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Purpose Current strategies for preventing and managing radiation-induced dermatitis, mucositis, and xerostomia are reviewed, with an emphasis on pharmacologic interventions. Summary Nearly two thirds of all patients with cancer receive radiation therapy during the course of treatment, frequently resulting in acute skin and mucosal toxicities. The severity of radiotherapy-associated toxicities varies according to multiple treatment- and patient-related factors (e.g., total radiation dose and dose fractionation schedule, volume of organ or tissue irradiated, use of concurrent versus sequential chemotherapy, comorbid conditions, functional performance status). Three major radiation toxicities encountered in clinical practice are (1) radiation dermatitis, typically managed with a variety of topical agents such as water-based moisturizing creams or lotions, topical steroids, antiinflammatory emulsions, and wound dressings, (2) radiation-induced oral mucositis, which can be managed through proper basic oral care practices, appropriate pain management, and the use of medicated mouthwashes and oral rinses and gels, and (3) radiation-induced xerostomia, which can be alleviated with saliva substitutes, moistening agents, and sialagogues. Pharmacists involved in the care of patients receiving radiotherapy can play an important role in optimizing symptom control, educating patients on self-care strategies, and adverse effect monitoring and reporting. Conclusion Radiation-induced dermatitis, mucositis, and xerostomia can cause significant morbidity and diminished quality of life. Pharmacologic interventions for the prevention and treatment of these toxicities include topical agents for dermatitis; oral products, analgesics, and palifermin for mucositis; and amifostine, saliva substitutes, and pilocarpine for xerostomia.

The effect of azacitidine (AZA) in therapy related MDS and AML (t-MDS/AML) is not well established. 54 patients (42 t-MDS and 12 t-AML), 71% of whom had complex karyotype, received AZA for at least one cycle (median 4 cycles). The overall response rate (ORR) was 39% in the whole cohort and 62% in patients who received ≥4 cycles. One, 2 and 3 year OS was 36%, 14% and 8% respectively. Female gender (p=0.01) and ECOG 0-1 (p=0.04) were associated with significantly better OS, while karyotype and marrow blast percentage had no significant impact. By comparison with de novo MDS/AML treated in the same program, t-MDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p=0.53), but significantly shorter OS (2 year OS of 14% vs 33.9%, p=0.0005). However, in a multivariate analysis performed in all patients (de novo and therapy related cases), only complex karyotype and high IPSS, and not etiology (i.e. de novo versus therapy related), had a significant impact on OS. Nine (15%) patients received allogeneic stem cell transplantation, 4 of whom were still alive.

Our laboratory has implemented an in vitro assay to estimate the response to chemotherapy in ovarian cancer cells pertaining to individual patients. In two selected patients, we determined the correlation between an in vitro assay of cells from suspected ovarian cancer ascites, with the clinical chemotherapy response. Cancer cells isolated from peritoneal fluid with suspected ovarian cancer were tested for cytotoxicity with corresponding chemotherapy regimens. Circulating Cal25 levels and attending physician consultation determined clinical course and response to chemotherapy. The in vitro assay result correlated with Cal25 levels, progression free survival and attending physician evaluation. The assay predicted correctly the failure of two successive chemotherapy regimes in the first patient, while predicting a favorable clinical response in the second subject.

Objective: To report on preliminary outcomes of single-dose intraoperative radiotherapy for early-stage breast cancer based on local recurrence rates and complications. Methods: Fifty postmenopausal women with ≤2.5cm breast tumors and clinically normal axillary lymph nodes were submitted to quadrantectomy, sentinel lymph node biopsy and intraoperative radiotherapy and studied. Mean follow-up time was 52.1 months. Results: Mean patient age was 65.5 years; mean tumor diameter was 1.41cm 82% of nodules were hormonal receptor positive and HER-2negative. All patients received a 21 Gy radiation dose for a mean time of 8.97 minutes. Distant metastases were not observed. Local recurrence was documented in three cases, with identical histological diagnosis as the primary tumors. Thirty-five (70%) patients had local fibrosis, with gradual improvement and complete resolution over 18 months. Postoperative infection and seroma formation were not observed. Conclusion: Partial radiotherapy is a potentially feasible and promising technique. Careful patient selection is recommended before a longer follow-up period has elapsed to confirm intraoperative radiotherapy safety and efficacy.

Supplemental Digital Content is available in the text, Background: Trials investigating the efficacy and safety of combining molecular targeted agent (MTA) with platinum–gemcitabine (PG) in first-line treatment of advanced non-small cell lung cancer (NSCLC) have shown inconsistent findings. This meta-analysis aimed to explore whether the addition of MTAs to PG in NSCLC could provide a survival benefit with a tolerable toxicity. Methods: Web of knowledge, PubMed, Ovid, Embase, and Cochrane Library were searched to identify relevant studies and extract data on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and common grade 3 or 4 adverse events. Subgroup analyses were conducted on the basis of race and the type of MTA. Results: Twelve trials with a total of 6143 patients were included in this meta-analysis. Compared with PG chemotherapy, combination therapy of MTA with PG did not improve OS (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.90–1.01) but improved PFS (HR = 0.77, 95% CI = 0.66–0.89) and ORR (risk ratio [RR] = 1.33, 95% CI = 1.11–1.60). Subanalysis indicated that there was more incidence of grade 3 or 4 rash (RR = 11.20, 95% CI = 6.07–20.68), anemia (RR = 1.21, 95% CI = 1.01–1.46), diarrhea (RR = 2.62, 95% CI = 1.21–5.65), and anorexia (RR = 2.08, 95% CI = 1.12–3.88) in combining epidermal growth factor receptor targeted therapy group compared to PG group. An increased risk of grade 3 or 4 rash (RR = 5.08, 95% CI = 1.53–16.79), thrombocytopenia (RR = 1.50, 95% CI = 1.03–2.18), and hypertension (RR = 2.36, 95% CI = 1.05–5.32) was observed in sorafenib combination group. Conclusion: The combination of PG plus MTA was superior to PG alone in terms of PFS and ORR but not in OS. The combination chemotherapy also showed a higher frequency of grade 3 or higher toxic effects in patients with advanced NSCLC than PG chemotherapy.

Objectives: The objective of this study was to assess the relation between cancer treatments and incident cognitive impairment in breast cancer patients, taking into account the levels of anxiety before treatment. Materials and methods: We conducted a prospective cohort study with 418 newly diagnosed breast cancer patients with no cognitive impairment, defined as values at least 1.5 standard deviations below age- and education-adjusted cut-offs in the Montreal Cognitive Assessment (MoCA), at baseline. The Hospital Anxiety and Depression Scale and MoCA were used for evaluations before treatment and at 1-year after diagnosis. We used Poisson regressions to compute adjusted relative risks (RR) and corresponding 95% confidence intervals (95%CI) to identify predictors of cognitive impairment. Results: The median (Percentile 25, Percentile 75) MoCA score before treatment was 24 (21, 26). A total of 8.1% (95%CI: 5.8, 11.2) of the patients presented incident cognitive impairment during the follow-up. There was a statistically significant interaction between anxiety at baseline and the effect of chemotherapy on the incidence of cognitive impairment (P for interaction ¼ 0.028). There was a significantly increased risk of incident cognitive impairment among patients with no anxiety prior to treatment with schemes including doxorubicin and cyclophosphamide (adjusted RR ¼ 4.22, 95%CI: 1.22, 14.65). Conclusion: There was a statistically significant association between chemotherapy and cognitive impairment, but only among women with no anxiety at baseline. The work of FF was co-funded by the Foundation for Science and Technology - FCT (Portuguese Ministry of Science, Technology and Higher Education) and the POPH/FSE Program (Ref. SFRH/BD/92630/2013). The Unidade de Investigação em Epidemiologia e Instituto de Saúde Pública da Universidade do Porto (EPIUnit) was funded by FEDER through the Operational Programme Competititveness and Internationalization and national funding from the FCT (POCI-01-0145-FEDER-006862; Ref. UID/DTP/04750/2013). Data management activities were supported by the Chair on Pain Medicine of the Faculty of Medicine, University of Porto and by the Grünenthal Foundation e Portugal.

Given the paucity of esophageal small cell carcinoma (SCC) cases, there are few large studies evaluating this disease. In this study, the National Cancer Data Base (NCDB) was utilized to analyze the clinical features, treatment, and survival of patients with esophageal SCC in a large, population-based dataset. We selected patients diagnosed with esophageal SCC from 1998 to 2011. Patients were identified as having no treatment, chemotherapy alone, radiation ± sequential chemotherapy, concurrent chemoradiation, and esophagectomy ± chemotherapy and/or radiation. Overall survival (OS) was analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was conducted to identify factors associated with OS. A total of 583 patients were identified. Most patients had stage IV disease (41.7%). Regarding treatment selection, chemoradiation was the most commonly utilized for patients with nonmetasatic disease, whereas chemotherapy alone was most common for metastatic patients. Esophagectomy (median survival 44.9 months with 3 year OS 50.5%) was associated with the best OS for patients with localized (node-negative) disease compared with chemotherapy alone (p 0.001) or chemoradiation (p = 0.01). For locoregional (node-positive) disease, treatment with chemoradiation resulted in a median survival of 17.8 months and a 3 year OS 31.6%. On multivariate analysis, treatment with chemotherapy alone (p = 0.003) was associated with worse OS while esophagectomy (p = 0.04) was associated with improved OS compared to chemoradiation. Esophageal SCC is an aggressive malignancy with most patients presenting with metastatic disease. Either esophagectomy or chemoradiation as part of multimodality treatment appear to improve OS for selected patients with nonmetastatic disease.

The origin of gastrointestinal stromal tumors (GIST) from interstitial cells of Cajal or their precursor cells has been understood since the early 1990s. The first mutations within the KIT-gene have been described in the late 1990s. Even though these mutations were the breakthrough of small molecular therapy, we still do not know the factors responsible for their malignant transformation. Until then, we can only speak of recurrence risk. This review gives an introduction on the current understanding of GIST and highlights the remaining questions for diagnosis, tumor progression, and treatment in progressive disease.

In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. Platform trials, basket trials, and umbrella trials are new approaches to clinical research driven by this need for enhanced efficiency in the modern era of increasingly specific cancer subpopulations and decreased resources to study treatments for individual cancer subtypes in a traditional way. In this review, we provide an overview of these new types of clinical trial designs, including discussions of motivation for their use, recommended terminology, examples, and challenges encountered in their application.

No standards for staging, systemic therapy or the timing of an operation are defined for patients newly diagnosed with synchronous metastases and a primary in the colon. An expert group of radiologists, medical, radiation and surgical oncologists therefore came together to discuss staging and treatment sequence for these patients and came up with a recommendation based on current evidence of potential therapeutic options. The discussion was organized to debate recommendations centred on 5 topics and therefore the position paper is built upon these titles and their subtitles. Editrice Gastroenterologica Italiana S.r.l.

Esophageal cancer is one of the most common digestive tract cancers in our country. Although multimodality therapy has been used in the treatment of esophageal cancer, such as radiotherapy, chemotherapy and targeted therapy, surgery plays its irreplaceable role. With the development of techniques and innovation of instruments, minimally invasive esophagectomy is introduced into practice worldwide. Due to its less trauma and fewer complications, minimally invasive esophagectomy draws great attention, however, controversy exists in the question whether minimally invasive esophagectomy has similar efficacy to open esophagectomy. With the aim of providing suggestions for selecting optimal surgical procedure, this review discusses differences between minimally invasive esophagectomy and open esophagectomy in the following three aspects: perioperative mortality and morbidity, margin status and harvested lymph node number, and postoperative survival. Nowadays, the advantage of minimally invasive esophagectomy has been widely recognized in reducing perioperative morbidity and mortality, however, in the aspect of radicality and prognosis, it is far from reaching a definite conclusion for lack of multicenter, large sample, prospective, randomized controlled trials. Such trials are warrented so as to show the strength and weakness of minimally invasive esophagectomy.

To compare the safety and efficacy between three-field lymphadenectomy and normative Ivor-Lewis two-field lymphadenectomy for thoracic esophageal squamous cell carcinoma METHODS: Clinical data of 375 patients with thoracic esophageal squamous cell carcinoma who underwent three-field lymphadenectomy(3FL) or Ivor-Lewis two-field lymphadenectomy(2FL, Ivor-Lewis) in Fudan University Shanghai Cancer Center during 2013 were retrieved and collected from electronic medical record system. Ninety-one patients received three-field lymphadenectomy (3FL group), including 16 cases of intra-cervical gastro-esophageal anastomosis and 75 cases of intra-thoracic gastro-esophageal anastomosis, while 284 patients received Ivor-Lewis two-field lymphadenectomy (2FL group) with all intra-thoracic gastro-esophageal anastomosis. Short-term outcomes were compared between two groups, including postoperative anastomotic leakage, pneumonia and respiratory failure, chylothorax, reoperation and 90-day death. Total harvested lymph nodes and positive lymph nodes in each group were also compared. A total of 338 patients were enrolled into survival analysis. Survival curve was presented by Kaplan-Meier method.As compared to 2FL group, the 3FL group had significantly higher ratio of N3 patients [19.8% (18/91) vs. 5.3% (15/284), P=0.000], stageIII( patients [58.2%(53/91) vs. 43.0%(122/284), P=0.007], and upper thoracic cancer patients [12.1%(11/91) vs. 3.5%(10/284), P=0.027]; also the 3FL group had more harvested lymph nodes (40.1±14.6 vs. 25.3±9.4, P=0.000) and more positive lymph nodes (3.3±4.0 vs. 1.7±3.2, P=0.000). With respect to pneumonia and respiratory failure, chylothorax, reoperation and 90-day death, no significant differences were found between the group (P=0.447, P=0.751, P=0.678, P=0.685). The 3FL group had a significantly higher incidence of anastomotic leakage than 2FL group [7.7% (7/91) vs. 1.8% (5/284), P=0.011], while its incidence of intrathoracic anastomosis leakage was 4.0% (3/75), which was not significantly different with 1.8%(5/284) of 2FL group (P=0.372). Median follow-up was 33 months. Overall 1-, 2-, 3-year survival rates were 94%, 81% and 70%, while 1-, 2-, 3-year survival rates of 3FL group were 90%, 73% and 66%, of 2FL group were 95%, 84% and 72%, respectively, without significant differences between the two group(P=0.135). Further subgroup analysis showed that no significant differences of postoperative survival in stage I(, II( and III( patients were observed between the two groups (P=0.541, P=0.511, P=0.402), meanwhile no significant differences of postoperative survival in patients with metastasis and without metastasis were found between the two groups as well (P=0.985, P=0.233).Three-field lymphadenectomy can be performed with acceptable perioperative morbidity and mortality. The prognosis value of three field lymphadenectomy needs further investigation. Patients with thoracic esophageal squamous cell carcinoma may have favorable survival through normative Ivor-Lewis two-field lymphadenectomy.

To compare the short-term efficacy and long-term survival between Sweet and Ivor-Lewis esophagectomy for patients with middle-lower esophageal squamous cell carcinoma.Clinicopathologic data of 1 308 patients with middle-lower esophageal squamous cell carcinoma undergoing Sweet or Ivor-Lewis procedures in our department from January 2007 to December 2014 were retrospectively analyzed, including 1 021 patients of Sweet operation (Sweet group) and 287 patients of Ivor-Lewis operation(Ivor-lewis group). Lymph node clearance, lymphatic metastasis, postoperative complication morbidity and long-term survival were compared between the two groups.There were no significant differences in baseline data between the two groups(all P0.05). There were more lymph nodes resected during the Ivor-Lewis procedure compared with the Sweet procedure (20.8 vs.19.3, P=0.030). Compared with Ivor-Lewis group, the incidence of wound infection in Sweet group was significantly lower[(3.2%(33/1 021) vs. 8.0%(23/287), P=0.000]. Sweet group had a significantly lower rate of delayed gastric emptying[1.9%(19/1 021) vs. 5.2%(15/287), P=0.002] and significantly shorter hospital stay (14.7 days vs. 17.2 days, P=0.029). With respect to other postoperative complications, such as pulmonary complications, cardiac events, anastomotic leakage, vocal cord palsy, chylothorax and pyothorax, the differences between the two groups were not statistically significant. The 5-year survival rate was not significantly different between the two group (54.0% vs. 56.9%, P=0.873). Stratified analysis based on TNM staging showed that no significant difference of 5-year survival rate was found between the two groups in stageI( and stageIII( patients (P0.05), while the 5-year survival rate of stageII( patients in Sweet group was significantly lower than that in Ivor-Lewis group (56.4%% vs. 70.4%, P=0.039).For patients with middle-lower esophageal squamous cell carcinoma, Sweet procedure has certain superiority regarding the incidence of wound infection and delayed gastric emptying compared with the Ivor-Lewis procedure. Ivor-Lewis esophagectomy can harvest more lymph nodes. The 5-year survival rate of these two procedures is similar. Sweet procedure is still valuable in clinical practice, especially for stageI( and stageIII( patients, while it requires thorough considerations for stageII( patients.

UVOD: Savremenim dijagnostičkim i terapijskim dostignućima, kao i unapređenjem preventivnih mera produžen je životni vek ljudi. Starenje stanovništva je fenomen koji zahvata ceo svet. Povećanje broja starijeg stanovništva je udruženo sa porastom broja obolelih od karcinoma u ovoj starosnoj grupi, jer je starenje samo po sebi riziko faktor za nastanak karcinoma. Incidenca pojave karcinoma naglo raste od 50-te godine života sa vrhom u 80-toj godini života. U osoba starijih od 65 godina se dijagnostikuje 58% svih karcinoma, a 30% u starijih od 70 godina. Godine starosti nisu kontraindikaciija za sprovođenje hemioterapije kod starih bolesnika sa karcinomom. Starenje je povezano sa izmenjenom farmakodinamikom i farmakokinetikom antitumorskih lekova i povećanom osetljivošću normalnog tkiva na toksične komplikacije, te je odluka kliničara kod davanja hemioterapije ovoj starosnoj kategoriji bolesnika sa karcinomom uvek vrlo kompleksna i zahteva dobru procenu i odgovarajuću selekciju bolesnika za ovaj tretman. MATERIJAL I METODE: Doktorska disertacija obuhvata rezultate delom restrospektivnog, a delom prospektivnog opservacionog istraživanja sprovedenog u periodu 01.01.2011. do 31.12.2013.godine u Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici, u kojem je praćeno 152 bolesnika starosti 65 i više godina kod kojih je dijagnostikovan nemikrocelularni karcinom bronha u uznapredovalom stadijumu bolesti, a koji su lečeni kombinovanim hemioterapijskim režimom na bazi platine. Kao prognostički faktori su uzeti: starosna dob bolesnika (grupa mlađih od 75 godina i starih 75 i više godina), pol, navika pušenja cigareta (pušač, nepušač, bivši pušač), navika konzumiranja alkohola, performans status (prema ECOG-Eastern Cooperative Oncology Group skali) u momentu postavljanja dijagnoze, patohistološki tip tumora (adenokarcinom, skvamozni karcinom, drugo), stadijum bolesti (IIIb, IV), veličina tumora (manje od 6 cm i 6 cm i više), TNM status prema klasifikaciji tumora (7.revizija), parametri krvne slike (vrednosti leukocita, hemoglobina, trombocita), biohemijski parametri (vrednosti laktat-dehidrogenaze (LDH), alkalne fosfataze, aspartat- aminotransferaze (AST), alanin-aminotransferaze (ALT), kalijuma, natrijuma, bilirubina) na početku terapije, komorbiditeti u momentu postavljanja dijagnoze (broj komorbiditeta po sistemima, Charlson index), simptomi bolesti (kašalj, hemoptizije, otežano disanje, bol u grudnom košu, promuklost, smetnje gutanja, sindrom gornje šuplje vene, bol u kostima, simptomi od strane centralnog nervnog sistema, povišena telesna temperatura), gubitak na telesnoj masi (više od 5% u prethodnih 6 meseci), indeks telesne mase (, INTRODUCTION: Nowadays life expectancy is prolonged due to modern diagnostic and therapy achievements, as well as promotion of preventive measurements. Aging of population is a phenomenon in the whole world. Increasing number of elderly population is accompanied with the increased number of diagnosed cancer in this age group, because the aging themselves is a risk factor for development of cancer. The appearance of cancer rapidly rises from the age of fifty with the peak at the age of eighty. 58% of cancer diagnoses are in the people older than sixty-five years and 30% in people older than seventy years. The age is not contraindication for chemotherapy treatment in older patient with cancer. The aging is associated with disturbed pharmacodynamics and pharmacokinetics of antitumor drugs and increased susceptibility of normal tissue for toxic complications, therefore clinical decision for introducing chemotherapy is very complex and requires good assessment and proper selection of the patients for this treatment. MATERIAL AND METHODS: This doctoral thesis includes results of partly retrospective and partly prospective observational research conducted in the period 01.01.2011. until 31.12.2013. at the Institute for pulmonary diseases of Vojvodina in Sremska Kamenica, which includes 152 lung cancer patients 65 and more years old with diagnosed non-small cell lung cancer in advanced stage treated with combined platinum based chemotherapy regimen. These prognostic factors are included: age of patients (group

Background The aim of this study was to evaluate an improved technique for expansion of tumor-infiltrating lymphocytes (TILs) based on the WAVE Bioreactor system with perfusion and tube-welding techniques. Our hypothesis was that the bioreactor would allow for optimized provision of nutrients and removal of spent media while minimizing culture volumes. These refinements might lead to a better quality of expanded cells with lower amounts of exhausted cells compared to static expansions in culture bags. Procedures Tumor-infiltrating lymphocytes from 4 melanoma patients were expanded and compared in parallel using either the WAVE Bioreactor 2/10 System or traditional static culture methods. The parameters viability, final cell number, phenotype and effector function were measured. Results Our results show that the bioreactor system with perfusion is suitable for large-scale expansion of tumor-infiltrating lymphocytes and allows for higher cell densities and absolute cell numbers as compared to static culture conditions. Phenotypic characteristics of TILs were compared pre and post expansion and showed no consistent difference between the two expansion methods. TILs harvested had the phenotype and function corresponding to intermediate to late effector cells. The system allows one technician to operate several bioreactors simultaneously, thereby reducing the labor for one expansion to approximately 1/3 compared to static expansion. Discussion The WAVE Bioreactor system is suitable for large-scale expansion of TILs. Due to constant perfusion of fresh media and removal of spent media much higher cell densities were achieved while the culture volume and the glucose and glutamine levels were kept constant. Expansion of TILs in the bioreactor system represents a labor- and cost-effective method to reach large numbers of T cells for adoptive cell transfer therapy in the clinic. Conclusion The system presented herein offers an effective alternative to large-scale production of cell products for clinical use while meeting requirements of therapeutic cell quantities and qualities of current protocols for treatment of malignant melanoma.

PURPOSE OF REVIEW: The past couple of years have seen a flurry of publications detailing potential prognostic and predictive biomarkers for colorectal cancer. However, most studies have been underpowered and demonstrate elements of a statistical 'fishing exercise', that is the carrying out of a huge number of analyses to find a hint of importance for a particular marker. RECENT FINDINGS: Recently some well powered analyses using separate development and validation datasets and multivariate statistics have been published and these are starting to change attitudes towards such markers. SUMMARY: Although there are very limited markers in standard clinical practice, we feel that there are now some that are ready to be translated into routine use or that at least deserve some further attention and 'service assessment'.

Pancreatic cancer carries a dismal prognosis, with surgical resection and adjuvant therapy offering the only hope for long-term survival. Recently, neoadjuvant therapy (NAT) has been employed to optimize outcomes. This study evaluates the impact of NAT in resected pancreatic cancer.Patients with clinically staged I-III resected carcinoma of the pancreas who underwent at least NAT or surgery first in the 2003-2011 National Cancer Data Base were included. Univariate statistics were used to compare characteristics between treatment groups. Kaplan-Meier and multivariate survival analyses using Cox proportional hazards models were also performed.1736 patients who underwent NAT, 6706 patients who underwent surgical resection alone, and 9890 patients who underwent surgical resection followed by adjuvant therapy were studied. In patients with clinical stage I disease, adjuvant therapy was associated with similar median survival to NAT, which was greater than surgery alone (24.9, 24.8, and 18.3 months, respectively, p 0.0001). However, in stage II, NAT offered improved median survival over adjuvant therapy, which was greater than surgery alone (21.78, 20.63, and 12.1 months, respectively, p 0.0001). In stage III disease, NAT had better median survival relative to other groups (22.6, 14.6, and 8.7 months, respectively, p 0.0001). In multivariate survival analysis, patients who received NAT had a 33% lower hazard of mortality up to 5 years as compared to surgical resection alone (p 0.0001).Neoadjuvant therapy in advanced stage pancreatic cancer is associated with a survival benefit, perhaps related to a selection bias. In early stage pancreatic cancer, NAT is associated with similar survival.

There is no consensus on whether patients with immunoglobulin light chain amyloidosis (AL) should receive induction therapy prior to an autologous stem cell transplant (ASCT). This study investigated the relationships between baseline bone marrow plasmacytosis (BMPC), cardiac staging, and pre-transplant induction in AL patients. All patients who received ASCT for AL within 12 months of diagnosis were included. Patient characteristics and outcomes were abstracted. Univariate and multivariate modeling was performed. Among 415 AL patients, 35% had induction prior to ASCT. Post-ASCT hematologic CR plus VGPR rates were significantly higher in those with baseline BMPC ≤ 10% compared to BMPC10% (58% versus 40%, P = 0.0013). Significant risk factors for lack of attainment of CR included attenuated dose melphalan conditioning, baseline BMPC 10%, no induction, and male gender. The 5-year OS for the entire group was 65%. On multivariate analysis, risk factors for inferior OS included no induction therapy, advanced AL amyloid staging, BMPC 10%, attenuated conditioning melphalan dose, and male gender. Patients with Mayo 2012 stage I-II patients with BMPC ≤ 10%, who comprised 56% of the ASCT population fared exceedingly well regardless of whether or not they received induction therapy with a 5-year OS of 81 to 83%. Induction therapy pre-ASCT may improve outcomes among AL patients due to a rapid reduction of toxic light chains or alternatively by elimination of less fit patients by "testing" their ability to tolerate chemotherapy. Prospective studies will be required to sort out these and other questions. Am. J. Hematol. 91:984-988, 2016. © 2016 Wiley Periodicals, Inc.

Canine osteosarcoma is the most common bone cancer, and an important cause of mortality and morbidity, in large purebred dogs. Previously we constructed two multivariable models to predict a dog's 5-month or 1-year mortality risk after surgical treatment for osteosarcoma. According to the 5-month model, dogs with a relatively low risk of 5-month mortality benefited most from additional chemotherapy treatment. In the present study, we externally validated these results using an independent cohort study of 794 dogs. External performance of our prediction models showed some disagreement between observed and predicted risk, mean difference: -0.11 (95% confidence interval [95% CI]-0.29; 0.08) for 5-month risk and 0.25 (95%CI 0.10; 0.40) for 1-year mortality risk. After updating the intercept, agreement improved: -0.0004 (95%CI-0.16; 0.16) and -0.002 (95%CI-0.15; 0.15). The chemotherapy by predicted mortality risk interaction (P-value = 0.01) showed that the chemotherapy compared to no chemotherapy effectiveness was modified by 5-month mortality risk: dogs with a relatively lower risk of mortality benefited most from additional chemotherapy. Chemotherapy effectiveness on 1-year mortality was not significantly modified by predicted risk (P-value = 0.28). In conclusion, this external validation study confirmed that our multivariable risk prediction models can predict a patient's mortality risk and that dogs with a relatively lower risk of 5-month mortality seem to benefit most from chemotherapy.

Summary Background Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. Methods We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0–2. Before enrolment, all patients had received 3–18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Findings Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40–61) and 40 of 95 in the imatinib group (42%, 32–53%; difference 7·9% in favour of nilotinib; 95% CI −6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3–4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. Interpretation While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Funding Novartis Pharmaceuticals.

Often, single-arm trials are used in phase II to gather the first evidence of an oncological drug's efficacy, with drug activity determined through tumour response using the RECIST criterion. Provided the null hypothesis of 'insufficient drug activity' is rejected, the next step could be a randomised two-arm trial. However, single-arm trials may provide a biased treatment effect because of patient selection, and thus, this development plan may not be an efficient use of resources. Therefore, we compare the performance of development plans consisting of single-arm trials followed by randomised two-arm trials with stand-alone single-stage or group sequential randomised two-arm trials. Through this, we are able to investigate the utility of single-arm trials and determine the most efficient drug development plans, setting our work in the context of a published single-arm non-small-cell lung cancer trial. Reference priors, reflecting the opinions of 'sceptical' and 'enthusiastic' investigators, are used to quantify and guide the suitability of single-arm trials in this setting. We observe that the explored development plans incorporating single-arm trials are often non-optimal. Moreover, even the most pessimistic reference priors have a considerable probability in favour of alternative plans. Analysis suggests expected sample size savings of up to 25% could have been made, and the issues associated with single-arm trials avoided, for the non-small-cell lung cancer treatment through direct progression to a group sequential randomised two-arm trial. Careful consideration should thus be given to the use of single-arm trials in oncological drug development when a randomised trial will follow.

Neoplastic myelopathy may be due to external compression or to direct intraparenchymal involvement of the spinal cord. In this review, the authors discuss the most common cause for compressive neoplastic myelopathy, metastatic disease. They also review other compressive lesions and discuss primary intramedullary spinal tumors. In the acute setting, compressive metastatic disease should be treated with high-dose steroids when clinically necessary; surgery should be considered for selected patients, followed by radiation therapy. For most primary intramedullary spinal tumors, surgical resection remains the standard initial therapy. Patients with incomplete resection of infiltrative tumors, high-grade pathology, or recurrent tumors may benefit from radiation, but most spinal tumors are relatively insensitive to traditional chemotherapy. Neoplastic myelopathy from either compressive or intraparenchymal causes remains a diagnostic and therapeutic challenge. In complex cases, referral to a specialty center with access to neurosurgeons, neuroradiologists, neuropathologists, and neurooncologists is recommended.

Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide, and novel therapeutic strategies are urgently required to improve clinical outcome. Interferon-alpha (IFN-α) and sorafenib are widely used as anti-tumor agents against various malignancies. In this study, we investigated the combined effects of IFN-α and sorafenib against HCC. We demonstrated that the combination therapy synergistically suppressed HCC cellular viability, arrested cell cycle propagation and induced apoptosis in HCC cells. Further research revealed that IFN-α and sorafenib collaboratively regulated the expression levels of cell cycle-related proteins Cyclin A and Cyclin B as well as the pro-survival Bcl-2 family proteins Mcl-1, Bcl-2 and Bcl-X(L). Moreover, sorafenib inhibited IFN-α induced oncogenic signaling of STAT3, AKT and ERK but not the activation of the tumor suppressor STAT1. Xenograft experiments also confirmed the combined effects of IFN-α and sorafenib on tumor growth inhibition and apoptosis induction in vivo. In conclusion, these results provide rationale for the clinical application of IFN-α and sorafenib combination therapy in HCC treatment.

OBJECTIVE: The aim of the current study was to examine demographic and contextual correlates of voluntariness in parents making research or treatment decisions for their children with cancer. METHODS: Participants included 184 parents of children with cancer who made a decision about enrolling the child in a research or treatment protocol within the previous 10 days. Parents completed questionnaires that assessed voluntariness, external influence by others, concern that the child’s care would be negatively affected if the parent did not agree, time pressure, information adequacy, and demographics. RESULTS: Lower perceived voluntariness was associated with lower education, male gender, minority status, and not having previous experience with a similar decision. Parents who reported lower voluntariness also perceived more external influence and time pressure, had more concern about the child’s care being negatively affected if they declined, and perceived that they had either too much or not enough information about the decision. In a multivariate regression, education, minority status, gender, external influence, and too little information remained significantly associated with voluntariness. CONCLUSIONS: Several groups of parents appear to be at risk for decreased voluntariness when making research or treatment decisions for their seriously ill children, including fathers, nonwhite parents, and those with less education. Parental voluntariness may be enhanced by helping parents to mitigate the effects of unhelpful or unwanted influences by others and ensuring that their information needs are met.

Key Points Cutaneous T-cell lymphoma (CTCL) is an uncommon cutaneous malignancy that usually presents with patches and/or plaques, less commonly with tumours and/or haematological involvement Mycosis fungoides is usually an indolent condition that can be managed with skin-directed therapies

Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T cell lymphoma, is an uncommon disease, with an aggressive clinical behavior. Differentiation with other types of cutaneous T-cell lymphoma (CTCL) that express a CD8+ cells, is based only on clinical grounds and in certain morphological characteristics, such as a marked epidermotropism with squamous cell necrosis. We report a 50-year-old male presenting with painless cutaneous lesions appearing in trunk, limbs, scalp and face, suggestive of cutaneous lymphoma. He was admitted to the hospital in bad conditions, with confluent papules and tumors, some of them ulcerated and with foul smelling honey-colored crusts, involving the complete body surface. Cutaneous biopsy demonstrated a CD8 positive epidermotropic cytotoxic T cell lymphoma. He was treated with chemotherapy with an excellent initial response, but cutaneous lesions reappeared after four cycles. He did not respond to rescue chemotherapy and died seven months after diagnosis.

Surgical debulking is a mainstay of therapy for epithelial ovarian cancer. The traditional timing of this surgery has been prior to chemotherapy, but this view has been challenged over the last decade. This review will focus on the recently completed phase III studies of surgical timing and discuss exceptions to the superior paradigm of neoadjuvant chemotherapy followed by interval debulking.The two completed studies have shown that neoadjuvant chemotherapy followed by interval debulking is the superior strategy for stage IIIc and IV ovarian cancer compared to primary surgery followed by chemotherapy. Survival outcomes were the same, but the morbidity for the patient and cost to the system and patient were less with interval debulking. Exceptions to this sequence are potentially stage I or II patients and those stage III patients who can be optimally debulked so as to receive intraperitoneal chemotherapy.Chemotherapy followed by interval debulking will result in fewer and simpler operations and lesser morbidity for the patients resulting in cost savings for the healthcare system and less inconvenience and toxicity for the patient with equivalent survival outcomes. As such it is the superior strategy.

Purpose of review There has been considerable progress in the imaging of cervical cancer over the last 5 years. In countries with access to cross-sectional imaging resources, technical advances have enabled a range of imaging techniques to become increasingly employed and established in the detection, staging and treatment planning of cervical cancer and for identifying disease recurrence. This review highlights these developments and summarizes recent significant articles. Recent findings Functional imaging techniques provide information on tumour biology by probing characteristics of tumour vascularity, cellularity and metabolism which critically contribute to decision making and stratification for management options. Particularly, functional MRI techniques have improved accuracy of disease staging and detection of recurrence. PET-computed tomography is useful in lymph node staging and targeted radiotracers are increasingly exploited as potential biomarkers of treatment response. Summary Improvements in hardware, software and contrast agents are revolutionizing the role of imaging in cervical cancer. Once standardized and validated, the techniques should enable individualized patient treatment and optimization of outcome.

To discuss the important technological advances that have taken place in the planning and delivery of both external beam radiotherapy and brachytherapy for patients with locally advanced cervical cancer, and the implications for improved clinical outcomes.Technological advances in external beam radiation treatment and brachytherapy for patients with cervical cancer allow more precise targeting of tumour and relative sparing of surrounding normal organs and tissues. Early evidence is emerging to indicate that these advances will translate into improvements in tumour control and reduced side effects. However, there are patient, tumour and treatment-related factors that can detract from these benefits. Foremost among these is complex, unpredictable and sometimes dramatic internal tumour and normal organ motion during treatment. The focus of current research and clinical development is on tracking internal anatomic change in individual patients and adapting treatment plans as required to assure that optimal tumour coverage and normal tissue sparing is maintained at all times. The success of this approach will depend on clear definitions of target volumes, high resolution daily soft tissue imaging, and new software tools for rapid contouring, treatment planning and quality assurance.Radiation treatment of locally advanced cervical cancer is evolving rapidly, driven by advances in technology, towards more individualized patient care that has the potential to substantially improve clinical outcomes.

The relative success of monoclonal antibodies in cancer immunotherapy and the vast manipulation potential of recombinant antibody technology have encouraged the development of novel antibody-based antitumor proteins. Many insightful reagents have been produced, mainly guided by studies on the mechanisms of action associated with complete and durable remissions, results from experimental animal models, and our current knowledge of the human immune system. Strikingly, only a small percent of these new reagents has demonstrated clinical value. Tumor burden, immune evasion, physiological resemblance, and cell plasticity are among the challenges that cancer therapy faces, and a number of antibody-based proteins are already available to deal with many of them. Some of these novel reagents have been shown to specifically increase apoptosis/cell death of tumor cells, recruit and activate immune effectors, and reveal synergistic effects not previously envisioned. In this review, we look into different approaches that have been followed during the past few years to produce these biologics and analyze their relative success, mainly in terms of their clinical performance. The use of antibody-based antitumor proteins, in combination with standard or novel therapies, is showing significant improvements in objective responses, suggesting that these reagents will become important components of the antineoplastic protocols of the future.

Background Solitary fibrous tumor is a rare mesenchymal tumor reported initially in the pleura but that is now reported in widely ranging anatomic sites with a variable clinical course. Solitary fibrous tumor arising from the female genital tract is extremely rare and the management of this condition is controversial. Cases We report three cases of female genital tract solitary fibrous tumors displaying different clinical behaviors and review literature with regard to diagnosis, possible prognostic factors, and management of this tumor. Conclusion The primary treatment of this disease should be surgical. The rarity and disparate clinical manifestations of this disease preclude a definitive statement on use and optimization of adjuvant therapy. Nevertheless, both pathologic and clinical findings may be useful in gauging risk and assessing the merits of individualized adjuvant therapy.

Renaud Seigneuric 1,2 , Jessica Gobbo 1,2 , Pierre Colas 3 , Carmen Garrido 1,2 1 Heat Shock Proteins and Cancer, INSERM, UMR 866 IFR 100, Faculty of Medicine, 7 Boulevard Jeanne D'Arc, 21000 Dijon, France 2 Universite de Bourgogne, Dijon, France 3 CNRS USR 3151, P2I2 Group, Station Biologique, Roscoff, Bretagne, France Received: June 22, 2011; Accepted: June 24, 2011; Published: June 24, 2011; Correspondence: Renaud Seigneuric, email: // // Abstract A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards successful clinical trials are presented such as optimizing the delivery of peptide aptamers thanks to Nanotechnology.

The objective of this research was to evaluate the efficacy of a recombinant nonviral vector for targeted delivery of a thymidine kinase (TK) suicide gene to xenograft SKOV-3 tumors. The vector was genetically engineered and used to condense the TK gene into particles of less than 100 nm. The nanoparticles were used to transfect and kill SKOV-3 cancer cells in combination with ganciclovir (GCV) in vitro. The results demonstrated that the vector could effectively kill up to 80% of the SKOV-3 cancer cells. In the next step, the ability of the vector to deliver the TK suicide gene to xenograft tumors of SKOV-3 was studied. The results demonstrated that the vector could transfect tumors and result in significant tumor size reduction during the period that GCV was administered. Administration of GCV for at least 3 weeks post transfection was of paramount importance. These results illustrate the therapeutic efficacy and application of a designed recombinant nonviral vector in cancer gene therapy. From the Clinical Editor A recombinant nonviral vector is used to deliver a suicide thymidine kinase gene under gancylovir control in vitro to SKOV-3 cancer cells with 70% efficiency. Follow on testing in a xenograft tumor demonstrated tumor reduction persisting for three weeks.

Vα24 natural killer T (NKT) cells have potent anti-tumor activity. We performed a phase II clinical study in patients with head and neck squamous cell carcinoma (HNSCC) using ex vivo expanded Vα24 NKT cells and α-galactosylceramide (αGalCer; KRN7000)-pulsed antigen-presenting cells (APCs) to investigate the efficacy and induction of NKT cell-specific immune responses. The subjects were 10 patients with locally recurrent and operable HNSCC. One course of nasal submucosal administration of αGalCer-pulsed APCs and intra-arterial infusion of activated NKT cells via tumor-feeding arteries was given before salvage surgery. Anti-tumor effects, NKT cell-specific immune responses in extirpated cancer tissue and peripheral blood, safety, and pathological effects were evaluated. Five cases achieved objective tumor regression. The number of NKT cells increased in cancer tissues in 7 cases and was associated with tumor regression. The combination therapy induced NKT cell-specific immune responses in cancer tissues that were associated with beneficial clinical effects.

The primary goal of phase II studies is to assess the efficacy of the new treatment in order to decide whether it has sufficient activity to warrant further evaluation in a phase III comparative trial. However, many adequately conducted phase II trials are negative leading to termination of drug development. Heterogeneity of the population is often considered to be a cause of treatment effect dilution. One approach to determine the sensitive subpopulation is to conduct several phase II trials, one in each specific subset of patients. This option might unethically increase the number of non-sensitive patients under evaluation. Adaptive two-stage designs have been recently proposed. London and Chang proposed a global one-sample test for response rates for stratified phase II clinical trials, whereas Jones and Holmgren proposed an adaptive design that allows preliminary determination of efficacy that may be restricted to a specific subpopulation defined by biomarker status. These two methods do not allow early termination for efficacy in one or several subgroups as they are extensions of the Simon design. The authors propose an alternative method to deal with stratification in phase II clinical trials and identification of the best target population. This method is based on the multiple-stage Fleming design allowing for early stopping rules for either efficacy or inefficacy. It also integrates a procedure testing whether treatment effects are similar or heterogeneous between the two groups. The operating characteristics of this method were compared with those of a standard Fleming design using exact binomial probabilities. Copyright © 2011 John Wiley & Sons, Ltd.

Contrary to the incidence of primary cancers, the incidence of brain metastasis has been increasing. This increase is likely because of the effects of an aging population, improved neuroimaging surveillance, and better control of systemic cancer, allowing time for brain metastasis to occur. Unlike systemic cancers, for which chemotherapy is the mainstay of treatment, the therapeutic strategies available to treat brain metastasis have traditionally been limited to surgical resection, whole brain radiation therapy, or stereotactic radiosurgery, either individually or in combination. It is important to put the treatment in the context of the prognosis for patients with brain metastases.

Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans histiocytosis that presents with erosive arthritis and skin nodules. Approximately 25% of patients with MRH have an associated malignancy. Dermatomyositis is an inflammatory autoimmune condition that has also been associated with malignancy. To date, 7 cases of MRH have been reported to present with cutaneous features of dermatomyositis. We describe an eighth patient with MRH who presented with dermatomyositis-like features (V-neck erythema, shawl sign, Gottron’s papules and periungual erythema), who developed metastatic breast cancer 1 year after diagnosis. We hypothesized that clinical overlap between MRH and dermatomyositis was not as uncommon as review of the literature suggested. Careful review of the physical exam findings and photographs of the 234 papers reporting MRH revealed 27 cases of MRH with dermatomyositis-like features. Of these 27 cases, 7 (26%) were associated with a malignancy. Skin biopsies of the cutaneous features mimicking dermatomyositis revealed pathologic features of MRH. This is a descriptive analysis of published case reports. Based on a review of published case reports, MRH presenting with dermatomyositis-like features is likely fairly common. Histological examination of skin biopsies allows for disease differentiation. Differentiating MRH from dermatomyositis is important for management decisions and comorbidity screening.

Skull base metastases (SBM) are rare among all tumors affecting the base of the skull. Because of their rarity, they have received limited attention in the published medical literature. Several clinical syndromes associated with SBM have been described. Knowledge of these syndromes and maintenance of a high index of suspicion are important for an early diagnosis. The majority of patients are best managed by radiotherapy. Other therapeutic options include stereotactic radiosurgery, chemotherapy, and surgery. Surgical resection is reserved for a minority of well-selected patients. The decision to intervene surgically is based on patients' clinical status, the degree of control of systemic disease, the accessibility of the lesion, and the potential morbidity of the procedure. Well-designed trials and evidence-based practice guidelines are not available. The management of these patients largely depends of the experience of the treating medical team.

The main objective of treating brain metastases is to improve survival and to reduce symptom burden, preserve function, and enhance quality of life. As such, concurrent local control of existing brain metastases, prevention of future metastasis elsewhere in the brain, and control of the systemic cancer are required. The treatment modalities used to achieve these aims include surgery, radiation, and medical therapy. This article is devoted to the medical management of brain metastases, namely the role of medical treatments and chemotherapy. Radiation therapy and surgery are discussed in detail elsewhere; however, a brief discussion of all of these modalities is included for the sake of thoroughness.

Item does not contain fulltext Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer. Owing to its rarity, most clinicians are unfamiliar with the clinical aspects and management of UPSC. Furthermore, little prospective evidence exists regarding how best to treat this subset of patients. In anticipation of prospective clinical trials, this article summarizes the latest results of various clinical management options in the different substages of UPSC, with a special focus on the effects of cytoreductive surgery, comprehensive surgical staging and different adjuvant treatment options in relation to recurrence rate and survival outcome.

The objective of this article is to present a concise summary of the most recent evidence-based guidelines in the management of metastatic brain tumors developed by the American Association of Neurologic Surgeons (AANS), Congress of Neurologic Surgeons (CNS), and the AANS/CNS Joint Section on Tumors in 2010. Target populations include patients with newly diagnosed metastases as well as recurrent or progressive lesions. The roles of radiotherapy, surgical resection, and stereotactic radiosurgery along with combination therapies are reviewed. Other topics include the role of chemotherapy, anticonvulsants, steroids, and investigational therapies.

Background Point mutations of the BCR-ABL tyrosine kinase domain are considered the predominant cause of imatinib resistance in chronic myeloid leukemia. The expansion of mutant BCR-ABL-positive clones under selective pressure of tyrosine kinase inhibition is referred to as clonal selection; there are few data on the reversibility of this phenomenon.Design and Methods The changes of expression of mutant BCR-ABL-positive alleles after cessation of tyrosine kinase inhibitor treatment were examined in 19 patients with chronic myeloid leukemia harboring different mutations in a longitudinal follow-up. The proportion of mutant alleles was quantified by amplification of rearranged ABL sequences followed by mutation-specific restriction digestion, electrophoresis and densitometry. The size of mutant clones was established as a measure of the absolute amount of mutant cells considering the proportion of mutant BCR-ABL transcripts and the total level of BCR-ABL obtained by quantitative reverse transcriptase polymerase chain reaction.Results The median proportion of mutant transcripts was 97% before and 8% after cessation of tyrosine kinase inhibitor treatment indicating a relative decline of 88% within a median of 6 months. The relative decrease in the size of the mutant clones was 86%. Repeated selection and deselection of the mutant clone after resumption and second cessation of tyrosine kinase inhibitor treatment was observed in individual patients.Conclusions Deselection of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor treatment might be a common, rapid and reproducible phenomenon, although some patients harboring the T315I mutation showed no deselection. Cessation of tyrosine kinase inhibitor treatment may lead to the regression of T315I mutant clones to a level under the limit of detection, offering the therapeutic option of resumed tyrosine kinase inhibitor treatment under close surveillance of the mutation status.

Venous thromboembolism (VTE) is common in patients with brain tumors. Anticoagulant therapy is feared due to the risk of bleeding, especially intracranial hemorrhage. Emerging treatment approaches targeting angiogenesis, may increase the risk of both thrombosis and bleeding. Recent advances in the cause, prevention, and treatment of VTE in brain tumor patients in the era of antiangiogenic therapy are reviewed.About 20-30% of malignant glioma patients develop clinically significant thromboembolism; however, a recent randomized trial suggested increased intracranial bleeding with the use of prophylactic anticoagulation. Antiangiogenic therapies, especially those targeting vascular endothelial growth factor or its receptor, may increase the risk of thrombosis. New data regarding the safety of anticoagulation concurrent with bevacizumab have emerged.VTE is common perioperatively and throughout the course of brain tumor therapy. Therapeutic anticoagulation followed by secondary anticoagulant thromboprophylaxis is indicated in most patients with DVT or pulmonary embolism, including patients receiving antiangiogenic agents. The role of primary antithrombotic prophylaxis remains unclear.

PURPOSE OF REVIEW: Advances in functional and metabolic imaging have been added to the diagnostic armamentarium for meningioma. New prospective trials have been initiated, and it is foreseen that American Society of Clinical Oncology evidence-level II will be soon available for this brain tumor. This review will focus on recent advances in radiology and their significance for clinical care. The new WHO classification will be detailed. RECENT FINDINGS: Brain invasion is an important criterion in the 2007 WHO classification for atypical meningioma. Apparent diffusion coefficient values on MRI observed with grade II and grade III meningiomas are significantly decreased when compared to benign tumors. [F]fluorodeoxyglucose PET may also predict tumor grade and tumor recurrence. Radio-labeled amino acid PET may be used to delineate target volume for radiotherapy planning. Stereotactic biopsy guidance and functional therapy monitoring could be foreseen using PET-MRI. One phase II study is assessing the benefit of dose escalation for nonbenign meningioma and another evaluates the therapeutic strategy of observation, standard- and high-dose radiotherapy for low-risk, intermediate-risk and high-risk patients. SUMMARY: The use of functional MRI, with or without PET imaging, may be useful in assessing the potential clinical outcome of meningioma. Various therapeutic strategies, including observation and high-dose radiotherapy, are evaluated in two ongoing phase II studies.

Purpose of review Pineal tumors are rare in children, with pineoblastoma and germ cell tumors (GCTs) being the most common. Here we discuss recent advances in treatment and controversies in the management of these tumors. Recent findings There is significant heterogeneity in the clinical behavior of pineoblastoma in children. We will discuss differences in outcome of children with pineoblastoma who are less than and greater than 3 years of age, and between pineoblastoma and nonpineal supratentorial primitive neuro-ectodermal tumors when treated with multiple different strategies. Significant controversies exist in the treatment of GCTs as well, including the levels of tumor markers in the blood and cerebrospinal fluid that are required to establish without biopsy the diagnosis of a GCT, the role of surgery in GCTs and the optimal treatment for germinomas as well as mixed malignant GCTs. Summary Although pineoblastoma in infants and very young children still remains a therapeutic challenge, significant progress has been made in the treatment of pineal GCTs with treatment strategies using a combination of chemotherapy and reduced dose and volume irradiation, resulting in increased survival rates and reduced long-term morbidity.

Purpose of review This review provides available clinical evidence regarding current therapies, discusses ongoing controversies, and introduces investigational approaches in the management of brain metastases. Recent findings Novel approaches to estimating prognosis of patients with brain metastases highlight the importance of tailoring treatment to each particular patient. In the setting of unfavorable prognosis, either hospice care, symptom management, or short-course whole-brain radiotherapy (WBRT) is a critical component of palliation. In the setting of favorable or intermediate prognosis, treatment options can include a slightly more prolonged course of WBRT, surgery, stereotactic radiosurgery, systemic therapy, or a combination. Selection of the appropriate treatment is influenced by the number of brain metastases, overall patient performance status and residual life expectancy, as well as an understanding of the benefits and toxicities of each modality. Recent clinical studies have shed novel insight on the temporal sequence of memory changes following WBRT. Innovative approaches to mitigating these radiation-induced memory effects are currently being investigated. Summary Evidence-based management of brain metastases represents an evolving field of active clinical research. Ongoing and future investigations focus on the preservation of cognition and quality of life, in addition to conventional outcomes such as intracranial tumor control and survival.

Background and Aim. It is unknown whether sorafenib can be combined with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma. This study assesses the safety and tolerability of a continuous regimen of sorafenib combined with TACE. Methods. This was an open-label phase I study testing a continuous administration of sorafenib (dose escalation from 200 mg twice daily [bid] to 400 mg bid) starting 7 days prior to TACE with doxorubicin (50 mg). Results. Twenty-one patients were screened and 14 received sorafenib combined with TACE. Because there were no dose-limiting toxicities in the first three patients who received sorafenib at a dose of 200 mg bid, subsequent patients received 400 mg bid. Twenty-seven procedures were performed (median, two per patient) and two local therapy–related severe adverse events occurred. The median duration of sorafenib therapy was 246 days (range, 14–547 days). Sorafenib-related adverse events of grade ≥3 were hand–foot skin reaction (n = 3), weight loss (n = 2), diarrhea (n = 1), abdominal pain (n = 1), and thrombocytopenia (n = 3). After treatment with sorafenib and TACE, there was a significant decrease in the concentration of plasma vascular endothelial growth factor (VEGF) from 93 ng/l to 67 ng/l. Conclusions. Continuous administration of sorafenib at a dose of 400 mg bid combined with TACE was tolerable. The adverse event profile of this regimen was comparable with that of sorafenib monotherapy with the exception of thrombocytopenia, which may be more frequent. There were no increases in the circulating VEGF levels after TACE with this combined regimen. (Swiss Association for the Study of the Liver study number 25; ClinicalTrials.gov trial identifier, NCT00478374).