MG (beta2-microglobulin) levels (P = 0.005), neutropenia (P = 0.018) and PRCA (P = 0.001) all displayed a significant association with STAT3 mutations. In univariate analysis, treatment-free survival (TFS) was affected by STAT3 mutation status (P = 0.008) and beta2-MG (P = 0.006). Our results demonstrate the remarkable correlation of STAT3 mutation with PRCA, neutropenia and beta2-MG.

via Journal of Hematology & Oncology

Breast adenomyoepithelioma: a case report with malignant proliferation of epithelial and myoepithelial elements

Background: Breast adenomyoepithelioma is an unusual tumor characterized by a biphasic proliferation of epithelial and myoepithelial cells. Most breast adenomyoepitheliomas are considered to be benign or to have a low-grade malignant potential, characterized by propensity for local recurrence. Malignant changes arising in this lesion are extremely rare and may involve one or both cellular components.Case report: We discuss a case of a 60 year-old woman who began to experience pain in her right breast in January 2009. Breast ultrasound and mammography were performed showing a rounded, hypoechoic solid lesion with ill-defined margins in the right inner-inferior quadrant, suspicious of malignancy. Quadrantectomy of the inner-inferior quadrant of the right breast with sampling of ipsilateral axillary lymph nodes was performed. The histological analysis confirmed the diagnosis of adenomyoepithelioma with focal malignant change of the epithelial component, associated with high-grade malignant myoepithelial change. The patient was treated with adjuvant radiotherapy and her right breast received a dose of Gy 50 with a boost of Gy 10 to the tumor bed. At present, the patient shows no sign of tumor recurrence. Conclusion: Breast malignant adenomyoepithelioma is a rare tumor which should be considered in the differential diagnosis of other solid breast lesions. Only few cases have been reported in the literature. Diagnosis, optimal therapy and predicting the outcome are problematic issues due to the rarity of this disease which appears to have hematogenous rather than lymphatic spread and usually occurs in primary tumors >= 1.6 cm in size.

via World Journal of Surgical Oncology