Cell-cycle synchronization reverses Taxol resistance of human ovarian cancer cell lines

Background: Taxol is a powerful chemotherapy agent leading to mitotic arrest and cell death; however, its clinical efficacy has been hampered due to the development of drug resistance. Taxol specifically targets the cell cycle. Progress through mitosis (M stage) is an absolute requirement for drug-induced death because cell death is markedly reduced in cells blocked at the G1-S transition. The measured doubling time for ovarian cancer cells is about 27h. As such, during treatment with Taxol most of the cells are not in the M stage of the cell cycle. Thus, the effect of cell-cycle synchronization was investigated in regard to reversing Taxol resistance in ovarian cancer cells. Methods: Giemsa-Wright staining was used for assessing the morphology of the cells. The doubling time of the cells was calculated using formula as follows: Td = In2/slope. The resistant index and cell cycle were measured via MTT assays and flow cytometry. Thymidine was used to induce cell-cycle synchronization, and cell apoptosis rates following exposure to Taxol were measured using a flow cytometer. Results: The growth doubling time of two Taxol-resistant cell lines were longer than that of Taxol-sensitive cells. Apoptotic rates in Taxol-sensitive and -resistant cell lines after synchronization and exposure to Taxol were all higher compared to unsynchronized controls (p <0.05). Conclusions: Synchronization of the cell-cycle resulted in an increased effectiveness of Taxol toward ovarian cancer cell lines. We speculated that formation of drug resistance toward Taxol in ovarian cancer could be partly attributed to the longer doubling time of these cells.

via Cancer Cell International

Major European study finds air pollution–lung cancer link

Exposure to ambient air pollution is associated with an increased risk for lung cancer, particularly adenocarcinoma, a large European cohort study indicates.

via Med Wire News

Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line

Background: Epithelial-mesenchymal transition (EMT) is a process implicated in cancer metastasis that involves the conversion of epithelial cells to a more mesenchymal and invasive cell phenotype. In breast cancer cells EMT is associated with altered store-operated calcium influx and changes in calcium signalling mediated by activation of cell surface purinergic receptors. In this study, we investigated whether MDA-MB-468 breast cancer cells induced to undergo EMT exhibit changes in mRNA levels of calcium channels, pumps and exchangers located on intracellular calcium storing organelles, including the Golgi, mitochondria and endoplasmic reticulum (ER). Methods: Epidermal growth factor (EGF) was used to induce EMT in MDA-MB-468 breast cancer cells. Serum-deprived cells were treated with EGF (50 ng/mL) for 12 h and gene expression was assessed using quantitative RT-PCR.Results and conclusionsThese data reveal no significant alterations in mRNA levels of the Golgi calcium pump secretory pathway calcium ATPases (SPCA1 and SPCA2), or the mitochondrial calcium uniporter (MCU) or Na+/Ca2+ exchanger (NCLX). However, EGF-induced EMT was associated with significant alterations in mRNA levels of specific ER calcium channels and pumps, including (sarco)-endoplasmic reticulum calcium ATPases (SERCAs), and inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RYR) calcium channel isoforms. The most prominent change in gene expression between the epithelial and mesenchymal-like states was RYR2, which was enriched 45-fold in EGF-treated MDA-MB-468 cells. These findings indicate that EGF-induced EMT in breast cancer cells may be associated with major alterations in ER calcium homeostasis.

via Cancer Cell International

Pemetrexed–bevacizumab effective maintenance therapy for NSCLC

Pemetrexed in combination with bevacizumab is superior to bevacizumab alone when given as continuation maintenance therapy in patients with advanced nonsquamous non-small-cell lung cancer, results of the AVAPERL trial show.

via Med Wire News

ROS1 rearrangement ‘specific for lung cancer in never-smokers’

Lung adenocarcinomas harboring genetic rearrangements of the receptor tyrosine kinase proto-oncogene ROS1 are more frequent in people who have never smoked than in smokers, a study by South Korean researchers shows.

via Med Wire News

Cytoreductive nephrectomy for small RCC tumors questioned

Researchers have found that cytoreductive radiofrequency ablation plus sunitinib offers limited benefits over sunitinib alone in the treatment of small tumors in patients with metastatic renal cell carcinoma.

via Med Wire News

Prevention of contamination by biopsy needle track contamination using a novel adriamycin-loaded gelatin sponge

Background: The gold standard of tumor diagnosis is histological examination of a biopsy; however, there is concern that tumor cell dissemination along the needle track during percutaneous biopsy can cause local tumor relapse. We aimed to evaluate the value of an adriamycin (ADM)-loaded gelatin sponge in preventing tumor cell contamination along the biopsy needle track. Methods: Data were obtained from 40 patients who were diagnosed by core needle biopsy as having osteosarcoma and who were followed up at our hospital between 2008 and 2011. Of the 40 patients, 20 had the needle biopsy tracks filled with ADM-loaded absorbable gelatin sponge immediately after the biopsy specimen was obtained, while the other 20 did not. All 40 patients underwent limb-salvage surgery, and specimens were obtained from the biopsy track for histopathologic examination of multiple sections. Results: On histological examination, there was less tumor cell contamination along the biopsy tracks in the ADM group. Conclusion: Use of ADM-loaded absorbable gelatin sponge may prevent tumor cell contamination of a biopsy track, and reduce the possibility of consequent tumor relapse.

via World Journal of Surgical Oncology

A characterization of four B16 murine melanoma cell sublines molecular fingerprint and proliferation behavior

Background: One of the most popular and versatile model of murine melanoma is by inoculating B16 cells in the syngeneic C57BL6J mouse strain. A characterization of different B16 modified cell sub-lines will be of real practical interest. For this aim, modern analytical tools like surface enhanced Raman spectroscopy/scattering (SERS) and MTT were employed to characterize both chemical composition and proliferation behavior of the selected cells. Methods: High quality SERS signal was recorded from each of the four types of B16 cell sub-lines: B164A5, B16GMCSF, B16FLT3, B16F10, in order to observe the differences between a parent cell line (B164A5) and other derived B16 cell sub-lines. Cells were incubated with silver nanoparticles of 50--100 nm diameter and the nanoparticles uptake inside the cells cytoplasm was proved by transmission electron microscopy (TEM) investigations. In order to characterize proliferation, growth curves of the four B16 cell lines, using different cell numbers and FCS concentration were obtained employing the MTT proliferation assay. For correlations doubling time were calculated. Results: SERS bands allowed the identification inside the cells of the main bio-molecular components such as: proteins, nucleic acids, and lipids. An "on and off" SERS effect was constantly present, which may be explained in terms of the employed laser power, as well as the possible different orientations of the adsorbed species in the cells in respect to the Ag nanoparticles. MTT results showed that among the four tested cell sub-lines B16 F10 is the most proliferative and B164A5 has the lower growth capacity. Regarding B16FLT3 cells and B16GMCSF cells, they present proliferation ability in between with slight slower potency for B16GMCSF cells. Conclusion: Molecular fingerprint and proliferation behavior of four B16 melanoma cell sub-lines were elucidated by associating SERS investigations with MTT proliferation assay.

via Cancer Cell International

Adenoma malignum of the uterine cervix: report of four cases

Adenoma malignum (AM) of the cervix is a rare disease and it is difficult to diagnose due to the deceptively benign appearance of the tumor cells. These lesions have mucin-rich cystic lesions and are usually situated deep in the cervix. Since AM is very rare, standard screening tests, diagnostic tools and treatments have not yet been established. Radiologically, it mimics multiple nabothian cysts as a benign-looking tumor. Histologically, AM is a well-differentiated adenocarcinoma and could be misdiagnosed as a benign lesion. These findings make a preoperative diagnosis of AM difficult and can result in surgery being performed based on a misdiagnosis. We report here on four cases of pathologically confirmed AM.

via World Journal of Surgical Oncology

Pemetrexed maintenance therapy prolongs survival in nonsquamous NSCLC

Pemetrexed maintenance therapy offers a survival benefit over placebo and is well tolerated in patients with advanced nonsquamous non-small-cell lung cancer, final results of the PARAMOUNT trial show.

via Med Wire News

Intercalated regimen demonstrates first-line efficacy for advanced NSCLC

Administration of erlotinib in combination with chemotherapy is a viable first-line treatment strategy in patients with advanced non-small-cell lung cancer, results from FASTACT-2 suggest.

via Med Wire News

Oncogenic transformation of mammary epithelial cells by transforming growth factor beta independent of mammary stem cell regulation

Background: Transforming growth factor beta (TGFbeta) is transiently increased in the mammary gland during involution and by radiation. While TGFbeta normally has a tumour suppressor role, prolonged exposure to TGFbeta can induce an oncogenic epithelial to mesenchymal transition (EMT) program in permissive cells and initiate the generation of cancer stem cells. Our objective is to mimic the transient exposure to TGFbeta during involution to determine the persistent effects on premalignant mammary epithelium.MethodCDbetaGeo cells, a transplantable mouse mammary epithelial cell line, were treated in vitro for 14 days with TGFbeta (5 ng/ml). The cells were passaged for an additional 14 days in media without TGFbeta and then assessed for markers of EMT and transformation. Results: The 14-day exposure to TGFbeta induced EMT and transdifferentiation in vitro that persists after withdrawal of TGFbeta. TGFbeta-treated cells are highly tumorigenic in vivo, producing invasive solid de-differentiated tumours (100%; latency 6.7 weeks) compared to control (43%; latency 32.7 weeks). Although the TGFbeta-treated cells have initiated a persistent EMT program, the stem cell population was unchanged relative to the controls. The gene expression profiles of TGFbeta-treated cells demonstrate de-differentiation with decreases in the expression of genes that define luminal, basal and stem cells. Additionally, the gene expression profiles demonstrate increases in markers of EMT, growth factor signalling, TGFbeta2 and changes in extra cellular matrix. Conclusion: This model demonstrates full oncogenic EMT without an increase in stem cells, serving to separate EMT markers from stem cell markers.

via Cancer Cell International

Severe eosinophilic pneumonia presenting during gemcitabine adjuvant chemotherapy

Gemcitabine is widely accepted as the standard treatment for pancreatic cancer, but it can cause unpredictable side effects. Acute respiratory distress syndrome is a rare complication with gemcitabine, but is sometimes fatal. We describe a cured case of acute, severe gemcitabine-induced pulmonary toxicity. The patient was a 76-year-old man with pancreatic cancer who was receiving adjuvant gemcitabine chemotherapy after surgery. The patient received gemcitabine 1,000 mg/m2 on days 1, 8, and 15 for three 4-week cycles, with intervals of 1 week. He developed severe general fatigue on day 1 of the third cycle. Computed tomography showed diffuse ground-glass opacity with pleural effusion. There was no increase in beta-D-glucan, and cytomegalovirus antigenemia assays were negative. No bacteria or acid-fast bacilli were found. The number of eosinophils in bronchoalveolar lavage fluid was increased. Considering these data, we diagnosed eosinophilic pneumonia induced by gemcitabine. The patient was immediately treated with a steroid and neutrophil elastase inhibitor under respiratory supportive therapy. After 4 weeks, his pulmonary symptoms were markedly improved. Physicians should be cognizant of the possible association of serious pulmonary toxicity with gemcitabine treatment. A delay in diagnosis and treatment could lead to a fatal outcome.

via World Journal of Surgical Oncology

Shrink pattern of breast cancer after neoadjuvant chemotherapy and its correlation with clinical pathological factors

Background: Breast conservation therapy (BCS) after neoadjuvant chemotherapy (NCT) can improve patients' quality of life. Currently used intraoperative examination for negative margins may not be sufficient to detect microresidual foci, which are a risk factor for local recurrence. This study was conducted to investigate the shrinking pattern of breast cancer and residual tumors as a risk factor for BCS after NCT. Methods: Ninety women with stage II or III invasive ductal carcinoma who achieved partial response after NCT with paclitaxel and epirubicin were enrolled. All patients had undergone modified radical mastectomy. One-half of the surgical specimens were subjected to subserial sectioning. Pathological changes of tumor bed and pericancerous tissues were examined with an optical microscope. The levels of estrogen receptors, progesterone receptors and HER2 were analyzed by immnohistochemical staining. Results: The residual tumors were classified into three types according to their microscopic morphology: solitary lesion, multifocal and patchlike lesions, and main residual tumor with satellite lesions. Type I residual tumors were found in 55 patients (61%), type II in 30 patients (33%) and type III in 5 patients (6%). Types II and III were often associated with larger primary tumors. The types of residual tumors were not correlated with the status of hormone receptors or HER2. Conclusion: Three types of residual tumors were observed after NCT. The solitary residual tumor is most common, but main residual tumors with satellite lesions are most likely to cause local recurrence after BCS. Subserial sectioning would improve the identification of microfoci and patient survival after BCS.

via World Journal of Surgical Oncology

Vertical platysma myocutaneous flap that sacrifices the facial artery and vein

Background: Platysma myocutaneous flap (PMF) is a generally used technique for defect reconstruction after an oral cancer resection. The aim of the study is to present our experience using vertical PMF that sacrificed the facial artery and vein for intraoral reconstruction. Methods: A retrospective review of the medical records of 54 patients who underwent vertical PMF that sacrificed the facial artery and vein for intraoral reconstruction was performed. A comparison between PMF that sacrificed and that preserved the facial vessels was made, and we also compared PMF that sacrificed the facial vessels with radial forearm free flap (RFFF). Statistics concerning the patients' clinical factors were gathered. Results: The mean age of the 54 patients who underwent PMF that sacrificed the facial artery and vein was 62.0 +/- 10.98 years. The co-morbid disease rate of PMF was 53.7%. The flap size ranged from 12 x 5.5 cm to 7 x 5 cm. Survival of the flap was found in all of the cases, with partial necrosis in four cases (7.4%) and total loss in none of the cases. The operation time was 5.7 +/- 1.17 h. The complication and success rates were 27.8% and 92.6%, respectively. The 3-year and 5-year survival rates were 77.8% (21/27) and 69.23% (9/13), respectively. The majority of the patients (87.0%) in our series were satisfied with the results of the surgery. There was no significant difference between PMF that sacrificed or that preserved the facial vessels, both in success rate (P = 1) or complication rate (P = 0.72). The patients in the PMF group were older than the patients in the RFFF group (P = 0.011), the operation time was shorter (P < 0.001), and the co-morbid disease rate was higher (P = 0.002). Although the complication rate of PMF (15/54, 27.8%) was higher than that of RFFF (2/34, 5.9%) (P = 0.011), their success rates were similar (92.6%, 94.1%) (P = 1.00). Conclusions: Vertical PMF that sacrifices the facial artery and vein has specific advantages including in ease preparation and limitations. This technique may provide an effective method for intraoral reconstruction. Our experience in handling the flap may contribute to the success rate.

via World Journal of Surgical Oncology

Influence on the behavior of lung cancer H1299 cells by silencing SLC35F2 expression

Background: To investigate the effects of RNA interference-mediated downregulation of Human Solute Carrier Family 35 member F2 (SLC35F2) expression on the biological behavior of lung cancer H1299 cells. Methods: The lentiviral vector of small interfering RNA targeting SLC35F2 was introduced into H1299 cells by liposome-mediated transfection. Expression of the SLC35F2 protein was measured by western blot. The proliferation of H1299 cells was determined by Cell Counting Kit-8 assay. The migration of H1299 cells was measured by Transwell migration assay. Cell cycle analysis used fluorescence-activated cell sorting. Results: SLC35F2 expression was markedly downregulated in H1299 cell clone (transfected with the lentiviral vector harboring small interfering RNA targeting SLC35F2). Proliferation decreased significantly compared with that of non-transfected H1299 cells. Transwell migration assay showed that fewer cells moved through the artificial basement membrane compared with untransfected H1299 cells (38.3 +/- 5.7 vs. 113.5 +/- 8.5, P < 0.05). The cell cycle of H1299 cells was changed, the percentage of H1299 cells in S and G2/M phases being significantly decreased compared with untransfected H1299 cells (S phase: 15.3% +/- 3.0% vs. 27.0% +/- 5.4%, P > 0.05; G2/M phase; 3.0% +/- 1.1% vs. 10.5% +/- 1.7%, P < 0.05), whereas the percentage of H1299 cells in G0/G1 phase increased markedly (81.7% +/- 4.0% vs. 62.5% +/- 1.9%, P < 0.05). Conclusion: RNA interference-mediated downregulation of SLC35F2 expression by lentiviral vector can attenuate the proliferation, migration and invasion of H1299 cells.

via Cancer Cell International

Adult HPV vaccination has limited impact

The Costa Rica Vaccine Trial for human papillomavirus in young women has had a “modest” impact on gynecologic outcomes in the first few years of the program.

via Med Wire News

Three-dimensional computed tomography angiography for the preoperative evaluation of coronary artery disease in lung cancer patients

Background: The number of elderly patients undergoing surgery for lung cancer is increasing. In this study, we assessed the usefulness of three-dimensional computed tomographicangiography (3D-CTA) for the detection of coronary disease in the elderly before surgical intervention for lung cancer. Methods: One hundred twenty patients admitted to our institution for lung cancer resection were enrolled in the study. 3D-CTA was performed in all 120 patients. Results: Seventy-one patients had normal findings, and forty-nine patients showed coronary stenosis on 3D-CTA examination. Among the latter 49 patients, 24 with slight stenosis underwent lung tumor resection, 23 had coronary angiography for severe stenosis before lung surgery and 2 were not eligible for lung resection because of very severe coronary stenosis. The diagnostic value of 3D-CTA was better than conventional CT. Conclusions: This study suggests the usefulness of 3D-CTA for the preoperative diagnosis of coronary ischemic disease in elderly lung cancer patients.

via World Journal of Surgical Oncology

Biomarkers for determining the prognosis in chronic myelogenous leukemia

The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for treatment of chronic myelogenous leukemia in chronic phase (CML-CP) has revolutionized therapy, altering the outcome from one of shortened life expectancy to long-term survival. With over 10 years of long-term treatment with imatinib and several years of experience with the next generation of TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib, it is becoming clear that many clinical parameters have great impact on the prognosis of patients with CML. Emerging novel gene expression profiling and molecular techniques also provide new insights into CML pathogenesis and have identified potential prognostic markers and therapeutic targets. This review presents the supporting data and discusses how certain clinical characteristics at diagnosis, the depth of early response, the presence of certain kinase domain mutations, and additional molecular changes serve as prognostic factors that may guide individualized treatment decisions for patients with CML-CP.

via Journal of Hematology & Oncology

Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma

Background: Burkitt leukemia/lymphoma is a major subtype of aggressive B-cell lymphoma. Biological targeted therapies on this disease need to be further investigated and may help to improve the clinical outcome of the patients. Methods: This study examined the anti-tumor activity of the histone deacetylases (HDAC) inhibitor valproic acid (VPA) combined with the mammalian target of rapamycin (MTOR) inhibitor temsirolimus in Burkitt leukemia/lymphoma cell lines, as well as in primary tumor cells and a murine xenograft model. Results: Co-treatment of VPA and temsirolimus synergistically inhibited the tumor cell growth and triggered the autophagic cell death, with a significant inhibition of MTOR signaling and MYC oncoprotein. Functioned as a class I HDAC inhibitor, VPA potentiated the effect of temsirolimus on autophagy through inhibiting HDAC1. Molecular silencing of HDAC1 using small interfering RNA (siRNA) attenuated VPA-mediated regulation of CDKN1A, CDKN1B and LC3-I/II, regression of tumor cell growth and induction of autophagy. Meanwhile, VPA counteracted temsirolimus-induced AKT activation via HDAC3 inhibition. HDAC3 siRNA abrogated the ability of VPA to modulate AKT phosphorylation, to suppress tumor cell growth and to induce autophagy. Strong antitumor effect was also observed on primary tumor cells while sparing normal hematopoiesis ex vivo. In a murine xenograft model established with subcutaneous injection of Namalwa cells, dual treatment efficiently blocked tumor growth, inhibited MYC and induced in situ autophagy. Conclusions: These findings confirmed the synergistic effect of the HDAC and MTOR inhibitors on Burkitt leukemia/lymphoma, and provided an insight into clinical application of targeting autophagy in treating MYC-associated lymphoid malignancies.

via Journal of Hematology & Oncology

Pulmonary benign metastasizing leiomyoma from uterine leiomyoma

Background: Benign metastasizing leiomyoma (BML) occurs in a low proportion of uterine leiomyomas and treatment methods for BML are diverse and controversial. The study introduces preliminary experiences in the diagnosis and treatment of BML with the purpose of finding a suitable management strategy for these patients. Methods: Three patients with BML were treated in our department from April 2008 to July 2012. Each of these patients presented with multiple nodules in both lungs, where we performed video-assisted thoracoscopic wedge resection to harvest enough tissue for histopathologic and immunohistochemical examination. The patients were treated with medical castration or surgical castration after the diagnosis of BML. Results: The ultimate pathologic results ruled out the possibility of leiomyosarcoma and other metastatic diseases, and confirmed that the pulmonary lesions were BML. The lung lesions remained stable in two patients who were treated by surgical castration, and the lung nodules regressed in one patient treated with gonadotropin-releasing hormone analogues. Conclusions: The diagnosis of BML is based on the medical history of uterine myomas and histopathologic and immunohistochemical examination of lung nodules. Video-assisted thoracoscopic wedge resection is the best way to harvest tissue for diagnosis. The better outcomes in BML seem to call for medical intervention, either chemical or surgical, after diagnosis is made.

via World Journal of Surgical Oncology

Prognostic analysis of esophageal cancer in elderly patients: metastatic lymph node ratio versus 2010 AJCC classification by lymph nodes

Background: Recent studies have proposed a new prognostic factor (metastatic lymph node ratio, or MLNR) for patients with esophageal cancer (EC). However, to the best of our knowledge, there have been no studies conducted to date regarding MLNR in elderly patients. The aim of this study was to determine the prognostic value of MLNR staging compared with the 2010 American Joint Committee on Cancer (AJCC) N staging in elderly patients with EC. Methods: From January 2001 to December 2009, a retrospective analysis of 132 consecutive patients older than 70 years of age with esophageal squamous cell carcinoma (ESCC) was conducted. Prognostic factors for disease-specific survival were analyzed. Receiver operating characteristic curves were also plotted to verify the accuracy of MLNR staging and N staging for survival prediction. Results: The disease-specific survival rates of N0, N1, N2 and N3 patients according to the AJCC Cancer Staging Manual Seventh Edition N staging were 65.5%, 42.9%, 22.2% and 0, respectively (N0 vs N1, P = 0.017; N1 vsN2, = 0.050; N2 vs N3, P < 0.001). The disease-specific survival rates of MLNR0, MLNR1, MLNR2 and MLNR3 patients were 65.5%, 45.0%, 21.1% and 0, respectively (MLNR0 vsMLNR1, P = 0.026; MLNR1 vs MLNR2, P = 0.033; MLNR2 vs MLNR3, P = 0.015). The areas under the curve were 0.731 for the 2010 AJCC N staging and 0.737 for the MLNR staging. Conclusion: MLNR is an independent predictor of survival in elderly patients with ESCC. MLNR staging predicts survival after EC similarly to the 2010 AJCC N classifications and should be considered an alternative to current N staging.

via World Journal of Surgical Oncology

Double-positive expression of high-mobility group box 1 and vascular endothelial growth factor C indicates a poorer prognosis in gastric cancer patients

Background: Although many studies have indicated that high-mobility group box 1 protein (HMGB1) is associated with oncogenesis and a worse prognosis, the prognostic value of HMGB1 in gastric cancer (GC) remains unclear. In the present work, we aimed to evaluate the role of HMGB1 in GC and examined whether aberrant expression of both HMGB1 and vascular endothelial growth factor C (VEGF-C) increased the malignant potential of GC. Methods: A total of 166 GC patients and 32 normal subjects were enrolled. HMGB1 and VEGF-C expression was detected by tissue microarrays (TMAs) and immunohistochemical staining. The correlation between HMGB1 and VEGF-C expression and their relationships with clinicopathological GC variables were examined. Univariate and multivariate analyses were performed using the Cox proportional hazard model to predict the factors related to the patients' overall survival rates. Results: HMGB1 and VEGF-C expression were observed in 81 (48.80%) and 88 (53.01%) tumors, respectively, significantly higher than the rates among the corresponding controls. In addition, HMGB1 and VEGF-C expression were positively correlated (R2 = 0.972). HMGB1 expression was also closely associated with tumor size, pT stage, nodal status, metastasis status, TNM stage, and poor prognosis. Multivariate survival analysis indicated that patients with HMGB1 and VEGF-C coexpression had the worst prognoses and survival rates (hazard ratio, 2.78; log rank P<0.001). Conclusions: HMGB1 is commonly expressed in GC. Combined evaluation of HMGB1 and VEGF-C may serve as a valuable independent prognostic factor for GC patients.

via World Journal of Surgical Oncology

Robotic pancreatic surgery -- no substitute for experience and clinical judgment: an initial experience and literature review.

Robotic pancreatic surgery offers technical advantages, and has found applications across many surgical specialties. We report an initial experience of 12 distal pancreatic resections for benign tumors, from an established pancreatic center with previous general and biliary laparoscopic experience. 7/12 were females, the mean age was 55.5 years; and the lesions included 8 distal Intraductal Papillary Mucinous Tumors, 1 insulinoma and in 3 a nonfunctioning neuroendocrine tumor. All operations were done between 90 and 180 minutes,and blood loss and hospital stay were minimal

via World Journal of Surgical Oncology

Extracorporeal tumor cell filtration during extended liver surgery: first clinical use of leukocyte depletion filters -- a case series

Background: During oncologic surgery, intraoperative manipulation of tumor tissue is almost unpreventable and causes a high risk of tumor cell dissemination into venous blood. A tumor cell-reducing effect of leukocyte adhesion filter systems has been shown under in vitro conditions. Methods: In a first clinical attempt, leukocyte adhesion filters were integrated into veno-venous bypass systems in four patients undergoing extended liver surgery for secondary hepatic malignancies.Practicability, handling, and safety aspects as well as potency of cell removal and clinical side effects of the filter system were analyzed. Results: All patients tolerated the application of the system without problems during operative and postoperative follow-up. Immunohistochemical staining of perioperative blood samples detected cytokeratin positive (CK+) cells in three cases during the hepatic mobilization. Conclusions: Effectiveness of CK+ cell depletion and safety of the procedure was shown. The presented surgical technique represents a safe and innovative tool; however, clinical significance has to be examined in a larger patient cohort.

via World Journal of Surgical Oncology

Diagnosis and treatment of cystic renal cell carcinoma

Background: To summarize the diagnosis and treatment of cystic renal cell carcinoma (CRCC). Methods: A retrospective study was conducted on 13 patients with CRCC at our center from August 2004 to April 2012. The pathologic features, clinical manifestation, imaging characteristics, treatment, and prognosis of CRCC were summarized according to available literature. Results: Of the 13 patients, 11 were diagnosed with CRCC by preoperative B ultrasonography and computed tomography (CT) scan. The remaining two cases were initially misdiagnosed with simple renal cysts. Open radical nephrectomy was performed on two of the 13 cases, laparoscopic radical nephrectomy on seven cases, and open partial nephrectomy on four cases. All diagnoses of CRCC were confirmed by pathological examination. After the operation, all patients had an uneventful recovery. During the follow-up (range, 6--60 months), the serum creatinine concentrations and GFR of the partially removed kidneys remained stable within the normal range. No tumor recurrence or metastasis occurred. Conclusions: By combining imaging examinations (B ultrasonography and CT scan) with intraoperative pathological examination, most cases of CRCC can be diagnosed and treated promptly and accurately. Nephrectomy is the first-line therapy. Nephron-sparing surgery should be preferred for CRCC. After a successful operation, the prognosis of CRCC is good.

via World Journal of Surgical Oncology

Video-assisted thoracoscopic surgery versus robotic-assisted thoracoscopic surgery in the surgical treatment of Masaoka stage I thymoma

Background: The purpose of this study was to compare perioperative outcomes in patients who underwent video-assisted thoracoscopic surgery or robot-assisted thoracoscopic surgery and assess the feasibility of robotic-assisted thymectomy for the treatment of Masaoka stage I. Methods: We evaluated the short-term outcomes of 46 patients who underwent surgery for Masaoka stage I thymoma without myasthenia gravis between January 2009 and June 2012. Of these patients, 25 received unilateral video-assisted thoracoscopic surgery (VATS group) and the rest 21 recieved unilateral robotic-assisted thoracoscopic surgery (RATS group). We evaluated the duration of surgery, amount of intraoperative blood loss, duration of chest drainage, duration of postoperative hospital stay, hospitalization costs, postoperative complications and oncological outcomes. Results: The duration of surgery was not significantly different between the two groups. Intraoperative blood loss volumes did not differ significantly between the VATS and RATS groups (86.8 mL and 58.6 mL, respectively; P=0.168). The postoperative hospital stay was significantly shorter in the RATS group (3.7 days vs. 6.7 days; P <0.01), and the postoperative pleural drainage volume of the RATS group was significantly less than VATS group (1.1 days vs. 3.6 days; P <0.01). No patients in the RATS group needed conversion to open surgery. However, in the VATS series, one patient had conversion to an open procedure. No surgical complications were observed except that one case had pulmonary atelectasis in the RATS group and one case developed pneumonia after surgery. Use of robot is much more expensive than video. No early recurrence was observed in both groups. Conclusions: Robotic thymectomy is feasible and safe for Masaoka stage I thymoma., RATS is equally minimally invasive as VATS and results in a shorter drainage period and reduced hospital stay compared with the VATS approach.

via World Journal of Surgical Oncology

Release and uptake of volatile organic compounds by human hepatocellular carcinoma cells (HepG2) in vitro

Background: Volatile organic compounds (VOCs) emitted by human body offer a unique insight into biochemical processes ongoing in healthy and diseased human organisms. Unfortunately, in many cases their origin and metabolic fate have not been yet elucidated in sufficient depth, thus limiting their clinical application. The primary goal of this work was to identify and quantify volatile organic compounds being released or metabolized by HepG2 hepatocellular carcinoma cells. Methods: The hepatocellular carcinoma cells were incubated in specially designed head-space 1-L glass bottles sealed for 24 hours prior to measurements. Identification and quantification of volatiles released and consumed by cells under study were performed by gas chromatography with mass spectrometric detection (GC-MS) coupled with head-space needle trap device extraction (HS-NTD) as the pre-concentration technique. Most of the compounds were identified both by spectral library match as well as retention time comparison based on standards. Results: A total of nine compounds were found to be metabolised and further twelve released by the cells under study (Wilcoxon signed-rank test, p<0.05). The former group comprised 6 aldehydes (2-methyl 2-propenal, 2-methyl propanal, 2-ethylacrolein, 3-methyl butanal, n-hexanal and benzaldehyde), n-propyl propionate, n-butyl acetate, and isoprene. Amongst the released species there were five ketones (2-pentanone, 3-heptanone, 2-heptanone, 3-octanone, 2-nonanone), five volatile sulphur compounds (dimethyl sulfide, ethyl methyl sulfide, 3-methyl thiophene, 2-methyl-1-(methylthio)- propane and 2-methyl-5-(methylthio) furan), n-propyl acetate, and 2-heptene. Conclusions: The emission and uptake of the aforementioned VOCs may reflect the activity of abundant liver enzymes and support the potential of VOC analysis for the assessment of enzymes function.

via Cancer Cell International

Emodin induces apoptosis of human cervical cancer hela cells via intrinsic mitochondrial and extrinsic death receptor pathway

Background: Emodin is a natural anthraquinone derivative isolated from the Rheum palmatum L. Aim: The aim of the present study was to investigate the effect of emodin on the apoptosis of the human cervical cancer line HeLa and to identify the mechanisms involved. Methods: Relative cell viability was assessed by MTT assay after treatment with emodin. Cell apoptosis was detected with TUNEL, Hoechst 33342 staining and quantified with flow cytometry using annexin FITC-PI staining. Results: The percentage of apoptotic cells was 0.8, 8.2, 22.1, and 43.7%, respectively. The mRNA levels of Caspase-9, -8 and -3 detected by Real-time PCR after treatment with emodin were significantly increased. Emodin increased the protein levels of Cytochome c, Apaf-1, Fas, FasL, and FADD but decreased the protein levels of Pro-caspase-9, Pro-caspase-8 and Pro-caspase-3. Conclusion: We conclude that the emodin inhibited HeLa proliferation by inducing apoptosis through the intrinsic mitochondrial and extrinsic death receptor pathways.

via Cancer Cell International

Contemporary adjuvant polymethyl methacrylate cementation optimally limits recurrence in primary giant cell tumor of bone patients compared to bone grafting: a systematic review and meta-analysis

Background: Reports of recurrence following restructuring of primary giant cell tumor (GCT) defects using polymethyl methacrylate (PMMA) bone cementation or allogeneic bone graft with and without adjuvants for intralesional curettage vary widely. Systematic review and meta-analysis were conducted to investigate efficacy of PMMA bone cementation and allogeneic bone grafting following intralesional curettage for GCT. Methods: Medline, EMBASE, Google Scholar, and Cochrane databases were searched for studies reporting GCT of bone treatment with PMMA cementation and/or bone grafting with or without adjuvant therapy following intralesional curettage of primary GCTs. Pooled risk ratios and 95% confidence intervals (CIs) for local recurrence risks were calculated by fixed-effects methods. Results: Of 1,690 relevant titles, 6 eligible studies (1,293 patients) spanning March 2008 to December 2011 were identified in published data. Treatment outcomes of PMMA-only (n = 374), bone graft-only (n = 436), PMMA with or without adjuvant (PMMA + adjuvant; n = 594), and bone graft filling with or without adjuvant (bone graft + adjuvant; n = 699) were compared. Bone graft-only patients exhibited higher recurrence rates than PMMA-treated patients (RR 2.09, 95% CI (1.64, 2.66), Overall effect: Z = 6.00; P <0.001), and bone graft + adjuvant patients exhibited higher recurrence rates than PMMA + adjuvant patients (RR 1.66, 95% CI (1.21, 2.28), Overall effect: Z = 3.15, P = 0.002). Conclusions: Local recurrence was minimal in PMMA cementation patients, suggesting that PMMA is preferable for routine clinical restructuring in eligible GCT patients. Relationships between tumor characteristics, other modern adjuvants, and recurrence require further exploration.

via World Journal of Surgical Oncology

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Background: The breast and ovarian cancer susceptibility gene (BRCA1) encodes a tumor suppressor. The BRCA1 protein is found primarily in cell nuclei and plays an important role in the DNA damage response and transcriptional regulation. Deficiencies in DNA repair capabilities have been associated with higher histopathological grade and worse prognosis in breast cancer. Methods: In order to investigate the subcellular distribution of BRCA1 in tumor tissue we randomly selected 22 breast carcinomas and tested BRCA1 protein localization in frozen and contiguous formalin-fixed, paraffin embedded (FFPE) tissue, using pressure cooker antigen-retrieval and the MS110 antibody staining. To assess the impact of BRCA1 germline mutations on protein localization, we retrospectively tested 16 of the tumor specimens to determine whether they contained the common Ashkenazi Jewish founder mutations in BRCA1 (185delAG, 5382insC), and BRCA2 (6174delT). We also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC). Results: In FFPE tissue, with MS110 antibody staining, we frequently found reduced BRCA1 nuclear staining in breast tumor tissue compared to normal tissue, and less BRCA1 staining with higher histological grade in the tumors. However, in the frozen sections, BRCA1 antibody staining showed punctate, intra-nuclear granules in varying numbers of tumor, lactating, and normal cells. Two mutation carriers were identified and were confirmed by gene sequencing. We have also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC) and found altered sub-nuclear and nucleolar localization patterns consistent with a functional impact of the mutation on protein localization. Conclusions: The data presented here support a role for BRCA1 in the pathogenesis of sporadic and inherited breast cancers. The use of well-characterized reagents may lead to further insights into the function of BRCA1 and possibly the further development of targeted therapeutics.

via Cancer Cell International

Sleep disturbance persists in women with ovarian cancer

Sleep disturbance appears to be common in women with ovarian cancer and persists for up to 1 year after diagnosis, study findings show.

via Med Wire News

Adenocarcinomas of the esophagogastric junction: experiences at a single institution in China

Background: The incidence of adenocarcinoma of the esophagogastric junction is increasing. This study aims to evaluate the clinicopathological features of Chinese patients with adenocarcinoma of the esophagogastric junction and to define prognostic factors. Methods: We retrospectively reviewed a database of 382 consecutive patients with adenocarcinoma of the esophagogastric junction at the First Affiliated Hospital of Xi'an Jiaotong University from January 2005 to March 2010. All patients were classified according to the Siewert's classification and staged according to the latest edition of the American Joint Committee on Cancer categories. Results: Six of the 382 patients had type I adenocarcinoma, 220 had type II, and 156 had type III. There was no significant difference in the overall survival of different Siewert subtypes. According to the multivariate analysis, pathological lymph node stage, age, and the existence of lymphovascular invasion were the independent factors of prognosis of adenocarcinoma of the esophagogastric junction following surgery. Conclusions: On the data, the distribution of the three types of tumor was found to be different from that reported in Western countries. Lymph node metastasis, lymphovascular invasion, and age were significant and independent factors for poor prognosis after R0 resection for adenocarcinoma of the esophagogastric junction.

via World Journal of Surgical Oncology

Inhibition of the angiogenesis and growth of Aloin in human colorectal cancer in vitro and in vivo

Background: Angiogenesis has been an attractive target for drug therapy. Aloin (AL), an natural compound derived from Aloe barbadensis Miller leaves, has been shown to possess anti-cancer potential activities. However, its roles in tumor angiogenesis and the involved molecular mechanism are unknown.MethodTo evaluate the antiangiogenic and anticancer activities of AL, endothelial cell scratch, modified Boyden chamber inserts and tube formation assays were done in HUVECs, and MTT and Live-Dead assays were used to determine the proliferation inhibition and apoptosis induction of colorectal cancer cells in vitro. The inhibition effects of AL were further confirmed by a mouse xenograft model in vivo. The expression levels of STAT3 signaling pathway and that mediated-target genes were measured in HUVECs and SW620 cells by Western blots. Results: Here, we demonstrated that AL significantly inhibited HUVECs proliferation, migration and tube formation in vitro. Western blotting showed that AL suppressed activation of VEGF receptor (VEGFR) 2 and STAT3 phosphorylation in endothelial cells. In addition, the constitutively activated STAT3 protein, and the expression of STAT3-regulated antiapoptotic (Bcl-xL), proliferative (c-Myc), and angiogenic (VEGF) proteins were also down-regulated in response to AL in human SW620 cancer cells. Consistent with the above findings, AL inhibited tumor cell viability and induced cell apoptosis in vitro, and substantially reduced tumor volumes and weight in vivo mouse xenografts, without obviously toxicity. Conclusion: Our studies provided the first evidence that AL may inhibit tumor angiogenesis and growth via blocking STAT3 activation, with the potential of a drug candidate for cancer therapy.

via Cancer Cell International

Is the use of preoperative breast MRI predictive of mastectomy?

Background: Several recent studies have described increasing rates of unilateral and bilateral mastectomy among women with newly diagnosed breast cancer. The use of breast magnetic resonance imaging (MRI) has also risen rapidly, leading to speculation that the high false-positive rate and need for multiple biopsies associated with MRI may contribute to more mastectomies. The objective of this study was to determine whether newly diagnosed patients who underwent preoperative MRI were more likely to undergo mastectomy compared with those who did not have a preoperative MRI. Methods: A retrospective review was performed of all newly diagnosed patients with breast cancer at our academic breast center from 2004 to 2009. Results: The proportion of newly diagnosed patients with breast cancer having MRI prior to surgery increased from 6% in 2004 to 73% in 2009. Of 628 patients who underwent diagnostic MRI, 369 (59%) had abnormal results, 257 (41%) had one or more biopsies, and 73 had additional sites of cancer diagnosed. Patients with a malignant biopsy, or those with an abnormal MRI who did not undergo biopsy, had an increased mastectomy rate (P<0.01). However, patients with a normal MRI or a benign biopsy actually had a decreased mastectomy rate (P<0.05). Although there was a trend toward more bilateral mastectomies, the overall mastectomy rate did not change over this time period. Conclusions: Although there is a strong relationship between the result of an MRI and the choice of surgery, the overall effect is not always to increase the mastectomy rate. Some patients who were initially considering mastectomy chose lumpectomy after an MRI.

via World Journal of Surgical Oncology

Protein biomarkers distinguish between high- and low-risk pediatric acute lymphoblastic leukemia in a tissue specific manner

The current study evaluated the differential expression detected in the proteomic profiles of low risk- and high risk- ALL pediatric patients to characterize candidate biomarkers related to diagnosis, prognosis and patient targeted therapy. Bone marrow and peripheral blood plasma and cell lysates samples were obtained from pediatric patients with low- (LR) and high-risk (HR) ALL at diagnosis. As controls, non-leukemic pediatric patients were studied. Cytogenetic analysis was carried out by G- banding and interphase fluorescent in situ hybridization. Differential proteomic analysis was performed using two-dimensional gel electrophoresis and protein identification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The differential expression of certain proteins was confirmed by Western blot analysis. The obtained data revealed that CLUS, CERU, APOE, APOA4, APOA1, GELS, S10A9, AMBP, ACTB, CATA and AFAM proteins play a significant role in leukemia prognosis, potentially serving as distinctive biomarkers for leukemia aggressiveness, or as suppressor proteins in HR-ALL cases. In addition, vitronectin and plasminogen probably contributed to leukemogenesis, whilst bicaudal D-related protein 1 could afford a significant biomarker for pediatric ALL therapeutics.

via Journal of Hematology & Oncology

Neuroendocrine small cell rectal cancer metastasizing to the liver: a unique treatment strategy, case report, and review of the literature

We describe the treatment of a 46-year-old Saudi man with advanced stage liver metastatic neuroendocrine rectal cancer. The patient presented with a large liver lesion and rectal bleeding. He was cachectic, with a firm tender mass 20 mm above the anal verge. Computed tomography (CT) showed a mass 9.5 x 13 cm in size in the right hemi-liver, abutting the middle hepatic vein. The patient refused treatment, and consulted another hospital. After 3 months, he presented with the same symptoms in addition to delirium. Colonoscopy showed an ulcerating anorectal mass, from which a biopsy was taken. Repeat CT showed an increase in the size of the liver lesion to 17 cm and no change in the pelvis. The final histopathology report identified anaplastic small cell carcinoma. The patient underwent extended right liver resection followed by abdominoperineal resection, then 13 cycles of chemotherapy and monthly somatostatin injections. At the most recent follow-up, the patient had been disease-free for 48 months. Surgical resection (R0) of the primary and secondary tumor, followed by platinum-based chemotherapy can result in good survival in cases of small cell carcinoma with large liver metastasis, irrespective of whether the primary or secondary tumor is resected first.

via World Journal of Surgical Oncology

Spinal metastasis from malignant meningeal intracranial hemangiopericytoma: one-staged percutaneous OnyxTM embolization and resection - a technical innovation

Background: We are the first to report one-staged resection of a spinal metastasis from malignant cranial hemangiopericytoma after preoperative OnyxTM-20 embolization by direct percutaneous puncture.Spinal metastases from cranial hemangiopericytoma are extremely rare. Surgical morbidity of these highly vascularized tumours results mainly from excessive blood loss. Preoperative embolization of hyper vascular tumours has been used to reduce intraoperative blood loss for a long time. To avoid complications from arterial catheter intervention, direct percutaneous puncture has been advocated as a safe and effective alternative. Methods: A 46-year-old man with a history of malignant cranial hemangiopericytoma deriving from the left frontal skull base presented with a short history of lower back pain. A magnetic resonance imaging scan revealed an intra- and extra spinal mass lesion of the thoracic spine at Th 12. Indication for tumour resection was made and the patient's written consent was obtained. Preoperatively, arterial catheter angiography was performed to reveal the tumour's angioarchitecture, revealing high-flow arteriovenous shunts. In order to impede the expected perioperative blood loss, tumour embolization by direct percutaneous puncture and application of OnyxTM-20 was performed prior to surgery. Results: After percutaneous OnyxTM-20 embolization, complete and safe resection of the lesion could be achieved. There was only minimal blood loss perioperatively. A pathohistological report confirmed malignant, anaplastic hemangiopericytoma. Conclusions: In our case OnyxTM-20 embolization via direct percutaneous puncture of a highly vascularized tumour was shown to be a safe and efficient tool prior to surgery. Despite high-flow arteriovenous shunts, direct percutaneous administration of non-adhesive ethanol liquid was an efficient alternative to transarterial catheter embolization. The perioperative blood loss could be substantially diminished.

via World Journal of Surgical Oncology

Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy

Background: To investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC). Methods: In this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation of sunitinib. The imaging protocol included an axial DWI sequence using b values of 50, 400 and 800 sec/mm2, and MRP using a series of coronal 3D-VIBE following 20 ml of Gd-DTPA at 2 ml/sec. These parameters were compared with clinical outcome and PFS at 6-months. Correlation between changes in MRI parameters and plasma biomarkers was also evaluated. Results: After 2-week of sunitinib, substantial Ktrans changes in HCC were observed from median baseline value 3.03 min-1 to 1.06 min-1 (P=0.009) with modest increases in median apparent diffusion coefficient (ADC) from 0.88x10-3 mm2/s to 0.98x10-3 mm2/s (P=0.027). Tumor size remained unchanged by RECIST and mRECIST (P=0.230, P=0.741). Patients who showed higher baseline tumor Ktrans and Kep and larger drop in Ktrans at 2 weeks correlated with favorable clinical outcome and longer PFS (all P<0.05). There was a significant association between a decrease in sVEGFR2 or TNF-alpha and the drop in Kep (P=0.031, P=0.046) and a trend for association with Ktrans. Conclusion: In HCC, MRP may be a more sensitive biomarker in predicting early response and PFS following sunitinib than RECIST and mRECIST.Trial registration: ClinicalTrials.gov: NCT00361309

via Journal of Hematology & Oncology

Signal transduction inhibitors in treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-beta, TNF-alpha and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-beta signaling has been therapeutically targeted by small molecule inhibitor of the TGF-beta receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-beta receptor kinase inhibition, members of TGF-beta super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

via Journal of Hematology & Oncology

Immunocytochemistry ‘highly accurate’ for ALK detection

Immunocytochemistry is highly accurate for detecting anaplastic lymphoma kinase rearrangements in non-small-cell lung cancers, a study by Swiss researchers has found.

via Med Wire News

PNA clamping outperforms standard EGFR mutation detection

Epidermal growth factor receptor mutations can be reliably detected in a range of lung cancer samples using peptic nucleic acid clamping, South Korean researchers report.

via Med Wire News

Vitamin supplementation unnecessary before pemetrexed

The duration of vitamin supplementation before the first dose of pemetrexed does not appear to influence the risk for treatment toxicity in lung cancer patients, a study has found.

via Med Wire News

Induction of acquired drug resistance in endothelial cells and its involvement in anticancer therapy

Background: Multidrug resistance (MDR) is one of the major problems in the treatment of cancer. Overcoming it is therefore expected to improve clinical outcomes for cancer patients. MDR is usually characterized by overexpression of ABC (ATP-binding cassette) protein transporters such as P-gp, MRP1, and ABCG2. Though the importance of ABC transporters for cancer cells is recognized, few studies have looked at its implications for the endothelial cells that are essential to tumor angiogenesis. This study investigated the expression and functions of these ABC transporters in endothelial cells in vitro and their potential contribution to cancer growth in mice. Methods: Human micro vessel endothelial cells (HMEC-1) and human umbilical vein endothelial cells (HUVEC) were exposed to increasing doses of Doxorubicin (Dox) to induce ABC gene expression. Cell viability was then quantified by 3H-thymidine and MTS assay. Flow cytometry, qPCR, and western blot were used to detect mRNA and the protein expression of P-gp, MRP1, and ABCG2. The intracellular accumulation of Rhodamine 123 (Rho) was used to evaluate drug efflux function and the inhibitors for P-gp, ABCG2, and MRP1 were used to verify their respective roles in vitro. In an attempt to evaluate drug resistance in endothelial cells in vivo, athymic mice were treated with Dox for 15 days before a MDA-MB-435 tumor graft to observe subsequent changes in the inhibition curves of tumor growth in response to Dox treatment. Furthermore, endothelial cells from multiple sites in these mice were also isolated to estimate their P-gp expression by flow cytometry. Results: Drug resistance in HMEC-1 and HUVEC was successfully induced by the addition of Dox to the culture media. Two stabilized subcell lines of HMEC1 (HMECd1 and HMECd2) showed 15- and 24-fold increases in resistance. Tests also showed that these induced endothelial cells were cross-resistant to the structurally unrelated drugs Daunorubicin, Vinblastine, and Etoposide. P-gp protein levels increased four and six fold in HMECd1 and HMECd2 as revealed by western blot. The qPCR demonstrated 3.4- and 7.2-fold increases in P-gp, and a slight increase in ABCG2, gene expression. The Rho accumulation within these cells was inversely correlated with the expression levels of P-gp. The inhibitors of P-gp, but not of ABCG2 or MRP1, were able to block the induced endothelial cell resistance to Dox. Furthermore, we also showed that injecting Dox into healthy mice induced an increase in P-gp expression in endothelial cells. Using these pretreated mice in a tumor growth experiment, we observed a dramatic diminution in the therapeutic efficiency of Dox treatment, suggesting implications for drug resistance in mice endothelial cells supporting tumor growth. Conclusions: ABC transporter expression can be induced in endothelial cells in vitro. This study also indicates that P-gp plays an important role in the acquisition of resistance to Dox in endothelial cells and that this reduces the efficiency of chemotherapy.

via Journal of Hematology & Oncology

MiR-214 regulate gastric cancer cell proliferation, migration and invasion by targeting PTEN

Background: MicroRNAs are a class of small non-coding RNAs that play an important role in various human tumor initiation and progression by regulating gene expression negatively. The aim of this study was to investigate the effect of miR-214 on cell proliferation, migration and invasion, as well as the functional connection between miR-214 and PTEN in gastric cancer. Methods: miR-214 and PTEN expression was determined in gastric cancer and matched normal tissues, and human gastric cancer cell lines by quantitative real-time PCR. The roles of miR-214 in cell proliferation, migration and invasion were analyzed with anti-miR-214 transfected cells. In addition, the regulation of PTEN by miR-214 was evaluated by Western blotting and luciferase reporter assays. Results: miR-214 was noted to be highly overexpressed in gastric cancer tissues and cell lines using qRT-PCR. The expression level of miR-214 is significantly associated with clinical progression and poor prognosis according to the analysis of the clinicopathologic data. We also found that the miR-214 levels are inversely correlated with PTEN in tumor tissues. And PTEN expression level is also associated with metastasis and invasion of gastric cancer. In addition, knockdown of miR-214 could significantly inhibit proliferation, migration and invasion of gastric cancer cells. Moreover, we demonstrate that PTEN is regulated negatively by miR-214 through a miR-214 binding site within the 3'-UTR of PTEN at the posttranscriptional level in gastric cancer cells. Conclusions: These findings indicated that miR-214 regulated the proliferation, migration and invasion by targeting PTEN post-transcriptionally in gastric cancer. It may be a novel potential therapeutic agent for gastric cancer.

via Cancer Cell International

A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors

Purpose: Ridaforolimus (AP23573, MK-8669 or deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an important regulator in the cell survival pathway. This open-label, single center phase I study aimed to investigate the pharmacokinetic (PK) and safety profiles of ridaforolimus in Chinese patients with treatment-refractory advanced or relapsed solid tumors. The PK data generated from these Chinese patients were further compared with those previously reported in Caucasian and Japanese patient populations.Experimental design: The patients were given an oral dose of 40 mg of ridaforolimus on Day 1 of the study. On Day 8, patients were initiated on a treatment regimen that comprised a once daily dose of 40 mg of ridaforolimus for five consecutive days, followed by a 2-day off-drug interval. Patients repeated this regimen until disease progression or intolerance. Blood samples were collected at specific times pre- and post-treatment to establish the PK profile of ridaforolimus in all patients. Results: Fifteen patients were given at least one dose of 40 mg of ridaforolimus. The median absorption lag-time was 2 hours, the median Tmax was 4 hours and the mean elimination half-life was 53 hours. The accumulation ratio for AUC0-24hr was 1.3 on day 19 (steady state)/day 1 (after a single dose). The most common drug-related adverse events (AEs) that occurred in >=40% of patients were stomatitis, proteinuria, leukopenia, hyperglycemia, and pyrexia. Grade 3/4 drug-related AEs were anemia, stomatitis, fatigue, thrombocytopenia, constipation, gamma glutamyltransferase increase, and proteinuria. All 11 evaluable patients achieved stable disease. Conclusions: Oral ridaforolimus at a daily dose of 40 mg were generally well tolerated in Chinese patients with advanced or refractory solid tumors. Adverse events and PK profiles of ridaforolimus in this study were similar to those from Caucasian and Japanese patients reported previously.

via Journal of Hematology & Oncology

Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges

Recent years have witnessed much progress in both basic research and clinical trials regarding cancer immunotherapy with chimeric antigen receptor (CAR)-engineered T cells. The unique structure of CAR endows T cell tumor specific cytotoxicity and resistance to immunosuppressive microenvironment in cancers, which helps patients to better tackle the issue of immunological tolerance. Adoptive immunotherapy (AIT) using this supernatural T cell have gained momentum after decades of intense debates because of the promising results obtained from preclinical models and clinical trials. However, it is very important for us to evaluate thoroughly the challenges/obstacles before widespread clinical application, which clearly warrants more studies to improve our understanding of the mechanism underlying AIT. In this review, we focus on the critical issues related to the clinical outcomes of CAR-based adoptive immunotherapy and discuss the rationales to refine this new cancer therapeutic modality.

via Journal of Hematology & Oncology

A phase II study of sorafenib (BAY 43--9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404)

Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43--9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1--12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 -- 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 -- 5 months). Median overall survival (OS) was 9 months (90% CI, 5 -- 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL.

via Journal of Hematology & Oncology

Sister Mary Joseph's nodule at a University teaching hospital in northwestern Tanzania: a retrospective review of 34 cases

Background: Sister Mary Joseph's nodule is a metastatic tumor deposit in the umbilicus and often represents advanced intra-abdominal malignancy with dismal prognosis. There is a paucity of published data on this subject in our setting. This study was conducted to describe the clinicopathological presentation and treatment outcome of this condition in our environment and highlight challenges associated with the care of these patients, and to proffer solutions for improved outcome. Methods: This was a retrospective study of histologically confirmed cases of Sister Mary Joseph's nodule seen at Bugando Medical Centre between March 2003 and February 2013. Data collected were analyzed using descriptive statistics. Results: A total of 34 patients were enrolled in the study. Males outnumbered females by a ratio of 1.4:1. The vast majority of patients (70.6%) presented with large umbilical nodule > 2 cm in size. The stomach (41.1%) was the most common location of the primary tumor. Adenocarcinoma (88.2%) was the most frequent histopathological type. Most of the primary tumors (52.9%) were poorly differentiated. As the disease was advanced and metastatic in all patients, only palliative therapy was offered. Out of 34 patients, 11 patients died in the hospital giving a mortality rate of 32.4%. Patients were followed up for 24 months. At the end of the follow-up period, 14(60.9%) patients were lost to follow-up and the remaining 9 (39.1%) patients died. Patients survived for a median period of 28 weeks (range, 2 to 64 weeks). The nodule recurred in 6 (26.1%) patients after complete excision. Conclusion: Sister Mary Joseph's nodule of the umbilicus is not rare in our environment and often represents manifestation of a variety of advanced intra-abdominal malignancies. The majority of the patients present at a late stage and many with distant metastases. The patient's survival is very short leading to a poor outcome. Early detection of primary cancer at an early stage may improve the prognosis.

via World Journal of Surgical Oncology

Clinicopathological significance of claudin-4 in gastric carcinoma

Background: Aberrant expression of claudin proteins has been reported in a variety of cancers. Previous studies have demonstrated that overexpression of claudin may promote tumorigenesis and metastasis through increased invasion and survival of tumor cells. However, the prognostic significance of claudin-4 in gastric cancer remains unclear. Methods: Immunohistochemistry was used to analyze the expression of claudin-4 in 329 clinical gastric cancer specimens and 44 normal stomach samples, 21 intestinal metaplasia samples, and 21 adjacent precursor lesions dysplasia samples. Statistical analysis methods were used to evaluate the relationship between claudin-4 expression and various clinicopathological parameters. Univariate and multivariate analyses were performed, respectively, to detect the independent predictors of survival. Results: Claudin-4 expression was present in only 7(15.9%) normal gastric samples, but expression of claudin-4 in the intestinal metaplasia lesions and dysplasia lesions was 90.5% and 95.2%, respectively. The expression of claudin-4 was significantly associated with histological differentiation (P<0.001) and tumor growth patterns (P<0.001) but not associated with patient survival. However, intermediate type staining of claudin-4 exhibited a trend of correlation with patients' survival (P=0.023). The five-year survival rate with low expression of claudin-4 in intermediate type (76.4%) was similar to expanding type (64.5%), while the high expression group (46.6%) was closer to infiltrative type (50.7%). Conclusions: The findings in this study demonstrate claudin-4 aberrant expression in gastric cancer and precursor lesions. The expression of claudin-4 could serve as a basis for identifying gastric cancer of the intermediate type.

via World Journal of Surgical Oncology

Correction: Clusterin confers gemcitabine resistance in pancreatic cancer

After the publication of this work [1], we noticed that we had incorrectly used the term 'OGX-011'. All instances of OGX-011 in the manuscript should be changed to 'ASO-CLU'.We apologise to the readers and OncoGenex Technologies for this oversight and any negative effects that may have resulted from it.

via World Journal of Surgical Oncology

Ubiquitin enzymes show lung cancer treatment promise

Deubiquitinating enzymes offer a novel target for the treatment of lung cancer through the receptor tyrosine kinase signaling pathway, scientists say.

via Med Wire News

Surrogate markers aid lung cancer trials

Research suggests that surrogate markers for overall survival are acceptable endpoints for clinical trials of chemotherapy and radiotherapy in patients with lung cancer.

via Med Wire News

Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells

Background: In order to search for new structural modification strategies on fluoroquinolones, we have designed and synthesized a series of fluoroquinolone derivatives by linking various hydrazine compounds to the C-3 carboxyl group of levofloxacin and assessed their anticancer activities. Several novel levofloxacin derivatives displayed potent cytotoxicity against the tested cancer cell lines in vitro. In the present study, we investigated the effect of 1-Cyclopropyl-6-fluoro-4-oxo-7- piperazin-1, 4-dihydro- quinoline- 3-carboxylic acid benzo [1,3] dioxol-5- ylmethylene- hydrazide (QNT11) on the apoptosis of human hepatocarcinoma cells in vitro. Methods: The inhibition effects of QNT11 on cell proliferation were examined by MTT assay. Cell apoptosis was determined by TUNEL and DNA agarose gel electrophoresis method. The topoisomerase IotaIota activity was measured by agarose gel electrophoresis using Plasmid pBR322 DNA as the substrate. Cell cycle progression was analyzed using flow cytometry in conjunction with ethanol fixation and propidium iodide staining. Mitochondrial membrane potential ([white up-pointing triangle]psim) was measured by high content screening image system. The caspase-9, caspase-8, caspase-3, Bcl-2, Bax, CDK1, Cyclin B1and cytochrome c protein expressions were detected by Western blot analysis. Results: QNT11 showed selective cytotoxicity against Hep3B, SMMC-7721, MCF-7 and HCT-8 cell lines with IC50 values of 2.21 muM, 2.38 muM, 3.17 muM and 2.79 muM, respectively. In contrast, QNT11 had weak cytotoxicity against mouse bone marrow mesenchymal stem cells (BMSCs) with IC50 value of 7.46 muM. Treatment of Hep3B cells with different concentrations of QNT11 increased the percentage of the apoptosis cells significantly, and agarose gel electrophoresis revealed the ladder DNA bands typical of apoptotic cells, with a decrease in the mitochondrial membrane potential. Compared to the control group, QNT11 could influence the DNA topoisomerase IIactivity and inhibit the religation of DNA strands, thus keeping the DNA in fragments. There was a significant increase of cytochrome c in the cytosol after 24 h of treatment with QNT11 and a decrease in the mitochondrial compartment. Observed changes in cell cycle distribution by QNT11 treated might be caused by insufficient preparation for G2/M transition. In addition, QNT11 increased the protein expression of Bax, caspase-9, caspase-8, caspase-3, as well as the cleaved activated forms of caspase-9, caspase-8 and caspase-3 significantly, whereas the expression of Bcl-2 decreased. Conclusions: Our results showed that QNT11 as a fluoroquinolone derivative exerted potent and selectively anticancer activity through the mechanism of eukaryotic topoisomerase II poisoning. The growth inhibition was in large part mediated via apoptosis-associated mitochondrial dysfunction and regulation of Bcl-2 signaling pathways.

via Cancer Cell International

Pre-op chemo timing no advantage in resectable NSCLC

The timing of chemotherapy in relation to surgery does not appear to influence survival in patients with early-stage non-small-cell lung cancer, a randomized trial has found.

via Med Wire News

Gene mutation clustering limited in NSCLC

Gene mutations in patients with non-small-cell lung cancer show some clustering by ethnicity and histology but are not exclusive to patient subgroups, indicates research by an international team.

via Med Wire News

Early stage follicular lymphoma: what is the clinical impact of the first-line treatment strategy?

Background: Less than 20% of patients with follicular lymphoma (FL) present with Ann Arbor Stage I or II disease at diagnosis. Numerous therapeutic options exist, however radiation therapy is considered the standard of care for early-stage disease based on single-institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the rituximab era.Patients and Methods: We analyzed the characteristics and outcomes of 145 early-stage FL patients, who were retrospectively divided into six groups according to their initial treatment: watchful waiting (WW), chemotherapy alone (CT), radiotherapy alone (RT), combined radiotherapy and chemotherapy (RT-CT), rituximab alone (Ri), and immunochemotherapy (Ri-CT). Results: Of the 145 patients, 84 (57.9%) had stage I disease and 61 (42.1%) stage II. The complete response (CR) rate varied from 57% for the Ri group to 95% for the RT-CT group. Overall survival (OS) at 7.5y of patients treated after 2000 was better than that of those treated prior to 2000. OS did not significantly differ from one treatment to another. In contrast, a significant difference was found for progression-free survival (PFS) at 7.5y, which favored Ri-CT (60%) therapy versus the others (p=0.00135). Conclusion: Delayed therapy initiation was associated with a similar OS than that observed in patients receiving immediate intervention. The "watchful waiting" strategy may thus be proposed as first-line therapy, similar to stage III and IV FL patients with a low tumor burden. However, when treatment is required, immunochemotherapy appears to be the best option.

via Journal of Hematology & Oncology

A prospective phase II study of L-asparaginase- CHOP plus radiation in newly diagnosed extranodal NK/T-cell lymphoma, nasal type

PurposeTo explore the efficacy and safety of L-asparaginase in newly-diagnosed extranodal nature killer (NK)/T --cell lymphoma (ENKTL), we conducted a prospective phase II study of L-asparaginase, cyclophosphamide, vincristine, doxorubicin and dexamethasone (CHOP-L) regimen in combination with radiotherapy.Patients and methodsPatients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included 6--8 cycles of CHOP-L (cyclophosphamide, 750 mg/m2 day 1; vincristine, 1.4 mg/m2 day 1 (maximal dose 2 mg), doxorubicin 50 mg/m2 day 1; dexamethasone 10 mg days 1--8; L-asparaginase 6000 u/m2 days 2--8). Radiotherapy was scheduled after 4--6 cycles of CHOP-L regimen, depending on stage and primary anatomic site. The primary endpoint was complete response (CR) rate. Results: A total of 38 eligible patients were enrolled. The median age was 40.5 years (range, 15 to 71 years). Their clinical characteristics were male to female ratio, 24:14; Ann Arbor stage I, 20; II, 11; III, 3; IV, 4. CR and overall response rates were 81.6% (95% CI, 69.3% to 93.9%) and 84.2%, respectively. With a median follow-up of 25 months, the 2-year overall survival, progression-free survival and disease-free survival rates were 80.1% (95%CI, 73.3% to 86.9%), 81% (95%CI, 74.5% to 87.5%) and 93.6% (95%CI, 89.3% to 97.9%), respectively. The major adverse events were myelosuppression, liver dysfunction, and digestive tract toxicities. Grade 3 to 4 leukopenia and neutropenia were 76.3% and 84.2%, respectively. No treatment-related death was observed. Conclusion: CHOP-L chemotherapy in combination with radiotherapy is a safe and highly effective treatment for newly diagnosed ENKTL.

via Journal of Hematology & Oncology