Sergio Parco, Fulvia VascottoInstitute for Maternal and Child Health – IRCCS Burlo Garofolo, Trieste, ItalyBackground: The immature (or reticulated) platelet fraction (IPF) is rich in nucleic acids, especially RNA, and can be used as a predictive factor for platelet recovery in platelet immunomediated consumption or in postchemotherapy myelosuppression. Our aim was to determine if transfusions with IPF-rich solutions, during autologous peripheral blood stem cell transplantation, reduce the occurrence of bleeding and hemorrhagic complications.Patients and methods: Transfusions were administered to 40 children, affected with hematological pathologies, who underwent autologous peripheral hematopoietic progenitor cell transplantation. There were two groups of 20 patients, one group treated with IPF-poor and the other with IPF-rich solutions. In the two groups, the conditioning regimen was the same for the same pathology (hematological pathologies: 14 acute lymphoblastic leukemia; twelve acute myelocytic leukemia; four non-Hodgkin's lymphoma; two Hodgkin's lymphoma; eight solid tumors). A new automated analyzer was used to quantify the IPF: the XE2100 (Sysmex, Kobe, Japan) blood cell counter with upgraded software.Results: The 20 patients who received solutions with a high percentage of IPF (3%–9% of total number of infused platelets) required fewer transfusions than the 20 patients who received transfusions with a low percentage of IPF (0%–1% of total number of infused platelets): 83 versus 129 (mean of number of transfusions 4.15 versus 6.45) and a significant difference was found between the two groups by using the Mann–Whitney test (P < 0.001). The prophylactic transfusions decreased from three to two per week. There was only one case of massive hemorrhage.Conclusion: The use of IPF solutions reduces the number of transfusions and bleedings after peripheral blood stem cell transplantation in pediatric patients.Keywords: children, reticulated platelet fraction, transfusion management, hemorrhage

Weili Sun1, Shakeel Modak21Department of Pediatrics, Keck School of Medicine, University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 2Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: Achieving a cure for high-risk neuroblastoma, the most common extracranial solid tumor in children, remains a formidable task despite the recent addition of antibody-mediated anti-GD2 immunotherapy to established multimodality therapy. The PI3K/Akt pathway is a pivotal signaling pathway utilized by a plethora of receptor tyrosine kinases that contribute to the aggressive phenotype of high-risk neuroblastoma. Akt is aberrantly activated in high-risk neuroblastoma and is therefore an attractive therapeutic target. Perifosine is the best-characterized Akt inhibitor in preclinical studies and in clinical trials in adults, although safety in children is not yet confirmed. It is a synthetic third-generation alkylphospholipid with good oral bioavailability and modest side effects. Perifosine targets the lipid-binding PH domain of Akt and inhibits the translocation of Akt to the cell membrane, an essential step for Akt activation. It decreases Akt phosphorylation and increases caspase-dependent apoptosis in neuroblastoma cell lines, inhibits growth of neuroblastoma xenografts, and overcomes RTK/ligand-mediated chemoresistance. It is currently being studied in two Phase I clinical trials in children with recurrent or refractory solid tumors including neuroblastoma. In the single agent trial (ClinicalTrials.gov identifier NCT00776867), maximum tolerated dose has not yet been reached and pharmacokinetic data has been accrued. In the second study (ClinicalTrials.gov identifier NCT01049841), patients are treated with a combination of perifosine and the mTOR-inhibitor temsirolimus based on preclinical data showing synergy of the two agents, and the premise that direct Akt inhibition may overcome Akt activation secondary to mTOR inhibition. Based on results from adult trials, it is unlikely that perifosine alone will produce dramatic therapeutic effects against high-risk neuroblastoma. However, given the recent encouraging early-phase combination therapy results in adults with multiple myeloma and colorectal carcinoma, rational perifosine-containing combination regimens hold promise for neuroblastoma therapy. These will be explored after safety in children is established in Phase I studies.Keywords: neuroblastoma, Akt pathway, perifosine

Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms.Keywords: hedgehog pathway, Smoothened inhibitors, cancer stem cells

Akinori SatoDepartment of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, JapanAbstract: Histone acetylation and deacetylation play important roles in the regulation of gene transcription and in the modulation of chromatin structure. The levels of histone acetylation are determined by the activities of histone acetyltransferases and histone deacetylases (HDACs). HDACs are associated with a number of oncogenes and tumor suppressor genes and can be aberrantly expressed and/or inappropriately activated in cancer cells. HDAC inhibitors have therefore recently emerged as a novel treatment modality against malignancies. They regulate gene expression by enhancing the acetylation of not only histones but also nonhistone proteins, including transcription factors, transcription regulators, signal transduction mediators, and DNA repair enzymes, and they inhibit cancer growth. Vorinostat (suberoylanilide hydroxamic acid) is one of the most potent HDAC inhibitors, and was approved in Japan in 2011 for the treatment of cutaneous T-cell lymphoma. Numerous clinical trials have shown it to be effective against cutaneous T-cell lymphoma but less so against other types of cancer. Because vorinostat can overcome resistance to or enhance the efficacy of other anticancer agents, such as 5-fluorouracil, carboplatin, paclitaxel, bortezomib, and tamoxifen, combination therapies using vorinostat and these agents have been investigated. This review introduces the background and mechanism of action of vorinostat and describes the results of clinical trials using vorinostat, both as a single agent and in combination with other anticancer agents, against cutaneous T-cell lymphoma and other malignancies.Keywords: vorinostat, T-cell lymphoma, cancer, novel treatment

Xing-You Jia1, Qi Yu2, Zhe-Hui Zhang3, Xiao-Feng Yang11School of the First Clinical Hospital, Shanxi Medical University, Taiyuan, Shanxi, China; 2Department of Information Management, Shanxi Medical University, Taiyuan, Shanxi, China; 3Research Center for Philosophy of Science and Technology, Shanxi University, Taiyuan, Shanxi, ChinaObjective: To study the practicality of the FITC-CSNRDARRC peptide ligand (containing the Cys–Ser–Asn–Arg–Asp–Ala–Arg–Arg–Cys nonapeptide) in diagnosing and monitoring bladder tumors.Materials and methods: Between March 2011 and September 2011, 80 consecutive patients with radiographic abnormalities, localizing hematuria, other symptoms, or signs were studied using the FITC-CSNRDARRC ligand, urinary cytology (UC), and fluorescence in situ hybridization (FISH). The sensitivity and specificity of these three technologies were determined and compared. Cystoscopy and tissue biopsy were taken as the “gold standards” for bladder tumor diagnosis in this study.Results: Twenty-nine out of 80 patients were diagnosed with a bladder tumor via histopathological examination. The FITC-CSNRDARRC ligand was positive in 23 out of 29 bladder tumor patients and produced false negatives in six (20.69%) patients. The UC was positive in six out of 29 bladder tumor patients and produced false negatives in 23 (79.31%) patients. The FISH was positive in 21 out of 29 bladder tumor patients and produced false negatives in eight (27.59%) patients. The overall sensitivity as verified by the FITC-CSNRDARRC ligand was much higher than in UC (79.31% versus 20.69%, P < 0.001) and was slightly higher than in FISH (79.31% versus 72.41%, P = 0.625). The sensitivity of FISH was significantly higher than that of UC (72.41% versus 20.69%, P < 0.001). Sensitivities of the FITC-CSNRDARRC ligand and UC by grade were 58.33% versus 8.3% for low-grade (LG) tumors (P = 0.031) and 94.12% versus 29.41% for high-grade (HG) tumors (P = 0.003), respectively. The advantage was maintained in terms of the detection of invasive tumors between the FITC-CSNRDARRC ligand and UC (90.48% versus 23.81%, P = 0.001) as well as between FISH and UC (85.71% versus 23.81%, P = 0.003). The specificities for the FITC-CSNRDARRC ligand, UC, and FISH were 100%.Conclusion: Results show that the FITC-CSNRDARRC ligand is a promising noninvasive tool for diagnosis and surveillance in patients suspected of having a new bladder tumor.Keywords: bladder tumor, tumor-targeting, FITC-CSNRDARRC ligand, fluorescent probe

Jiasheng Zheng,1,* Bin Sun,1,* Daojie Liu,2 Li Yan,2 Yanjun Wang2 1Intervention Therapy Center of Liver Diseases, 2Beijing Institute of Liver Diseases, Beijing You An Hospital, Capital Medical University, Beijing, China,*These authors contributed equally to this workBackground: The purpose of this study was to investigate the impact of treatment with transcatheter arterial chemoembolization on the expression of chemokine receptors on memory T cells around tumor sites in vivo in patients with hepatocellular carcinoma.Methods: Blood samples from the hepatic artery and a peripheral vein were collected from 100 patients with hepatocellular carcinoma before and 4 weeks after treatment with transcatheter arterial chemoembolization. Mononuclear cells were isolated and examined for the expression of L-selectin (CD62L) and CXCR3 (CD183) on CD8+ T cells in patients with hepatocellular carcinoma during transcatheter arterial chemoembolization.Results: Both the frequency and number of L-selectinlow CXCR3+ proinflammatory effector T cells in patients with hepatocellular carcinoma increased significantly following treatment versus pretreatment (61.92% ± 8.69% versus 24.45% ± 7.36%, P < 0.05, and 18.98 ± 2.33 e7/L versus 6.10 ± 1.21 e7/L, P < 0.001, respectively). There was no significant difference in its frequency whether in the hepatic artery or peripheral vein. Furthermore, the frequency of CD69+ T cells in patients with hepatocellular carcinoma increased from 2.53% ± 0.51% in the artery and 2.38% ± 0.49% in the vein to 3.80% ± 0.62% and 4.48% ± 0.75%, respectively, after treatment (both P < 0.05).Conclusion: Treatment with transcatheter arterial chemoembolization may lead to an increase in L-selectinlow CXCR3+ effector T cells in patients with hepatocellular carcinoma.Keywords: hepatocellular carcinoma, transcatheter arterial chemoembolization, T cells, L-selectin, CXCR3

Adetola L Shodeinde,1 Beverly E Barton21Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA; 2Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USAAbstract: In 2012, prostate cancer will once again be the second-leading cause of cancer death of American males. Although initially treatable, prostate cancer can recur in a hormone refractory form that is not responsive to current available therapies. The mortality rate associated with hormone refractory prostate cancer is high, and there is an urgent need for new therapeutic agents to treat prostate cancer. A common feature of prostate cancer is the dependence on activated signal transducer and activator of transcription 3 (STAT3), a transcription factor, for survival. More important, inhibition of STAT3 has been shown to induce apoptosis in prostate cancer cells. In recent years, inhibitors of STAT3 have emerged as promising molecular candidates for targeted prostate cancer therapy. The aim of this review is to examine the role of STAT3 in prostate cancer and how inhibitors of STAT3 could advance the quest for treatment of the disease. Janus kinase 2 (JAK2)-targeted therapy appears very promising in the treatment of prostate cancer. It has been shown to decrease symptoms associated with myeloproliferative disorders and increase overall survival of patients compared with the best available therapy. In addition to improved outcome, many JAK2 inhibitors have been found to be tolerable with no adverse impact on quality of life. As such, JAK2 inhibitors may play an important role in the management of patients with prostate cancer. Current studies are evaluating the role of JAK2 inhibitors in solid tumors. Pending clinical trial results will determine the future direction of JAK2 inhibitors in the treatment of patients with prostate cancer.Keywords: JAK2 inhibitors, transcription factors, therapy development, targeted cancer therapy 

Jyotsna FuloriaOchsner Medical Center, New Orleans, LA, USAAbstract: The biological agents approved for the treatment of patients with metastatic colorectal cancer – bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor A, along with cetuximab and panitumumab, two monoclonal antibodies that target the epidermal growth factor receptor – are associated with a number of adverse events that range in severity from relatively mild to potentially life threatening. Hypertension, thromboembolic events, proteinuria, bleeding, and gastrointestinal perforation have all been associated with bevacizumab, while dermatologic toxicities are common with cetuximab and panitumumab. Hypersensitivity reactions and hypomagnesemia are also a concern with cetuximab and panitumumab. The frequency of these adverse events in randomized clinical trials is reviewed, and recommendations for managing these events in patients undergoing treatment for metastatic colorectal cancer are provided.Keywords: adverse events, antiangiogenic agents, bevacizumab, cetuximab, metastatic colorectal cancer, panitumumab

Vicki L KeedyVanderbilt University Medical Center, Nashville, TN, USAAbstract: Sarcomas of soft tissue and bone are a rare group of cancers hallmarked by relative insensitivity to cytotoxic chemotherapy. The development of targeted therapies in the treatment of sarcoma has been difficult due to the significant heterogeneity and rarity of these diseases. Inhibition of the mammalian target of rapamycin (mTOR) has emerged as an exciting treatment approach and is being studied extensively in sarcoma patients. Ridaforolimus is a second generation mTOR inhibitor that has shown potential benefit in the treatment of sarcoma. Recently a Phase III study demonstrated an improvement in progression-free survival when patients with at least stable disease after treatment with standard chemotherapy received maintenance ridaforolimus compared to placebo. The results of this study show that mTOR is an important pathway in soft tissue and bone sarcomas and represents an exciting opportunity for the improvement in the treatment of our patients.Keywords: sarcoma, mTOR, ridaforolimus

Qi Wan,1 Ai Zheng,1 Xiaojing Liu,2 Yali Chen,1 Ling Han11Department of Obstetric and Gynecology, West China Second University Hospital, 2Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, ChinaBackground: Recent studies have reported that aberrant expression of transient receptor potential channel C6 (TRPC6) in a variety of human cancers is associated with aggressive behavior. However, the functional significance of TRPC6 in human cervical cancer is not known. This study was planned to detect whether TRPC6 is expressed in cervical cancer tissue and to evaluate the association between TPRC6 expression and clinicopathologic features.Methods: Tissue samples were collected from the West China Second UNIV Hospital of Sichuan University. TRPC6 expression was detected by quantitative real-time reverse transcription polymerase chain reaction and Western blotting. TRPC6 expression was evaluated by immunohistochemistry analysis of 40 cervical cancer specimens, and correlations were sought between elevated expression of TRPC6 and clinicopathologic features.Results: Increased expression of TRPC6 was detected in 25 of the 40 cervical cancer samples. Positive cells found in cervical carcinomas were significantly increased in numbers compared with specimens without lymphovascular space invasion. Elevated expression of TRPC6 was neither related to International Federation of Gynecology and Obstetrics stage nor pelvic lymph metastases. Indeed, the clinicopathologic analysis indicated that overexpression of TRPC6 was significantly associated with lymphovascular space invasion.Conclusion: These results indicate that elevated expression of TRPC6 might be associated with an aggressive cervical cancer phenotype.Keywords: cervical cancer, transient receptor potential channel C6, overexpression, invasion

Daigo Yamamoto,1,3 Satoru Iwase,2 Yu Tsubota,1 Noriko Sueoka,1 Chizuko Yamamoto,3 Kaoru Kitamura,4 Hiroki Odagiri,5 Yoshinori Nagumo61Department of Surgery, Kansai Medical University, Hirakata, Osaka, 2Department of Palliative Medicine, University of Tokyo Hospital, Tokyo, 3Department of Internal Medicine, Seiko Hospital, Neyagawa, Osaka, 4Breast Unit, Nagumo Clinic, Fukuoka, 5Department of Surgery, Hirosaki National Hospital, Hirosaki, 6Breast Unit, Nagumo Clinic, Tokyo, JapanBackground: Brain metastases from breast cancer occur in 20%–40% of patients, and the frequency has increased over time. New radiosensitizers and cytotoxic or cytostatic agents, and innovative techniques of drug delivery are still under investigation.Methods: Five patients with brain metastases who did not respond to whole-brain radiotherapy and then received bevacizumab combined with paclitaxel were identified using our database of records between 2011 and 2012. The clinicopathological data and outcomes for these patients were then reviewed.Results: The median time to disease progression was 86 days. Of five patients, two (40%) achieved a partial response, two had stable disease, and one had progressive disease. In addition, one patient with brain metastases had ptosis and diplopia due to metastases of the right extraocular muscles. However, not only the brain metastases, but also the ptosis and diplopia began to disappear after 1 month of treatment. The most common treatment-related adverse events (all grades) were hypertension (60%), neuropathy (40%), and proteinuria (20%). No grade 3 toxicity was seen. No intracranial hemorrhage was observed.Conclusion: We present five patients with breast cancer and brain metastases, with benefits from systemic chemotherapy when combined with bevacizumab.Keywords: brain, bevacizumab, metastatic breast cancer

Federica Zoratto,1 Luigi Rossi,1 Angelo Zullo,2 Anselmo Papa,1 Eleonora Zaccarelli,1 Luigi Tomao,3 Erika Giordani,1 Maria Colonna,4 Giovanni Baiano,5 Silverio Tomao11Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University, Oncology Unit, “SM Goretti” Hospital, Latina; 2Gastroenterology and Digestive Endoscopy Unit, “Nuovo Regina Margherita” Hospital, Rome; 3Biology Department, “Regina Elena National Cancer Institute”, Rome; 4Oncology Unit, “Don Luigi di Liegro” Hospital, Gaeta, 5Surgery Unit, “San Giovanni di Dio” Hospital, Fondi, ItalyAbstract: Colorectal cancer is one of the most common cancers worldwide. The prognosis of patients with metastatic colorectal cancer in recent years has increased from 5 months with best supportive care to nearly 2 years with chemotherapy combined with bevacizumab, an antivascular endothelial growth factor monoclonal antibody. New prognostic and predictive biomarkers have been identified to guide chemotherapy in metastatic colorectal cancer, such as KRAS and BRAF oncogenes. However, the status of these oncogenes does not affect the efficacy of bevacizumab, and biomarkers predicting response to treatment with bevacizumab are still lacking. Addition of bevacizumab to regimens based on fluoropyrimidines or irinotecan has been shown to improve overall survival in treatment-naïve patients with metastatic colorectal cancer. Similarly, a significant increase in overall survival rate is achieved by adding bevacizumab to fluoropyrimidines and oxaliplatin in patients with disease progression. Bevacizumab has been found to be effective even when used as third-line therapy and later. In addition, cohort studies have shown that bevacizumab improves survival significantly despite disease progression. Finally, bevacizumab therapy in the neoadjuvant setting for the treatment of liver metastasis is well tolerated, safe, and effective.Keywords: metastatic colorectal cancer, bevacizumab, chemotherapy, biomarkers, liver metastases

Putao Cen, Robert J AmatoDivision of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston (Medical School), Houston, TXAbstract: Pancreatic neuroendocrine tumors (PanNETs) are frequently diagnosed at unresectable stage and remain a medical challenge. Everolimus (RAD001, Afinitor®, Novartis, Basel, Switzerland), an orally administered inhibitor of mammalian target of rapamycin (mTOR), was recently approved by the Food and Drug Administration to treat patients with advanced PanNETs. This review will examine the mechanism of action of everolimus, the function of mTOR and its inhibition, PanNETs and the mTOR pathway, and clinical trials of everolimus in PanNETs. Future investigations will focus on everolimus combination therapy to treat PanNETs and the discovery of predictive biomarkers for response to everolimus.Keywords: pancreatic neuroendocrine tumor, PanNETs, everolimus, RAD001, mTOR inhibitor, biomarker

Paul Zarogoulidis,1,2 Maria Mavroudi,1 Konstantinos Porpodis,1 Kalliopi Domvri,1 Antonios Sakkas,3 Nikolaos Machairiotis,1 Aikaterini Stylianaki,1 Anastasios Tsiotsios,1 Nikolaos Courcoutsakis,4 Konstantinos Zarogoulidis11Pulmonary Department-Oncology Unit, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Pulmonary Department-Interventional Unit, Ruhrland Klinik, University of Essen, Essen, Germany; 3Department of Pathology, “G Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 4Department of Radiology, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, GreeceAbstract: Malignant pleural mesothelioma is a rare and aggressive malignancy of the pleura correlated with exposure to asbestos, with a medium survival of 11–12 months after diagnosis. A case of a 67-year-old male who had previously worked in the asbestos industry and is a current smoker is reported. The computed tomography evaluation revealed a right pleural mass with pleural thickening, and the pleural biopsy confirmed a diagnosis of malignant pleural mesothelioma. He was treated with chemotherapy consisting of etoposide, paclitaxel, and pegylated liposomal doxorubicin hydrochloride. After completion of chemotherapy, radiologic evaluation confirmed a reduction of pleural thickening and improvement in his symptoms. A complete presentation of each drug formulation and characteristics are also included in this paper. The patient’s follow-up is continuing, and computed tomography reveals stable disease 9 years after initial examination.Keywords: mesothelioma, asbestos, pegylated liposomal doxorubicin

Chen-Hsi Hsieh,1,4–6 Pei-Wei Shueng,1,3 Sheng-Mou Hsiao,2 Ming-Chow Wei,2 Wen-Yih Wu,2 Hsu-Dong Sun,2 Hui-Ju Tien,1 Li-Ying Wang,7 Yen-Ping Hsieh81Division of Radiation Oncology, Department of Radiology, 2Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei City, 3Department of Radiation Oncology, National Defense Medical Center, 4Department of Medicine, 5Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 6Oriental Institute of Technology, New Taipei City, 7School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, 8Department of Senior Citizen Service Management, National Taichung University of Science and Technology, Taichung, Taiwan, ChinaBackground: The purpose of this study was to compare the efficacy of intensity-modulated radiotherapy (IMRT) and helical tomotherapy for endometrial cancer.Methods: Between November 1, 2006 and November 31, 2010, 31 patients with histologically confirmed endometrial cancer were enrolled. All enrolled patients received total abdominal hysterectomy and bilateral salpingo-oophorectomy with adjuvant whole pelvic IMRT or helical tomotherapy.Results: The actuarial 3-year overall survival, disease-free survival, locoregional control, and distant metastasis-free rates for the IMRT and helical tomotherapy groups were 87.5% versus 100%, 91.7% versus 51.7%, 91.7% versus 83.3%, and 91.7% versus 51.7%, respectively. The conformal index and uniformity index for IMRT versus helical tomotherapy was 1.25 versus 1.17 (P = 0.04) and 1.08 versus 1.05 (P < 0.01), respectively. Two of 31 patients with cervical stump failure were noted, one in the IMRT group and the other in the helical tomotherapy group. No acute or late grade 3 or 4 toxicities were noted, including proctitis, or genitourinary or gastrointestinal disturbances.Conclusion: Helical tomotherapy is as effective as IMRT and has better uniformity and conformal indices, and critical organ-sparing properties. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT versus helical tomotherapy.Keywords: endometrial cancer, helical tomotherapy, intensity-modulated radiotherapy

Hong-qing Zhuang, Zhi-yong Yuan, Jun Wang, Ping Wang, Lu-jun Zhao, Bai-lin ZhangDepartment of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin, People's Republic of ChinaAbstract: The clinical success of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.Keywords: epidermal growth factor receptor, drug discontinuation, acquired drug-resistance

Yuanyue Li,1 Congjie Dai,2 Juan Li,3 Weiwei Wang,3 Gang Song31Fisheries College, Jimei University, Fujian, China; 2School of Chemical and Life Science, Quanzhou Normal University, Fujian, China; 3Cancer Research Center, Medical College of Xiamen University, Xiamen, ChinaBackground: Growing evidence supports BH3-interacting domain death agonist (Bid) playing a dual role in DNA damage response. However, the effects of Bid on hepatocellular carcinoma (HCC) cell proliferation in response to etoposide-induced DNA damage have not been sufficiently investigated.Methods: Using a stable Bid-overexpression HCC cell line, Bid/PLC/PRF/5, overexpression of Bid promoted loss of viability in response to etoposide-induced DNA damage. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]- and BrdU (5'-bromo-2'-deoxyuridine)-labeling assays revealed that etoposide-inhibited HCC cells grew in concentration- and time-dependent manners. The phosphorylations of Akt and mitogen-activated protein kinases (MAPKs) in response to etoposide-induced DNA damage were analyzed by Western blotting.Results: The survival rates of 100 µM etoposide on the cells with control vector and Bid/PLC/PRF/5 at 48 hours amounted to 71% ± 0.75% and 59% ± 0.60% with MTT assay, and similar results of 85% ± 0.08% and 63% ± 0.14% with BrdU-labeling assay respectively. Moreover, overexpression of Bid sensitized the cells to apoptosis at a high dose of etoposide (causing irreparable damage). However, it had little effect on the proliferation at a low dose of etoposide (repairable damage). Furthermore, the phosphorylation status of Akt and MAPKs were investigated. Overexpression of Bid suppressed the activation of Akt with respect to etoposide-induced DNA damage. Similar to Akt, the levels of phosphorylated p38 and phosphorylated c-Jun were attenuated by Bid-overexpression. On the contrary, the level of phosphorylated ERK1/2 was sustained at a high level, especially in Bid/PLC/PRF/5 cells.Conclusion: Taken together, these results suggest that overexpression of Bid suppressed the activation of Akt, p38, and c-Jun, and promoted the activation of ERK1/2 induced by etoposide, suggesting that the promotion of ERK1/2 activation may have a negative effect on Bid-mediated HCC DNA damage induced by etoposide.Keywords: HCC, mitogen-activated protein kinases, BH3-interacting domain death agonist

Daniel E Spratt, Nancy LeeDepartment of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: In this article, we focus on the current and emerging treatments in nasopharyngeal cancer (NPC). A detailed evolution of the current standard of care, and new techniques and treatment options will be reviewed. Intergroup 0099 established the role for chemoradiotherapy (chemo-RT) in the treatment of nasopharyngeal carcinoma. Multiple randomized Phase III trials have shown the benefit of chemo-RT; however, none of these studies utilized modern radiotherapy (RT) techniques of intensity-modulated radiation therapy (IMRT). IMRT has the ability to deliver high doses of radiation to the target structures while sparing adjacent bystander healthy tissues, and has now become the preferred RT treatment modality. Chemotherapy also has had a shifting paradigm of induction and/or adjuvant chemotherapy combined with RT alone, to the investigation with concurrent chemo-RT. New treatment options including targeted monoclonal antibodies and small molecule tyrosine kinase inhibitors are being studied in NPC. These new biologic therapies have promising in vitro activity for NPC, and emerging clinical studies are beginning to define their role. RT continues to expand its capabilities, and since IMRT and particle therapy, specifically intensity-modulated proton therapy (IMPT), has reports of impressive dosimetric efficacy in-silica. Adaptive RT is attempting to reduce toxicity while maintaining treatment efficacy, and the clinical results are still in their youth. Lastly, Epstein–Barr virus (EBV) DNA has recently been studied for prediction of tumor response and its use as a biomarker is increasingly promising to aid in early detection as well as supplementing the current staging system. RT with or without chemotherapy remains the standard of care for nasopharyngeal carcinoma. Advances in RT technique, timing of chemotherapy, biologically targeted agents, particle therapy, adaptive RT, and the incorporation of EBV DNA as a biomarker may aid in the current and future treatment of nasopharyngeal cancer.Keywords: nasopharyngeal cancer, radiation, chemotherapy, cancer

Oscar Peralta-Zaragoza,1 Víctor Hugo Bermúdez-Morales,1 Carlos Pérez-Plasencia,2,3 Jonathan Salazar-León,1 Claudia Gómez-Cerón,1 Vicente Madrid-Marina11Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Cuernavaca, Morelos, México; 2Oncogenomics Laboratory, National Cancer Institute of Mexico, Tlalpan, México; 3Biomedicine Unit, FES-Iztacala UNAM, México City, MéxicoAbstract: Cervical cancer is the second most common cause of cancer death in women worldwide and the development of new diagnosis, prognostic, and treatment strategies merits special attention. Although surgery and chemoradiotherapy can cure 80%–95% of women with early stage cancer, the recurrent and metastatic disease remains a major cause of cancer death. Many efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent decades, research on treatment strategies has proposed several options, including the role of HPV E6 and E7 oncogenes, which are retained and expressed in most cervical cancers and whose respective oncoproteins are critical to the induction and maintenance of the malignant phenotype. Other efforts have been focused on antitumor immunotherapy strategies. It is known that during the development of cervical cancer, a cascade of abnormal events is induced, including disruption of cellular cycle control, perturbation of antitumor immune response, alteration of gene expression, and deregulation of microRNA expression. Thus, in this review article we discuss potential targets for the treatment of cervical cancer associated with HPV infection, with special attention to immunotherapy approaches, clinical trials, siRNA molecules, and their implications as gene therapy strategies against cervical cancer development.Keywords: Cervical cancer, clinical trials, gene therapy, HPV E6 and E7 oncogenes, siRNAs

Qi-Long Sun, Xu-Guang Zhang, Quan-Tai Xing, Peng Ding, Jin-Bo Feng, Xiao-Peng Wu, Zhan-Min WangDepartment of General Surgery, Qilu Hospital of Shandong University, Jinan, ChinaObjective: To investigate the effects of mifepristone, a progesterone receptor (PR) antagonist, through the proliferation of human cholangiocarcinoma cell line FRH-0201 in vitro and the possible mechanisms involved.Methods: A two-step addition of poly-HRP anti-mouse immunoglobulin G detection system was used to detect the expression of PR in FRH-0201 cells. After treatments with various concentrations of mifepristone (10, 20, 40, 80, 160, and 320 µmol/L) at various time intervals (24, 48, and 72 hours), the rate of cell inhibition, the rate of cell apoptosis, and the expression of bax/bcl-2/Fas were analyzed with tetrazolium blue (MTT) assay, flow cytometry, reverse transcription polymerase chain reaction and Western blotting. The effect of mifepristone and mifepristone combined with interferon (IFN)-γ-inducing apoptosis on the cells was observed.Results: Mifepristone remarkably inhibited the proliferation of FRH-0201 cells, which was revealed by MTT assay in a dose- and time-dependent manner. The inhibitory rate gradually increased following the increase of the dosage of mifepristone from a low dosage (10 µmol/L) to a high dosage (320 µmol/L) at different time intervals. Flow cytometry analysis showed mifepristone increased the rate of the FRH-0201 cell-line apoptosis. Notably, the rate of apoptosis increased markedly when the cells were pretreated with IFN-γ and then treated with mifepristone. In addition, mifepristone obviously upregulated bax and Fas expression and downregulated bcl-2 expression.Conclusion: Mifepristone effectively inhibited the growth of PR-positive human cholangiocarcinoma cell line FRH-0201 in vitro through multiple mechanisms. Mifepristone combined with IFN-γ might therefore induce the apoptosis of the cell line, which is possibly a beneficial clinical scheme for patients suffering from cholangiocarcinoma.Keywords: cholangiocarcinoma, apoptosis, mifepristone, progesterone, IFN-γ

Jianwei Zhang,* Yan Huang,* Xiaoling Li, Ying Guo, Yuanyuan Zhao, Cong Xue, Zhihuang Hu, Li Zhang, Hongyun ZhaoState Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China*These authors contributed equally to this work and share the first authorshipPurpose: To explore whether changes in tumor size impact survival in advanced non-small-cell lung cancer (NSCLC) after target therapy, especially in patients with evaluation of stable disease (SD), and to review the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria in target therapy.Patients and methods: Data from 88 NSCLC patients receiving gefitinib (250 mg, daily [qd]), erlotinib (150 mg, qd), and ZD6474 (100 mg, qd) in three clinical trials (IRESSA registration clinical trial, TRUST study, ZD6474 study) during November 2003 to June 2005 were retrospectively analyzed. The treatment effect (complete response, partial response, stable disease [SD], or progressive disease) was evaluated with radiologic assessment according to the RECIST criteria. SD patients were divided into two groups: SD-/0, in which the sum of the longest diameter of target lesions decreased by less than 30% or did not change; and SD+, in which the sum of the longest diameter of target lesions increased by less than 20%. The differences of progression-free survival (PFS) and overall survival (OS) between these groups were analyzed.Results: In the whole group, 27 patients achieved complete response or partial response as best response, 40 achieved SD, and 22 had progressive disease. The median PFS and OS were 4 months and 11.1 months, respectively. In SD patients, 27 were SD-/0 and 13 patients were SD+. The PFS and OS of SD+ patients was shorter than that of SD-/0 patients (5.65 months vs 2.03 days, P < 0.001 and 12.2 months vs 7.1 months, P < 0.001).Conclusion: The applicability of RECIST criteria was called into question in the evaluation of target therapy. Change in tumor size might predict survival in advanced NSCLC patients with target therapy and may be a surrogate endpoint for efficacy in target therapy.Keywords: non-small-cell lung cancer, target therapy, stable disease, prognostic factor

Panagiotis Hountis,1 Periklis G Foukas,2 Dimitrios Matthaios,3 Maria Kefala,2 Leonidas Chelis,3 Aikaterini Pantelidaki,4 Ioannis G Panayiotides,2 Petros Karakitsos,5 Stylianos Kakolyris31Department of Thoracic Surgery, Athens Naval Hospital, Athens, 2Second Department of Pathology, University of Athens Medical School, “Attikon” University Hospital, Athens, 3Department of Oncology, Democritus University of Thrace, Alexandroupolis, 4Department of Pathology, Evangelismos General Hospital, Athens, 5Department of Cytopathology, University of Athens, Medical School, “Attikon” University Hospital, Athens, GreeceAbstract: S100 proteins are involved in carcinogenesis, metastasis, and survival. S100A2 is a member of the S100 family, and its expression and precise role in patients with non-small cell lung carcinoma (NSCLC) has been debated. Therefore, we examined the immunohistochemical expression patterns of S100A2 in NSCLC in relation to clinicopathological parameters, important molecular biomarkers, and patient outcome. Microarray data for 74 paraffin-embedded specimens from patients with NSCLC were immunostained for S100A2 and p53 proteins. Immunohistochemical staining patterns of S100A2 in the NSCLC tissue samples examined were either nuclear (nS100A2), cytoplasmic (cS100A2), or both. A significant association between nS100A2 positivity and better disease-free interval was observed (hazards ratio 0.47; 95% confidence interval 0.23–0.99; P = 0.047). Similarly, cS100A2 negativity was marginally associated with shorter overall survival (P = 0.07). Patients without lymphatic infiltration and an earlier disease stage had significantly better overall survival and disease-free interval. The S100A2 expression pattern in operable NSCLC varies widely, and this differential expression (nuclear, cytoplasmic or both) seems to correlate with prognosis. Intensity of expression was highest in the early and advanced stages, and equally distributed in the middle stages. This observation may be indicative of a dual role for this protein both during earlier and advanced disease stages, and may also explain the differential immunoexpression of S100A2. Analysis of the disease-free interval showed that nS100A2-negative and p53-positive expression was associated with a statistically significant (P = 0.003) shorter disease-free interval in comparison with nS100A2-positive and p53-negative expression (12 versus 30 months, respectively). Further studies are required to establish whether S100A2 protein may have a substantial role as a prognostic or predictive indicator in this unfavorable group of patients.Keywords: S100A2, expression, lung cancer, thoracic surgery

Canturk Tasci,1 Sevket Ozkaya,2 Bikemgul Ozkara,3 Ergun Tozkoparan,1 Metin Ozkan,1 Nuri Karadurmus,4 Muhittin Serdar,5 Arzu Balkan,1 Hayati Bilgic11Gulhane Medical Faculty, Department of Pulmonary Diseases, Ankara; 2Dr Suat Seren Education and Research Hospital for Chest Diseases and Thoracic Surgery, Department of Pulmonary Medicine, Izmir; 3Department of Pulmonary Diseases, Military Hospital, Diyarbakir; 4Gulhane Medical Faculty, Department of Medical Oncology, Ankara; 5Gulhane Medical Faculty, Department of Biochemistry, Ankara, TurkeyAim: Both of the diagnosis and treatment evaluation are time-consuming conditions in patients with pulmonary and pleural tuberculosis. The aim of this study was to establish the validity of tumor markers CA 125, CA 15-3, and CA 19-9 in the diagnosis of pulmonary and pleural TB and to verify the success of the treatment protocol.Patients and methods: The levels of tumor markers CA 125, CA 15-3, and CA 19-9 were measured before and after treatment in 67 TB patients, 54 of whom had pulmonary TB and 13 of whom had pleural TB. All values were compared with the results of a healthy control group of 44 subjects.Results: CA 125 and CA 15-3 levels were significantly high when compared with those of the healthy control group and there was a significant decrease in both tumor marker levels after treatment in patients with pulmonary TB (P < 0.001 and P < 0.004, respectively). However, the difference found in CA 19-9 levels before and after treatment in patients with pulmonary TB was not statistically significant (P < 0.08). When the CA 125, CA 15-3, and CA 19-9 values of the pulmonary TB group before treatment were compared with that of the healthy control group, the results were statistically significant in all parameters except CA 19-9 (P < 0.001, P < 0.001, and P < 0.09 for CA 125, CA 15-3, and CA 19-9, respectively). In the patients with pleural TB, CA 125, CA 15-3, and CA 19-9 values did not change significantly after treatment.Conclusion: The authors suggest that CA 125 and CA 15-3 tumor markers may be important for verification of the success of treatment protocol in pulmonary TB, as the differences found for these tumor markers between the pre- and the posttreatment periods are statistically significant.Keywords: TB, evaluation, treatment efficacy, tumor marker

Rui Chen, Kai Yang, Ning-Bo Zhao, Dan Zhao, Dan Chen, Chun-Rong Zhao, Hong TangDepartment of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of ChinaBackground: The PER1 circadian-clock gene plays an important role in the regulation of many normal physiological rhythms in vivo. It has been revealed recently that abnormal expression of PER1 correlates closely with the occurrence and development of many cancers. However, the expression and significance of PER1 in oral squamous cell carcinoma (OSCC) remains unknown. The purpose of the present study was to investigate the direct links between aberrant PER1 expression and clinicopathological features of OSCC.Methods: PER1 expression in cancerous and adjacent noncancerous tissues from 41 patients with OSCC was detected by immunohistochemical staining and real-time reverse transcriptase polymerase chain reaction, and correlations were sought with clinicopathological features in patients.Results: Expression of PER1 mRNA and protein in OSCC was significantly reduced compared with that in adjacent noncancerous tissue (P < 0.05). Expression of PER1 protein in oral phase III–IV SCC specimens was significantly lower than that in phase I–II specimens (P < 0.05), and stage T1–T2 patients expressed significantly higher levels of PER1 protein than T3–T4 patients (P < 0.05). Expression of PER1 in patients without lymph node metastasis was significantly higher than that in those with lymph node metastasis (P < 0.05). PER1 protein expression showed no significant correlation with patient gender and age, or with degree of tumor cell differentiation (P > 0.05).Conclusion: Changes in PER1 expression may play an important role in the development, invasion, and metastasis of OSCC, and may also provide novel ideas and methods for investigation of the occurrence, development, and targeted treatment OSCC.Keywords: oral cancer, squamous cell, circadian gene, PER1, immunohistochemistry, real-time reverse transcriptase polymerase chain reaction

Giuliana Cangemi,1 Giorgio Reggiardo,2 Sebastiano Barco,1 Laura Barbagallo,1 Massimo Conte,3 Paolo D'Angelo,4,# Maurizio Bianchi,5,# Claudio Favre,6,# Barbara Galleni,3 Giovanni Melioli,1 Riccardo Haupt,7 Alberto Garaventa,3 Maria V Corrias81Clinical Pathology Laboratory Unit, Giannina Gaslini Institute, Genoa, Italy; 2Data Management and Biostatistics Unit, Medi Service, Genoa, Italy; 3Department of Hematology-Oncology, Giannina Gaslini Institute, Genoa, Italy; 4Pediatric Oncology Unit, Azienda Civico, Di Cristina e Benfratelli, Palermo, Italy; 5Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy; 6Department of Hematology-Oncology, Pisana University Hospital, Pisa, Italy; 7Epidemiology and Biostatistics Unit, Giannina Gaslini Institute, Genoa, Italy; 8Laboratory of Oncology, Giannina Gaslini Institute, Genoa, Italy#On behalf of the Italian Association of Pediatric Hematology and Oncology (AIEOP)Abstract: Different plasma and urinary parameters have been tested as valuable prognostic markers for children with neuroblastoma (NB), but conclusive results from multivariate analyses are still lacking. Samples collected at diagnosis from 505 patients diagnosed in Italy between June 1994 and November 2010 were analyzed at the Italian reference laboratory according to standard methodologies. Patient clinical data were retrieved from the Italian NB Registry. For statistical analysis, patients were grouped according to stage, age, MYCN status, and outcome. Cumulative survival was calculated by the Kaplan–Meier procedure using the first quartile of the marker distribution as a cut-off value to stratify the patients. Multivariate analysis was performed by the Cox regression model by considering only the significant variables. When the entire cohort of patients was considered, none of the different parameters had an independent prognostic value. However, in patients with localized disease without MYCN amplification the significant positive associations between urinary and plasmatic vanillylmandelic acid (VMA)/homovanillic acid (HVA) ratio and a better prognosis remained significant (P < 0.05 and P < 0.01, respectively), as well as, the positive association between high lactate dehydrogenase (LDH) values and a worse prognosis (P < 0.001). Moreover, in stage 4 patients without MYCN amplification, neuron-specific enolase levels above 200 ng/mL and LDH levels above 2500 IU/mL maintained their significant association with a worse outcome (P = 0.01 and P = 0.0001, respectively). In conclusion, LDH had an independent prognostic value in patients of all stages without MYCN amplification. Moreover, the urinary and plasmatic VMA/HVA ratio was an independent predictor of prognosis in patients with localized disease without MYCN amplification. Since LDH and catecholamine metabolites are measured in all patients at diagnosis, these findings may be helpful for an easy, cost-effective, patient risk stratification.Keywords: neuroblastoma, markers, prognosis

Michael Karanikas,1 Nikolaos Machairiotis,2 Paul Zarogoulidis,3,4 Aikaterini Stylianaki,3 Nikolaos Corcoutsakis,5 Alexandros Mitrakas,1 Panagiotis Touzopoulos,1 Nikolaos Lyratzopoulos,1 George Kouklakis,6 Manolis Spanoudakis,7 Alexandros Polychronidis111st University Surgery Department, 2Surgery Department, University General Hospital of Alexandroupolis, Alexandroupolis, Greece; 3Pulmonary Department-Oncology Unit, G. Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 4Pulmonary Department-Interventional Unit, Ruhrland Clinic, University of Duisburg-Essen, Essen, Germany; 5Radiology Department, 6Endoscopy Unit, 7Hematology Department, University General Hospital of Alexandroupolis, Alexandroupolis, GreeceAbstract: We report the case of a 64-year-old woman with a gastrointestinal stromal tumor and a diffuse large cell lymphoma. For this case, we conducted a literature review in an attempt to correlate these two neoplasms on a molecular basis. Diffuse large cell lymphoma is a subtype of non-Hodgkin lymphomas. The etiologic factor of these lymphomas is considered to be the mutations or allelic losses of the TP53 tumor suppressor gene and the overexpression of the bcl-2 oncogene. Gastrointestinal stromal tumors are mesenchymal tumors, which are typically defined by the expression of c-KIT (CD117) and CD34 genes in the tumor cells. Although there are references to dispersants in the literature about patients with both non-Hodgkin lymphoma and gastrointestinal stromal tumors, there is no common molecular pathway between these two diseases. In conclusion, there is no indication that these two neoplasms are relevant on a molecular basis.Keywords: hematological malignacies, mesenchymal cells, gastrointestinal cancer

Maurizio Iacoangeli,1 Alessandro Di Rienzo,1 Roberto Colasanti,1 Antonio Zizzi,2 Maurizio Gladi,1 Lorenzo Alvaro,1 Niccolò Nocchi,1 Lucia Giovanna Maria Di Somma,1 Marina Scarpelli,2 Massimo Scerrati11Department of Neurosurgery, 2Department of Pathology, Università Politecnica delle Marche, Umberto I General Hospital, Ancona, ItalyAbstract: Although various prognostic indices exist for patients with malignant brain tumors, the prognostic significance of the subependymal spread of intracranial tumors is still a matter of debate. In this paper, we report the cases of two intraventricular lesions, a recurrent glioblastoma multiforme (GBM) and a brain metastasis, each successfully treated with a neuroendoscopic approach. Thanks to this minimally invasive approach, we achieved good therapeutic results: we obtained a histological diagnosis; we controlled intracranial hypertension by treating the associated hydrocephalus and, above all, compared with a microsurgical approach, we reduced the risks related to dissection and brain retraction. Moreover, in both cases, neuroendoscopy enabled us to identify an initial, precocious subependymal tumor spreading below the threshold of magnetic resonance imaging (MRI) detection. This finding, undetected in pre-operative MRI scans, was then evident during follow-up neuroimaging studies. In light of these data, a neuroendoscopic approach might play a leading role in better defining the prognosis and optimally tailored management protocols for GBM and brain metastasis.Keywords: subependymal spreading, glioblastoma, brain metastasis, endoscopy, minimally invasive surgery, prognosis