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During semen preservation, with the passage of time, there is decrease in fertilization rate or conception rate. The decrease occurs due to the gradual deterioration of semen quality. Hence, the investigation was planned to evaluate the effect of Asparagus racemosus aqueous extract on buck semen quality during preservation. In the current study, 8 ejaculates from 8 Jakhrana bucks were collected (total 64 ejaculates). Good quality semen samples were pooled during each collection. Pooled semen samples were then divided into 4 equal parts, and diluted in TRIS buffer containing different concentration of Shatavari aqueous extract (Different groups, i.e., G I -500 mg, G II-250 mg, G III-125 mg, G IV-0 mg of Shatavari aqueous extract in 100 ml TRIS Buffer). All the diluted semen samples were kept at refrigerated temperature (5ºC) for seven days, and on each day diluted semen was evaluated for various sperm characteristics and antioxidant status. Shatavari aqueous extract exhibited significant (P

Phenytoin toxicity occurs when serum levels exceed the therapeutic level, leading to symptoms such as nystagmus, slurred speech, and decreased coordination. This toxicity is sometimes caused by drug interactions. Interactions between phenytoin and capecitabine are not commonly documented. We report the case of a 52-year-old man taking phenytoin for atypical meningioma who developed symptoms of phenytoin toxicity while receiving capecitabine in the treatment of rectal adenocarcinoma.

Background: Eribulin mesylate is a synthetic microtubule inhibitor that showed cytotoxic synergy in combination with gemcitabine preclinically. This combination was assessed in a Phase I dose-finding trial in patients diagnosed with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort). Methods: Dose escalation was performed in a 3+3 design to identify the recommended phase II dose (RP2D). Two additional expansion cohorts in women with gynaecologic cancers at the RP2D (G), and further dose escalation of metastatic chemotherapy-naive patients (CN), were evaluated. Results: 45 patients were treated: 21 (CP), 10 (G) and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle; however, due to 2 out of 6 dose-limiting haematological toxicities at the first dose level, a reduced dose-intense schedule was assessed. The RP2D was defined at 1.0 mg m−2 eribulin and 1000 mg m−2 gemcitabine day 1 and 8 q3 weeks. No other significant toxicities were observed in the G expansion cohort. Neutropenia prevented further dose escalation in the CN cohort. Objective responses were seen in all three cohorts – 2/21 (CP), 1/10 (G) and 2/14 (CN). Conclusions: The combination of eribulin and gemcitabine was well tolerated at the RP2D.

Various tyrosine kinase signalling pathways affect the development and progression of colorectal cancer (crc). In clinical trials, regorafenib has been associated with a survival benefit in metastatic crc (mcrc). We assessed the safety and efficacy of regorafenib in real-world patients. In a retrospective review of patients with mcrc treated with regorafenib at our institution from 2013 to 2015, patient demographics, treatment, and survival data were collected. Progression-free survival (pfs) and overall survival (os) were estimated using the Kaplan&ndash, Meier method. In total, 48 patients were offered regorafenib, and 35 (73%) started treatment. Of the patients who started regorafenib, 57% were men. Median age in the cohort was 61 years, and all patients had a performance status in the range 0&ndash, 2. Time from diagnosis of mcrc to regorafenib treatment was more than 18 months in 71% of patients. Starting dose was 160 mg in 54% of the patients, 120 mg in 40%, and 80 mg in 6%. Dose reductions occurred in 34% of the patients, and interruptions, in 29%. Best response was progressive disease (60%) and stable disease (17%), response in the rest of the patients was unknown. The most common adverse events on regorafenib (any grade) were fatigue (57%), hyperbilirubinemia (43%), thrombocytopenia (37%), anorexia (31%), and hypertension (31%). The most common grade 3 or 4 adverse events were fatigue (29%), hypophosphatemia (17%), weight loss (11%), and hyperbilirubinemia (9%). Common reasons for discontinuing regorafenib included progressive disease (51%) and toxicity (26%). In patients treated with regorafenib, pfs was 2.4 months (95% confidence interval: 1.8 to 3.3 months) and os was 5.6 months (95% confidence interval: 3.7 to 8.9 months). No factors were associated with survival in univariate or multivariate analysis. In a real-world setting, regorafenib is associated with survival similar to that reported in the randomized controlled trials, but at the expense of toxicity leading to discontinuation in many patients. Future studies of regorafenib should focus on identifying the patients most likely to benefit and on minimizing toxicity.

The annual Eastern Canadian Colorectal Cancer Consensus Conference held in Montreal, Quebec, 17&ndash, 19 October 2013, marked the 10-year anniversary of this meeting that is attended by leaders in medical, radiation, and surgical oncology. The goal of the attendees is to improve the care of patients affected by gastrointestinal malignancies. Topics discussed during the conference included pancreatic cancer, rectal cancer, and metastatic colorectal cancer.

The recurrence of pressure ulcers (PrUs) and dehiscence of reconstructive flap have always been a problem. The present study aimed to evaluate the results of reconstructive flap surgeries in patients with spinal cord injury (SCI) having PrUs, using classic and modified flaps with improvisations to decrease wound dehiscence, flap necrosis and tension in flap. This is a prospective clinical study. The setting was a tertiary care centre in northern India. Thirty-five patients with SCI having 37 stage III and IV PrUs. PrUs were treated using classic and modified flaps with improvisations. The outcome was evaluated using criteria of wound dehiscence, flap necrosis and recurrence. The results of flap surgery were excellent in 32 (86·48%) patients, good in 4 (10·81%) patients and poor in 1 (2·7%) patient. Partial flap necrosis (2·7%), low incidence of PrU recurrence rate at flap site (5·4%) and overall PrU recurrence (11·4%) were the complications observed. Improvisation of classic and modified techniques of flap surgeries along with reinforcement of general care principles of paraplegia can be effective in minimising complications often associated with PrU reconstructive surgery thus improving the ultimate outcome.

Background Numerous studies have demonstrated that EBC survivors report more memory problems than healthy controls. However, evidence of impairment on objective tests of memory remains inconclusive. Past research has focussed exclusively on retrospective memory (remembering information from the past when asked to do so), but the complaints of EBC patients appear better described as “prospective memory” failures defined as forgetting to carry out in the future previously formed intentions. The effective performance of many day-to-day activities relies on PM and its impairment has negative consequences in everyday life. Despite its high ecological relevance, no study has evaluated PM functioning in EBC survivors. Consequently, we assessed the prevalence of PM impairment among EBC survivors in the year following completion of chemotherapy. Methods We undertook a cross sectional quantitative case-control study aiming to recruit 80 patients from the Ottawa Hospital Regional Cancer Centre and 80 matched healthy controls from the community. Patients were within 1 year of having completed a first course of chemotherapy. A standardized test of prospective memory (Memory for Intention Screening Test) was administered to both groups. Following the International Cognition and Cancer Task Force recommendation (2008), impairment was defined as a score that fell one standard deviation below the mean performance of the control group. Standardized measures of depression (CESD), anxiety (STAI) and fatigue (Fact-F) were also completed. Results Data are available on 36 patients and 18 controls. Age was well balanced between the groups (case-control mean age 54y vs. 51y, respectively, p=.204). Overall PM impairment was observed in 41% of the participants. More importantly, the rate of PM impairment was significantly higher in the EBC group than controls (53% vs 17%; p < 0.005; odds ratio = 5.588; 95% CI=1.376 to 22.7). Multivariate logistic regression showed that PM performance was unaffected by age (p=0.459), depression (p=0.358), anxiety (p=0.512) or fatigue (p=0.595). Conclusions These preliminary findings provide further support for the hypothesis that breast cancer treatment can impair cognitive processes and yield new and important insights into the type of memory problems experienced by EBC survivors. They suggest that a significant proportion of patients exhibit deficits in PM, an aspect of memory involved in effective daily functioning. Our results also suggest that emotional distress and fatigue do not contribute to PM functioning. Further studies in this area should be directed at understanding the severity and duration of PM impairment. Acknowledging and studying this vexing problem in EBC survivors will aid in developing appropriate rehabilitation strategies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-15-01.

Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief. We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain. In this multicentre open-label longitudinal trial, 30 &mu, g tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. &ldquo, Responder&rdquo, was defined as a mean reduction of 30% or more in pain intensity from baseline, and &ldquo, clinical responder&rdquo, as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred. Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for &ldquo, responder&rdquo, [16 patients (36%)] or &ldquo, [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after administration ended, the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (2526 patient&ndash, days in total and a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance. Long-term treatment with tetrodotoxin is associated with acceptable toxicity and, in a substantial minority of patients, resulted in a sustained analgesic effect. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Montreal, Quebec, 23&ndash, 25 October 2014. Expert radiation, medical, and surgical oncologists and pathologists involved in the management of patients with gastrointestinal malignancies participated in presentations and discussions resulting in consensus statements on such hot topics as management of neuroendocrine tumours, advanced and metastatic pancreatic cancer, and metastatic colorectal cancer.

Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans.This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose.Thirty-seven patients were accrued on study. Doses ranged from 80 microg/m(2) to 1500 microg/m(2)/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 microg/m(2) and 1350 microg/m(2)/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 microg/m(2) daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer.Aplidine given at a dose of 1200 microg/m(2) daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.

Purpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 × institutional upper limit of normal (IULN) and ALT/AST ≤5.0 × IULN; Group 2 (n = 7): total bilirubin 3.1 to 5.0 × IULN and ALT/AST ≤5.0 × IULN; Group 3 (n = 6): total bilirubin ≤1.5 × IULN and ALT/AST 5.1 to 20.0 × IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 × IULN and ALT/AST 5.1 to 20.0 × IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m2. After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups. Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m2. Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.

Summary Background: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies. Patients and methods: BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred. Results: A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements. Conclusions: The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Halifax, Nova Scotia, October 20&ndash, 22, 2011. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of rectal cancer, including pathology reporting, neoadjuvant systemic and radiation therapy, surgical techniques, and palliative care of rectal cancer patients. Other topics discussed include multidisciplinary cancer conferences, treatment of gastrointestinal stromal tumours and pancreatic neuroendocrine tumours, the use of folfirinox in pancreatic cancer, and treatment of stage ii colon cancer.

Original citation Curr Oncol 2015;22:e305–15. (doi: http://dx.doi.org/10.3747/co.22.2603) Author Description of the Error and Correction It came to our attention that, over the course of putting together this article, we inadvertently forgot to include one of our colleagues, Dr. Celia Marginean, who had contributed to the guidelines. That omission was a complete oversight on our part. The correct author list, affiliations, and conflict of interest disclosures appear here.

BACKGROUND Standard therapy for febrile neutropenia after chemotherapy has consisted of intravenous antibiotic until resolution of both fever and neutropenia. We attempted to shorten the hospital stay by discontinuing intravenous antibiotics in blood culture negative patients who remained clinically stable and afebrile for 48 hours. PATIENTS AND METHODS Febrile neutropenic admissions of non-leukemic patients were reviewed. They were divided by three consecutive six month intervals into Group 1 (prior to initiation of the policy), Group 2 (after the policy was instituted), and Group 3 (to monitor the implementation of the policy after the initial six months). RESULTS There were 134 admissions for neutropenic fever. Median duration of intravenous antibiotic for Group 1 was 7 days (95% Confidence Interval 6-9). It was significantly decreased to 5 days (4-6) and 4 days (3-5) for Groups 2 and 3 respectively (p = 0.004 and p < 0.001). Median duration of hospital stay for Group 1 was 10 days (7-13). It was also significantly decreased to 7 (5-8) and 6 days (5-7) for Groups 2 and 3 respectively (p = 0.04 and p = 0.002). CONCLUSION Early discontinuation of intravenous antibiotics in patients with negative blood culture who remain afebrile and clinically stable for 48 hours results in shorter duration of hospital stay with potential for reduction in hospital costs.

Summary Purpose Dose intensity (DI, expressed in mg/m2wk) may be an important factor in the clinical use of cisplatin (DDP). We have explored the shortening of the cycle interval as a way to increase the DI of DDP. Patients and methods DDP 180 mg/m2 was given intravenously (i.v.) over 4 hours; sodium thiosulfate (STS) was given i.v. in the opposite arm at a loading dose of 4 g/m2, followed by 12 g/m2 over 6 hours. Each cycle was repeated every two weeks. Seventy-five cycles were administered to 28 patients in this clinical trial. Results In 19 patients who received 2 or more cycles of chemotherapy, a delay of three or more days was required on 17/66 courses (26%); the mean DDP DI actually received by these patients was 83 mg/m2/wk (88% of the planned DI). The major side effect was ototoxicity; this occurred in 9 patients (33%), but none required a hearing aid. Myelosuppression was moderate with thrombocytopenia greater than neutropenia. Nephrotoxicity (creatinine > 2 mg/dl) occurred on only 2 cycles (3%). Three patients (11%) developed symptoms of peripheral neuropathy. In 23 evaluable patients, the overall response rate was 39%. Conclusions It is feasible to give 180 mg/m2 of DDP and STS every two weeks with tolerable nephrotoxicity but without blocking other types of toxicity, such as myelosuppression and ototoxicity. The shortening of cycle intervals resulted in a markedly increased DI.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Montreal, Quebec, October 22&ndash, 24, 2009. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management colorectal cancer, such as the management of hepatic and pulmonary metastases, the role of monoclonal antibodies to the epidermal growth factor receptor, and the benefits and safety of chemotherapy in elderly patients. The management of gastrointestinal neuroendocrine tumours and gastric cancer are also discussed.

Hepatocellular carcinoma (hcc) is an uncommon tumour, but its incidence is increasing in Canada and elsewhere. Currently, there are no Canadian recommendations for diagnosis and treatment of hcc, and possible options may have regional limitations. A consensus symposium was held in the Ottawa region to consider current diagnostic and management options for hcc. These recommendations were developed: Diagnosis&mdash, with adequate imaging, a biopsy is not required pre-surgery, but is required before the start of systemic therapy, lesions smaller than 1 cm should be followed and not biopsied, repeat biopsies should be core tissue biopsies, magnetic resonance imaging is preferred, but triphasic computed tomography imaging can be useful Resection&mdash, recommended for localized hcc Radiofrequency ablation&mdash, recommended for unresectable or non-transplantable hcc, should not be performed in the presence of ascites Trans-arterial chemoembolization (tace)&mdash, doxorubicin with lipiodol is the agent of choice, trans-catheter embolization is an alternative for patients if tace is not tolerated or is contraindicated Medical management&mdash, first-line sorafenib should be considered the standard of care Transplantation&mdash, suitable patients meeting Milan criteria should be assessed for a graft regardless of other treatments offered

Background: To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy. Patients and methods: A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS). Results: PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83-1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86-1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand-foot syndrome (4% versus < 1%) were more common with XELOX. Conclusion: XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

Background: HCC is the sixth most common cancer and the third most common cause of cancer death worldwide. Sorafenib treatment improves survival in advanced disease, but no therapy has demonstrated significant activity after progression on sorafenib. Increased methylation of genes implicated in tumorigenesis has been described in HCC and has been associated with outcome and etiology. We evaluated the therapeutic and biologic effects of SGI-110, a hypomethylating agent in patients with HCC. SGI-110, a dinucleotide of decitabine and deoxyguanosine, increases decitabine exposure by protecting it from deamination due to slow release on subcutaneous (SC) injection. PK and PD results of an open-label, phase 2 study in patients with HCC are presented here. Methods: Adults with histologically confirmed, advanced-stage HCC who had received sorafenib, had evidence of disease progression, and ECOG PS 0-1 were enrolled. SGI-110 (SC) was given on D1-5 of a 28-day cycle. Blood samples were taken for PK/PD analysis and, when possible, paired tumor biopsies were taken for analysis of global DNA (LINE-1) and gene-specific methylation and gene expression. Patients were imaged every 8 weeks and allowed to continue treatment after radiologic but not clinical progression. End points include disease control rate (DCR) at 16 weeks, overall response rate, progression-free survival, and overall survival. Results: 50 HCC patients (43M/7F; median age 60 years [range 32-82]; ECOG PS 0/1: 21/29) were enrolled. The initial dose of SGI-110 was 60 mg/m2 (4 patients treated), but due to grade 4 neutropenia, the dose was decreased to 45 mg/m2 for subsequent patients. SGI 110 was well tolerated at 45 mg/m2; myelosuppression was the major adverse event. Full PK was available from 16 patients (3F/13M). The PK profile for SGI-110 after 45 mg/m2 showed protracted conversion to deliver active metabolite decitabine with exposure window lasting beyond 8-hr and mean(SD) decitabine AUC exposures of 94(22) ng*hr/mL that were comparable to those achieved in AML/MDS after 60 mg/m2. Potent LINE-1 demethylation was observed in blood (-35.6%, n = 27) and in tumor (-12.9%, n = 10) DNA; significant demethylation (-27.4%, n = 6) was also observed on promoter of tumor suppressor gene MZB1 which is frequently hypermethylated and silenced in HCC. Conclusions: SGI-110 was well tolerated at a dose of 45 mg/m2 administered SC on D1-5 of a 28-day cycle. PK was consistent with that seen in another solid tumor study and provided more persistent decitabine exposures compared with PK in hematologic malignancies. The PD changes in blood and tumor LINE-1 and MZB-1 methylation are promising and consistent with the desired biologic effect of SGI-110. Analysis for clinical efficacy is ongoing. Citation Format: Anthony El-Khoueiry, Mary F. Mulcahy, Tanios Bekaii-Saab, Richard Kim, Crystal Denlinger, Rakesh Goel, Shweta Gupta, Simone Jueliger, Aram Oganesian, Harold Keer, John Nemunaitis. Pharmacodynamic (PD) and pharmacokinetic (PK) results of the second-generation hypomethylating agent, SGI-110, in patients with hepatocellular carcinoma (HCC) after progression on sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2947. doi:10.1158/1538-7445.AM2015-2947

High performance liquid chromatographic (HPLC) techniques for the quantification of 5-fluorouracil (5-FU) in human plasma have been reported in the literature, however, a low limit of detection was generally found to result in a comparatively low extraction yield. We have developed a simple, rapid and sensitive HPLC method for the measurement of 5-FU in plasma which provides both a low limit of quantification and a high extraction yield. This method involves the solid phase extraction of 5-FU from a 500 microl plasma sample. The extract is then injected into an HPLC system equipped with a C18 (mu)Bondapak column, and a UV detector set at 260 nm. Ethyl acetate and potassium dihydrogen phosphate are used for the solid phase extraction and the HPLC mobile phase, respectively. This method provides in a good baseline, a sharp and symmetrical peak for 5-FU, and a high resolution between 5-FU and the internal standard. The retention time of 5-FU using this method is 4.7 min with a limit of detection of 5 ng/ml, and an extraction yield of 96.2+/-0.5% (SE). The next injection is possible in 11 min, and the coefficients of variation are 4.2-8.9% for interday precision, and 5.2-10.6% for day-to-day reproducibility. An HPLC method has been developed that has a low limit of detection and a high extraction yield. This technique was successfully applied in a clinical pharmacokinetic study of 5-FU.

Aim: Gemcitabine, a nucleoside analogue, and eribulin (E7389), an investigational tubulin-based anti-mitotic drug exhibited synergistic cytotoxic effects pre-clinically and were combined in a Phase I dose finding clinical trial. Methods: A phase I clinical dose-escalation study of these 2 drugs in combination was initiated in patients with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort). Dose escalation was performed in a 3 + 3 design to identify the recommended phase II dose (RPTD). Two additional expansion cohorts consisting of women with gynecologic cancers at the recommended phase II dose (G cohort), and further dose-escalation of chemotherapy-naive patients (CN cohort), were evaluated. Results: Forty five patients were treated in 3 cohorts - 21 (CP), 10 (G), and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, 15 of a 28 day cycle (CP) but due to 2/6 DLTs, a less dose-intense schedule with the 2 drugs given days 1 and 8 on a q21day cycle was assessed. Dose Dose Level N Schedule E7389 (mg/m2) Gemcitbaine (mg/m2) DLT Toxicity 1 (q28) 6 D1,8,15 q28d 0.7 800 2 Thrombocytopenia 1 (q21) 3 D1,8 q21d 0.7 800 2 3 D1,8 q21d 0.7 1000 3-CP 6 D1,8 q21d 1.0 1000 1 Neutropenia 3-G 10 D1,8 q21d 1.0 1000 4-CP 3 D1.8 q21d 1.4 1000 2 Diarrhea; fatigue 4-CN 7 D1,8 q21d 1.4 1000 1 Elevated transaminases 5-CN 5 D1,8 21d 1.6 1000 6-CN 2 D1,8q21d 1.8 1000 1 Neutropenia The RPTD was at dose level 3. No other significant hematologic or non-hematologic toxicities were observed with the CP patients. For the CN cohort, additional escalation at dose levels 4, 5, and 6 was attempted, but due to dose limiting neutropenia seen after Cycle 1, DL3 remained RPTD. Objective responses were seen in all three cohorts – 2/21 (CP), 1/10 (G) and 2/14 (CN). Conclusions: The combination of eribulin and gemcitabine was well tolerated with preliminary evidence of activity being seen. Phase II investigation of this regimen should be considered at a dose of 1.0mg/m2 eribulin and 1000 mg/m2 gemcitabine day 1 and 8 q3 weeks. Support by contract HHSN261201100032C/NO1-CM-2011-00032. Disclosure: All authors have declared no conflicts of interest.

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.

Background: Clinical trial results are usually not validated once a regimen is introduced in clinical practice. The efficacy, tolerability, and quality of life of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were demonstrated in the ACCORD clinical trial (Conroy et al, NEJM 2011). Concerns were related to safety, particularly neutropenic sepsis. Knowledge about oncologists’ implementation approach of this regimen, and clinical management and outcomes of patients receiving FOLFIRINOX combination in clinical practice could help improve on treatment delivery options. Methods: Members of the Canadian Association of Medical Oncologists were invited to participate in a registry to collect information on the treatment and clinical course of patients with advanced/metastatic pancreatic cancer treated with FOLFIRINOX in a regular clinical setting. Data for the planned 200 registry patients is collected via a commissioned web-based collection system. The registry covers all consecutive

Using Lobatto nodes, one-step methods of order six and eight have been obtained for the second-order differential equation y″ = f(x, y), y(x0) = y0, y′(x0) = y′0. The methods are shown to be P-stable. If , then at each integration step a system of dimension 3s, 4s, respectively, has to be solved. The numerical results, for two problems, obtained by using these methods are given in the end.

Erosion of a silastic catheter into the small bowel occurred in two patients who previously had received multiple courses of uncomplicated intraperitoneal (IP) chemotherapy. Although bowel perforation is a recognized complication at the time of Tenckhoff catheter insertion, late erosion of the catheter into the bowel after its use for IP chemotherapy has not been previously reported. Catheter injection with radiographic contrast confirmed the diagnosis, evidence for which included nonspecific clinical findings of intraabdominal infection and pain during chemotherapy infusion.

The dynamic effect of cis-diamminedichloroplatinum(II) (DPP) and its aquated metabolite (DDP-OH) on a dimyristoylphosphatidylserine (DMPS) model membrane was investigated by pressure tuning vibrational spectroscopy. The native species (DDP-Cl) and the aquated species (DPP-OH) were both observed to bind to the carboxylate group of the serine as evidenced by a frequency shift of 1622-1620 cm-1. However, only DDP-OH was observed to bind to the phosphate group (PO(-)2). The binding of either drug to DMPS resulted in an increased pressure required to halt the reorientational fluctuations of the acyl chains, indicating that the distance between the chains were increased. The two drugs did not partition into the matrix of the hydrophobic section in the model membrane. Collectively, these data suggest that DDP-Cl and DDP-OH are capable of binding to the polar head group of DMPS, resulting in an enlargement of the area of the head and a subsequent increase in the intermolecular distance between the acyl chains.