Administration Of Chemotherapeutic Agents Research Articles

Concurrent delivery of carmustine, irinotecan, and cisplatin to the cerebral cavity using biodegradable nanofibers: In vitro and in vivo studies

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and the prognosis of patients afflicted with GBM has been dismal, exhibiting progressive neurologic impairment and imminent death. Even with the most active regimens currently available, chemotherapy achieves only modest improvement in the overall survival. New chemotherapeutic agents and novel approaches to therapy are required for improving clinical outcomes. In this study, we used an electrospinning technique and developed biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes that facilitated a sustained release of carmustine (or bis-chloroethylnitrosourea, BCNU), irinotecan, and cisplatin. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the nanofibrous membranes. The experimental results showed that the biodegradable, nanofibrous membranes released high concentrations of BCNU, irinotecan, and cisplatin for more than 8 weeks in the cerebral cavity of rats. A histological examination revealed progressive atrophy of the brain tissues without inflammatory reactions. Biodegradable drug-eluting nanofibrous membranes may facilitate sustained delivery of various and concurrent chemotherapeutic agents in the cerebral cavity, enhancing the therapeutic efficacy of GBM treatment and preventing toxic effects resulting from the systemic administration of chemotherapeutic agents.

A mathematical programming approach to the fractionation problem in chemoradiotherapy

In concurrent chemoradiotherapy, chemotherapeutic agents are administered during the course of radiotherapy to enhance the primary tumor control. However, this treatment often comes at the expense of increased risk of normal-tissue complications. The additional biological damage is mainly attributed to two mechanisms of action, which are the independent cytotoxic activity of chemotherapeutic agents and their interactive cooperation with radiation. The goal of this study is to develop a mathematical framework to obtain drug and radiation administration schedules that maximize the therapeutic gain for concurrent chemoradiotherapy. In particular, we analyze the impact of incorporating these two mechanisms into the radiation fractionation problem. Considering each mechanism individually, we first derive closed-form expressions for the optimal radiation fractionation regimen and the corresponding drug administration schedule. We next study the case in which both mechanisms are simultaneously present and develop a dynamic programming framework to determine optimal treatment regimens. Results show that those chemotherapeutic agents that interact with radiation may change optimal radiation fractionation regimens. Moreover, administration of chemotherapeutic agents possessing both mechanisms may give rise to optimal non-stationary fractionation schemes.

Role of imaging in neoadjuvant therapy for breast cancer.

Neoadjuvant chemotherapy (NAC) involves administration of chemotherapeutic agents to patients with newly diagnosed breast cancer prior to definitive surgical treatment. Assessment of disease response to chemotherapeutic agents in vivo prior to any surgical intervention is necessary as medical oncologists are commonly tailoring or changing therapy during NAC based on response. It can also maximize the pathologic complete response (pCR) rate, resulting in more women undergoing breast conservation rather than mastectomy. Although some studies show a pCR to NAC in only 13-26% of women, recent studies have shown higher pCR rates, especially for HER2-positive disease treated with targeted anti-HER2 therapy. Thus, accurate imaging tools for quantifying disease response are critical in the evaluation and management of patients undergoing NAC. There is currently no standard imaging method for monitoring response to therapy. Response to therapy tends to vary by tumor subtype and can be accurately assessed on imaging. We review the role of imaging before and after neoadjuvant therapy and discuss the advantages and limitations of currently available modalities, including mammography, ultrasonography, magnetic resonance imaging, and nuclear imaging.

Development of a Nanoparticle-Embedded Chitosan Sponge for Topical and Local Administration of Chemotherapeutic Agents.

The following work describes the development of a novel noninvasive transmucosal drug delivery system, the chitosan sponge matrix (CSM). It is composed of cationic chitosan (CS) nanoparticles (NPs) that encapsulate cisplatin (CDDP) embedded within a polymeric mucoadhesive CS matrix. CSM is designed to swell up when exposed to moisture, facilitating release of the NPs via diffusion across the matrix. CSM is intended to be administered topically and locally to mucosal tissues, with its initial indication being oral cancer (OC). Currently, intravenous (IV) administered CDDP is the gold standard chemotherapeutic agent used in the treatment of OC. However, its clinical use has been limited by its renal and hemotoxicity profile. We aim to locally administer CDDP via encapsulation in CS NPs and deliver them directly to the oral cavity with CSM. It is hypothesized that such a delivery device will greatly reduce any systemic toxicity and increase antitumor efficacy. This paper describes the methods for developing CSM and maintaining the integrity of CDDP NPs embedded in the CSM.

Abstract 2984: Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: A clinical study to determine the timing and effect

Abstract Background: Clinically, combination of anti-angiogenic agents with chemotherapeutic agents demonstrated better antitumor efficacy. Instead of merely effect on vasculature regression, careful use of anti-angiogenic therapy may cause the grossly abnormal structure and function of tumor blood vessels to return to a more normal state. Treatment with anti-angiogenic agents can primarily improve chemotherapy efficacy by normalizing tumor vasculature, decrease the intra-tumor interstitial pressure, thereby leading to a more effective drug delivery. We planned to investigate the timing and effect of tumor vascular normalization in human after the administration of anti-angiogenic agent. It may help determine the appropriate timing of administration of chemotherapeutic agents after anti-angiogenic treatment. Materials and methods: This study enrolled the last 8 consecutive patients who participated in a phase II trial for treatment of refractory brain metastases from breast cancer (Eur J Can 49:2s, 2013 suppl; abstr 1878). The protocol treatment consists of bevacizumab 15mg/kg on day 1, chemotherapy of etoposide and cisplatin on day 2 (24 hours after administration of bevacizumab), in 21-day cycles. These 8 patients specifically received four dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations. DCE-MRI was performed before treatment, 1 hour after the end of bevacizumab infusion (i.e., 2.5 hours after starting bevacizumab infusion), 24 hours and 21 days after bevacizumab infusion. This study was registered with ClinicalTrials.gov, identifier NCT01281696, and was approved by the ethical review board. Results: Clinically, all the 8 patients achieved partial remission at central nervous system. All of the 4 DCE-MRI parameters decreased after bevacizumab infusion. Compared to baseline values, the mean reductions at 1 hour and 24 hours were -12.8% and -24.7% for Peak, -46.6% and -65.8% for Slope, -27.9% and -55.5% for iAUC60, -46.6% and -63.9% for Ktrans, respectively (all P values <0.05). The differences between 1 hour and 24 hours reached statistical significance (all P values <0.05) for all the parameters. However, the differences in the mean percentage change between 24 hours and 21 days did not reach significance in any of the four parameters Conclusion: Normalization of tumor vasculature induced by bevacizumab was clearly demonstrated in brain metastases in human at 1 hour after completion of bevacizumab infusion, but significantly became more obvious at 24 hours after bevacizumab administration. Citation Format: Yen-Shen Lu, Bang-Bin Chen, Ching-Hung Lin, Wei-Wu Chen, Pei-Fang Wu, Ann-Lii Cheng, Tiffany Ting-Fang Shih. Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: A clinical study to determine the timing and effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2984. doi:10.1158/1538-7445.AM2014-2984

Epirubicin-loaded superparamagnetic iron-oxide nanoparticles for transdermal delivery: cancer therapy by circumventing the skin barrier.

The transdermal administration of chemotherapeutic agents is a persistent challenge for tumor treatments. A model anticancer agent, epirubicin (EPI), is attached to functionalized superparamagnetic iron-oxide nanoparticles (SPION). The covalent modification of the SPION results in EPI-SPION, a potential drug delivery vector that uses magnetism for the targeted transdermal chemotherapy of skin tumors. The spherical EPI-SPION composite exhibits excellent magnetic responsiveness with a saturation magnetization intensity of 77.8 emu g(-1) . They feature specific pH-sensitive drug release, targeting the acidic microenvironment typical in common tumor tissues or endosomes/lysosomes. Cellular uptake studies using human keratinocyte HaCaT cells and melanoma WM266 cells demonstrate that SPION have good biocompatibility. After conjugation with EPI, the nanoparticles can inhibit WM266 cell proliferation; its inhibitory effect on tumor proliferation is determined to be dose-dependent. In vitro transdermal studies demonstrate that the EPI-SPION composites can penetrate deep inside the skin driven by an external magnetic field. The magnetic-field-assisted SPION transdermal vector can circumvent the stratum corneum via follicular pathways. The study indicates the potential of a SPION-based vector for feasible transdermal therapy of skin cancer.

COMPARATIVE INVESTIGATION OF DIFFERENT METHODS FOR THE DETECTION OF INFECTION IN RABBITS CHALLENGED WITH L. interrogans SEROTYPE hardjo

Keeping up-to-date with modern diagnostic techniques for leptospirosis as well as continuous improvement of laboratory diagnostic methods resulted in abundant knowledge on the nature and consequences of this infection and its importance in both human and veterinary medicine. In that respect, development and introduction of novel diagnostic tests and procedures have become the paramount issue in the diagnostics of leptospirosis and related infectious diseases. Thus, the goal of this research was to investigate the application of diverse laboratory methods and to evaluate their validity in the diagnostics of leptospirosis. Eleven rabbits were artificially infected with live cultures of L. interrogans serovar hardjo by the method of skin scarification. Blood and blood serum samples of challenged animals were collected every other day throughout the 3-week period (i.e. until day 21), and then once weekly during following five weeks. Blood sera were tested for the presence of L. interrogans serovar hardjo specific antibodies applying the methods of microscopic agglutination (MA) test and ELISA. Blood samples were examined using the method of cultivation in liquid medium by Johnson supplemented with 200μg/1ml 5- fluorouracil (5-FU). Presence/absence of L.interrogans serovar hardjo was confirmed by polymerase chain reaction (PCR) method. In this reaction, a pair of primers separated from the basic structure of the Leptospira interrogans rrs (16S) gene. In MA test, the presence of specific antibodies against L. hardjo in rabbits was confirmed in 67 (36.61%) of 183 investigated sera. Initial positive specific antibody finding was recorded on day 9 post challenge, and it persisted until day 17. In ELISA test, positive and suspect findings were confirmed in 67 and 18 samples, respectively. Initial ELISA-positive finding was observed on day 15, showing increasing tendency throughout the monitoring period and reaching its maximum value on day 42. Method of blood sample cultivation resulted in isolation of L. interrogans serovar hardjo in 33 (18.03%) on day 3 at the earliest, whilst highest isolation rate was observed on day 17 post challenge. Applying polymerase chain reaction (PCR) method, genome or genome sequences of L. interrogans serovar hardjo were detected in 67 (56.30%) out of 119 blood serum samples. PCR method revealed positive finding as early as on day 1 post challenge, whereas the highest rate of positive findings was recorded on day 19. Comparison of the results obtained by methods of cultivation and PCR during the period from experimental day 1 to 21, i.e. period prior to administration of chemotherapeutic agents, demonstrated high level of linear correlation of r = 0.8105 at the 0.01 significance level. After dihydrostreptomycin therapy administered from day 21 post infection, L. interrogans serovar hardjo could not be isolated using the method of blood sample cultivation. Contrary to that, PCR method revealed the presence of L. interrogans serovar hardjo genome in 23 samples.

Calculation of Operating Expenses for Conventional Transarterial Chemoembolization in an Academic Medical Center: A Step toward Defining the Value of Transarterial Chemoembolization

PurposeTo determine the “real cost” of conventional transarterial chemoembolization in the treatment of patients with unresectable hepatocellular carcinoma (HCC). Materials and MethodsComprehensive cost data for performance of conventional transarterial chemoembolization were calculated from a retrospective review of records of 50 consecutive outpatient transarterial chemoembolization procedures in 36 patients with HCC. Costs included labor, equipment, facility acquisition and maintenance, overhead, and administrative costs in a single academic medical center. Hourly rate operational costs for the angiography suite and recovery area were calculated, to which the consumable supply costs were added. Conventional transarterial chemoembolization was defined as selective intrahepatic administration of chemotherapeutic agents (doxorubicin and mitomycin C) emulsified in ethiodized oil (Lipiodol). ResultsThe hourly rate to operate an angiography suite at the institution was calculated to be $539/h. Recovery time was calculated at $108/h. Median overall cost of conventional transarterial chemoembolization was $3,269 (range, $2,223–$5,654). This overall cost comprised median room and personnel costs of $763 (range, $404–$1,797), consumable costs of $1,886 (range, $1,134–$4,126), and recovery costs of $378 (range, $162–$864). ConclusionsThe largest contribution (62%) to the real cost of outpatient transarterial chemoembolization comes from the expendable equipment used in the procedure. The angiography suite and personnel costs constitute 25% of the total, and recovery costs constitute 13%. This finding is a change from previous reports in which angiography suite operation was the greatest contributor to cost. Understanding real cost is an essential step in determining the value of the procedure.

Role of podocalyxin in astrocytoma: Clinicopathological and in vitro evidence

The present study examined the expression of podocalyxin (PODX) in surgically-resected astrocytomas, associated the levels of PODX expression with the clinicopathological characteristics and survival outcomes of astrocytoma and assessed how PODX affected the viability of astrocytoma cells following the administration of chemotherapeutic agents. The immunohistochemical analysis of 102 patient samples revealed that a high expression of PODX was significantly associated with high-grade astrocytomas (P<0.001) and a high Ki-67 labeling index (LI; P<0.001). A Kaplan-Meier survival analysis demonstrated that the high PODX expression group had significantly shorter disease-free survival (DFS) and overall survival (OS) rates compared with the low expression group (P<0.001). The multivariate analysis using the Cox’s proportional hazards model revealed that a high expression of PODX, a high World Health Organization grade and a high Ki-67 LI were independent factors for shorter DFS and OS times. A subsequent in vitro study using SW1783 and U-87 human astrocytoma cell lines revealed that knocking down PODX decreased astrocytoma cell viability against temozolomide-induced apoptotic stress through the inhibition of the Akt survival signaling pathway. In conclusion, the in vivo findings indicated that a high expression of PODX is predictive of a poor survival outcome and, thus, may be used as a prognostic factor to predict the survival outcomes of astrocytoma patients. The in vitro findings indicated that PODX may promote astrocytoma cell viability against chemotherapeutic agent-induced apoptotic stress through the Akt pathway, indicating that PODX may be a novel target for overcoming chemoresistance in astrocytomas.

Effects of 5-Fluorouracil on Oxidative Stress and Calcium Levels in the Blood of Patients with Newly Diagnosed Colorectal Cancer

The administration of chemotherapeutic agents for colorectal carcinoma is associated with an increase in oxidative stress and a concomitant decrease in antioxidant and element levels in the blood. This study investigated the effects of 5-fluorouracil (5-FU) chemotherapy on the levels of lipid peroxidation, reduced glutathione (GSH), glutathione peroxidase (GSH-Px), antioxidant vitamins, and elements in colorectal cancer patients. Twelve patients with newly diagnosed colorectal carcinoma and 12 healthy subjects were included in this study. Blood samples were collected from both the healthy controls and patients. 5-FU was intravenously administered to the patients for 6weeks, and blood samples were collected again from the treatment group. In the patient group, lipid peroxidation levels were increased in both the plasma and erythrocyte samples, whereas GSH-Px activity and concentrations of GSH, vitamin E, and β-carotene in erythrocytes were decreased. The oxidant, antioxidant, and plasma calcium values were lower in 5-FU-treated patients than in the controls. Plasma vitamin A, chloride, sodium, and potassium concentrations did not change with 5-FU treatment. In conclusion, oxidative stress in patients with newly diagnosed colorectal cancer is attributable to the disease and not to 5-FU treatment. Blood vitamin E, β-carotene, GSH, and GSH-Px levels could be useful as early biomarkers of the prognosis of colorectal cancer patients.

Should We Modify Follow Up Recommendations for Cardiac Follow-Up of Patients during Oncologic Treatment Using other Parameters in Replacement of LVEF?

Since the initial description of cardiac abnormalities induced by the administration of chemotherapeutic agents there has been a documented evolution of methods to find the evidence of such cardiac dysfunction in the heart. The obvious interest has been, not only to treat, but to perhaps even prevent the cardiac changes altogether. This is well illustrated thru recent history; in particular with the case of adriamycin toxicity (1-2). One of the first methods suggested early on this evolution (1974) was the combination of ECG and chest X Ray films in conjunction to phonocardiography and carotid pulse tracing with serial photography used to describe the ratio of pre-ejection period to left ventricular ejection time (3). Shortly after, in 1976, a new non-invasive method was described using sphygmo-recording of the pulse wave delay (4). Ultrasound imaging quickly followed in a report from the pediatric population (5). Once cardiac imaging was established in the late 70’s and early 80’s; a number of publications supported the different modalities available (5-8). It is then; fair to say that early in the decade of the 1980’s left ventricular ejection fraction (LVEF) was recognized as the traditional method for initial and follow-up evaluation of ventricular function during the administration of cardiotoxic chemotherapeutic agents. At the time the most developed modality, and what was considered the gold standard for the evaluation of LVEF non-invasively was radionuclide angiography. A look into the literature of that time will clearly reveal a chronological and timing advantage of the nuclear imaging modalities. LVEF by radionuclide proved to be sensitive, specific, reproducible and in at least one early report a predictor of early toxicity when used with stress (9). LVEF, as a single measure, was clearly the real strength of this imaging technique. It took years for echocardiography, as an imaging method, to parallel the accuracy values that nuclear tests had so well displayed. After all, it was in 1979 when the LVEF by two dimensional echocardiography methods started to be established and compare favorably with Agonist Jose Banchs, MD, FAcc, FASe

EL12 - Malignant Pleural and Peritoneal Carcinomatosis Treatment

ABSTRACT Malignant pleural and peritoneal carcinomatosis is a potential complication of various types of cancer, the most common of which is lung cancer (accounting for ∼35%), followed by breast cancer, lymphoma, ovarian, and gastrointestinal cancers. Although malignant pleural effusion represents end-stage incurable disease, when symptomatic, they can have a significant effect on quality of life and should be treated. Pleural and peritoneal effusion is considered malignant only when the cytology is positive for malignant cells; in fact, 25% of effusions associated with malignancies may have a negative cytology, which can be misleading. Malignant pleural effusions associated with some malignancies may be responsive to systemic therapy and do not require pleurodesis. Effusions developed during small-cell lung cancer, breast cancer, and lymphoma may respond to systemic therapy and only require occasional therapeutic thoracentesis. However, patients in whom effusion cannot be resolved with systemic therapy should be quickly treated by pleurodesis to minimize the possibility of trapped lung syndrome. While pleurodesis is frequently used in the management of malignant pleural effusion, the optimal strategy remains undefined. Pleurodesis can be carried out in a variety of ways, including instillation of a sclerosing agent such as OK-432, talc, bleomycin, or doxycycline, mechanical pleurodesis, and pleurectomy. In the case of malignant peritoneal effusion, systemic chemotherapy should be used for control of the primary tumor as well as intraperitoneal administration of chemotherapeutic agents. However, no consensus has thus far been reached on the management of this complication other than in ovarian cancer. In this educational seminar, the treatment strategy for managing malignant pleural and peritoneal effusion will be discussed.

Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway in vitro and in vivo.

To investigate reversal effects of pantoprazole (PPZ) on multidrug resistance (MDR) in human gastric adenocarcinoma cells in vivo and in vitro. Human gastric adenocarcinoma cell SGC7901 was cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and antibiotics in a humidified 5% CO(2) atmosphere at 37°C. Adriamycin (ADR)-resistant cells were cultured with addition of 0.8 µg/ml of ADR maintaining MDR phenotype. ADR was used to calculate ADR releasing index; CCK-8 Assay was performed to evaluate the cytotoxicity of anti-tumor drugs; BCECF-AM pH-sensitive fluorescent probe was used to measure intracellular pH (pHi) value of cells, whereas pH value of medium was considered as extracellular pH (pHe) value; Western blotting and immunofluorescent staining analyses were employed to determine protein expressions and intracellular distributions of vacuolar H(+) -ATPases (V-ATPases), mTOR, HIF-1α, P-glycoprotein (P-gp), and multidrug resistant protein 1 (MRP1); SGC7901 and SGC7901/ADR cells were inoculated in athymic nude mice. Thereafter, effects of ADR with or without PPZ pretreatment were compared by determining the tumor size and weight, apoptotic cells in tumor tissues were detected by TUNEL assay. At concentrations greater than 20 µg/ml, PPZ pretreatment reduced ADR releasing index and significantly enhanced intracellular ADR concentration of SGC7901 (P < 0.01). Similarly, PPZ pretreatment significantly decreased ADR releasing index of SGC7901/ADR dose-dependently (P < 0.01). PPZ pretreatment also decreased cell viabilities of SGG7901 and SGC7901/ADR dose-dependently. After 24-h PPZ pretreatment, administration of chemotherapeutic agents demonstrated maximal cytotoxic effects on SGC7901 and SGC7901/ADR cells (P < 0.05). The resistance index in PPZ pretreatment group was significantly lower than that in non-PPZ pretreatment group (3.71 vs. 14.80). PPZ at concentration >10 µg/ml significantly decreased pHi in SGC7901 and SGC7901/ADR cells and diminished or reversed transmembrane pH gradient (P < 0.05). PPZ pretreatment also significantly inhibited protein expressions of V-ATPases, mTOR, HIF-1α, P-gp, and MRP1, and alter intracellular expressions in parent and ADR-resistant cells (P < 0.05). In vivo experiments further confirmed that PPZ pretreatment could enhance anti-tumor effects of ADR on xenografted tumor of nude mice and also improve the apoptotic index in xenografted tumor tissues. PPZ pretreatment enhances the cytotoxic effects of anti-tumor drugs on SGC7901 and reverse MDR of SGC7901/ADR by downregulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway.

Metronomic Chemotherapy in Progressive Pediatric Malignancies: Old Drugs in New Package

Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional chemotherapy at maximal tolerated dose imposes many side effects that further limits the dosing and therefore decreases the anticancer effects. Usually limited options remain when a malignancy progresses after one or two lines of standard chemotherapy protocol. The goal of an oncologist at this point of time remains mainly palliative with an effort to halt the progression of cancer and improve quality of life. Metronomic chemotherapy is defined as the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. It is thought this type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms, promoting apoptosis and immune- surveillance.

Abstract 3789: Development of an animal model for microdialysis sampling of pons and cerebral cortex in rhesus macaques

Abstract Background: We developed a nonhuman primate model using rhesus macaques (Macaca mulatta) to compare drug exposure in cortical brain, pontine tissue, and cerebrospinal fluid (CSF) during systemic administration of chemotherapeutic agents by microdialysis (MD), a continuous in vivo extracellular sampling technique. Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that respond minimally to chemotherapy. We hypothesize that, because of its role in maintaining basic life-sustaining functions, the protective features of the pons, including the blood brain barrier and the blood-cerebrospinal fluid barrier, may further limit antitumor agents from entering the pons compared to cortical brain tissue. Methods: The coordinates and surgical approach for probe placement were determined using 3T MRI (Philips Healthcare, Best Netherlands) and OsiriX imaging software (v 3.9.4) in 4 adult male rhesus macaques (Macaca mulatta). Custom MD cannulas and probes (CMA, Solna, Sweden) were stereotactically implanted in the brain. The pontine MD cannula (34 mm) was implanted superior to the pons, and the MD probe (34 mm shaft plus 8 mm membrane) was then lowered through the cannula, into the pons. The cortical MD cannula (10 mm) was implanted in frontal cortex and a MD probe (10 mm shaft plus 8 mm membrane) was lowered through the cannula. The MD probe inlet/outlet capillaries were connected to a MD infusion pump (CMA 106, flow rate 0.3 µL/min). Retrodialysis was performed to assess in vivo recovery. A systemic intravenous (IV) drug infusion of temozolomide was then administered over 1hr. Single continuous MD samples were collected from both the pons and cortex over 4 hours with concurrent serial plasma and CSF samples (via a subarachnoid or lumbar catheter). Post-surgical MRI verification of MD probe placement was obtained in 2 of 4 animals. Verification of probe placement was obtained via gross pathology and histology in all 4 animals. Results: MRI-determined coordinates and surgical approach for MD probe placement and sample collection in the pons and cerebral cortex was successful in 3 of 4 animals. Surgical monitoring for heart and respiration rates, ETCO2 and SPO2 remained normal in all animals during probe placement and sample collection. Conclusions: MRI-determined coordinates and surgical methodologies resulted in accurate placement of a MD probe in the pons and cerebral cortex of a rhesus macaque allowing for MD sampling from these sites, in conjunction with CSF and plasma sampling, following systemic drug administration. This new animal model allows for the determination of differences in penetration of chemotherapeutic agents in pons, cerebrum, and CSF following systemic drug administration. Additionally, this model provides the foundation for a subcutaneous, semi-permanent, closed system for CNS MD probe placement and continuous sampling in rhesus macaques. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3789. doi:1538-7445.AM2012-3789

Management of Chemotherapy Induced Nausea and Vomiting

Chemotherapy induced nausea and vomiting (CINV) is typically biphasic. The acute phase usually peaks in 5-6 hours after the administration of chemotherapeutic agents and the delayed phase can occur subsequently over 24hours after chemotherapy. Antiemetic therapy is crucial to prevent this unwanted side effect effectively, and NK1 antagonist, 5-HT3 antagonist, corticosteroid are the main player. The combination and dosing is determined by the emetogenicity of the chemotherapeutic agents to be administrated. (Korean J Med 2012;82:532-536)

Metronomic antiangiogenic therapy in children with recurrent brain tumours of different histologies

Children with relapsed malignant brain tumours have a poor prognosis despite intensive treatment including high-dose chemotherapy with stem cell rescue [1, 2]. Angiogenesis, the formation of new blood vessels, is an important component of normal physiological processes such as wound healing and development. Moreover, tumour growth and metastasis is closely related to formation of new blood vessels [3, 4]. Antiangiogenic therapy inhibits neovascularization, thereby inhibiting tumour progression indirectly [5]. The term metronomic chemotherapy refers to the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and without prolonged drug-free breaks. Beside the antiangiogenic effect, metronomic chemotherapy has been shown to modulate anti-tumoural immunity and has the ability to induce tumour dormancy [6]. The combination of agents used in our metronomic antiangiogenic therapy is based on a four-drug regimen (thalidomide, celecoxib, etoposide and cyclophosphamide) published by Kieran et al. in 2005 [7]. We augmented this regimen with bevacizumab, fenofibrate, and intrathecal therapy with the goal to improve progression-free survival for patients with recurrent or refractory CNS tumours for whom no curative therapy is available. We report on our experience with an antiangiogenic metronomic chemotherapy for paediatric patients with recurrent CNS tumours of different histologies.

Circulating tumor cells in the cerebrospinal fluid: “tapping” into diagnostic and predictive potential

Metastatic spread of breast cancer into the central nervous system (CNS) carries an especially ominous prognosis. Successful treatment depends on early and accurate diagnosis [1]. Therefore, it is of paramount clinical importance to develop sensitive and specific methods to detect circulating tumor cells (CTCs) in the cerebrospinal fluid (CSF). Routine cytological examination of the cerebrospinal fluid for tumor cells has many limitations including low sensitivity necessitating repeated lumbar punctures to increase the diagnostic yield [2]. In the October issue of Oncotarget, Patel et al developed a method to adapt the FDA approved CellSearch platform to isolate CTCs from the CSF after spiking them into blood [3]. This novel approach adds a “molecular dimension” to the detection of malignant epithelial cells in the CSF. It hones in on single cells and begins to characterize their surface markers thus opening the door to a better understanding of their role in the metastatic cascade. The CellSearch system defines CTCs as EpCAM+, Cytokeratin+, CD45- nucleated cells. These cells, when isolated from the CSF, may represent a special subpopulation of CTCs capable of surviving the perilous journey in the blood stream and subsequent invasion of the CNS. The next logical step in understanding the biology of this unique cell population will be to search for markers that would predict special affinity for homing into and invading the CNS, surviving and proliferating (i.e. stem cell markers) or for drug resistance [4]. Studying ER/PR and HER-2 concordance between primary or metastatic tumor sites and CTCs in the CSF could also have profound implications. Further studies are needed to create surface marker and genetic “profiles” of this important subset of CTCs. This study also demonstrated correlation between CTC counts in the CSF and the administration of chemotherapeutic agents, a pattern that mirrors that observed with CTCs in the peripheral blood of patients with metastatic breast cancer. Previous studies have confirmed the validity of circulating tumor cell counts in predicting progression free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. For instance, in one study of metastatic breast cancer, patients with more than 5 CTCs had lower PFS (2.7 months vs. 7.0 months, P 18 months, P<0.001). These differences persisted at the first follow-up visit after the initiation of therapy [5]. It would be interesting to see if larger studies confirm similar prognostic and predictive correlation between CTC counts in the CSF and survival or response to therapy. Our understanding of the role of CTCs in the biology of metastases continues to evolve. This valuable study sheds the light on a subset of CTCs capable of invading the blood brain barrier to reach the CNS. Further characterization and profiling of CTCs in the CSF is likely to yield valuable insights into the biology and the behavior of this important subset of cells and to improve our understanding of how CNS metastases occur. Correlation between CTCs counts, their biological characteristics and clinical outcomes will continue to make this area both promising and clinically relevant.

Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.

KRAS assay selection: sensitivity and accuracy in clinical application

KRAS mutation status is routinely tested before the administration of chemotherapeutic agents that target EGFR such as cetuximab and panitumumab. Various commercial assays to analyze KRAS mutational status are currently certified for in vitro diagnostic use. However, the differences in the operational characteristics of the different assays have not been investigated. Since different assays could be different in specificity, sensitivity and precision, studies to clarify the best option for an adequate determination of KRAS mutation status are necessary. Until a gold standard for testing KRAS mutation status is established, the treating physician must interpret the results of any given assay keeping this limitation in mind.