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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

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2–15 X-1900 mg/m2/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2–15 X-1425 mg/m2/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.

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 present book has been well prepared to meet the requirements of the students of Animal and Veterinary Science, Animal Biotechnology and other related fields. The book will serve as a text book not only for students in Veterinary science but also for those who want to know “What statistics in all about” or who need to be familiar with at least the language and fundamental concepts of statistics. The book will serve well to build necessary background for those who will take more advanced courses in statistics including the specialized applications. The salient features are: • The book has been designed in accordance with the new VCI syllabus, 2016 (MSVE-2016). • The book will be very useful for students of SAU's/ICAR institutes and those preparing for JRF/SRF/various competitive examinations. • Each chapter of this book contains complete self explanatory theory and a fairly number of solved examples. • Solved examples for each topic are given in an elegant and more interesting way to make the users understand them easily. • Subject matter has been explained in a simple way that the students can easily understand and feel encouraged to solve questions themselves given in unsolved problems.

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.

Aim This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. Patients and Methods Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m2) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥4 months (SD4) rate; if ≥8 patients had OR+SD4, the study would proceed to stage 2. Results Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. Conclusion Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.

e16107Background: CALGB 80802 study determined that doxorubicin plus sorafenib did not improve survival (OS) compared to sorafenib. The association between platelet count and outcome of patients wi...

Pemetrexed (PEM) is a novel folate antimetabolite which inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. This phase II study was designed to assess the efficacy of Gemcitabine (GEM) and PEM given in a novel schedule in metastatic breast cancer (MBC) patients. Eligible patients had MBC and received one prior chemotherapy regimen for metastatic disease; Performance status (PS) 0–2; measurable disease (RECIST criteria). PEM(500 mg/m2) was administered intravenously (IV) over 10 min prior to GEM(1,500 mg/m2) IV given over 30 min on day 1 every 14 days. Median age of the 16 patients in the study was 54 years (range 33–77). Fourteen patients had a PS of 0/1 and were evaluable for response. There were no reported complete or partial responses, seven patients with stable disease, six patients with disease progression and one patient with unknown response. Most common toxicities were skin rash: Grade 1/2(8) and Grade 3/4(1). Grade 3/4 non-hematological toxicities were fatigue(1); anorexia(1); pneumonia(1); peripheral ischemia(1) and elevation of liver transaminases(1). Three patients experienced febrile neutropenia (FN). This study did not meet the predefined criteria to proceed with additional accrual. This regimen of PEM and GEM showed no clinical activity in the dose and schedule tested.

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.

Thirty-one patients with metastatic colorectal cancer were enrolled in this phase I/II trial of a triple combination of camptosar (C), oxaliplatin (O) and tomudex (T), all given on day one of a convenient three-week schedule. Patients received 257 cycles (1–18) in five cohorts. Toxicity was manageable and haematological toxicity was mild to moderate. Diarrhoea was the main dose-limiting toxicity; nausea and vomiting were common. Fatigue was frequent, moderate in severity and a reason for discontinuation in some patients. The recommended phase II doses were (C) 220 mg/m 2 , (O) 100 mg/m 2 , (T) 2.75 mg/m 2 . A 50% response rate in 30 evaluable patients was confirmed by an independent radiology review board; progression-free survival and overall median survival were 7.3 months and 16.6 months, respectively. Of the 16 patients treated at the recommended dose, 9 (56.3%) experienced partial response. Further evaluation in a randomized study compared to sequential doublets is warranted. Triple combinations could be relevant in curative settings for high-risk patients.

Background: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin in patients with advanced solid tumours, and to identify the maximum tolerated dose of these agents in combination and the dose for use in subsequent studies. Patients and methods: 14 patients were entered onto 3 dose levels consisting of escalating doses of doxorubicin (50 mg/m2, 60 mg/m2 and 70 mg/m2) with 800 mg po bid BAY 12-9566. At all three dose levels, patients received doxorubicin alone in cycle one on day 1. Daily oral dosing with BAY 12-9566 was started on day 8 of cycle 1, and thus doxorubicin was given concurrently with BAY 12-9566 in cycle 2. Patients were continued on treatment until a dose limiting toxicity or tumour progression occurred. Results: Pharmacokinetic studies from cycles 1 and 2 from the patients treated in the first three dose levels demonstrated that the addition of BAY 12-9566 increased the AUC0-12h levels of doxorubicin by a median of 48%. No effects were seen on the BAY 12-9566 pharmacokinetic values. Two dose limiting toxicities were seen at the third dose level. One patient experienced grade 3 stomatitis in cycle 2, and another patient experienced grade 4 granulocytopenia in cycle 1 and grade 4 thrombocytopenia in cycle 2. Thus the maximum tolerated dose of 60 mg/m2 was declared. These toxicities were those that would have been expected from doxorubicin alone. Conclusions: BAY 12-9566 can be safely administered with full doses of doxorubicin without evidence of clinical interaction. The recommended dose of doxorubicin to be combined with BAY 12-9566 800 mg po b.i.d is 60 mg/m2, however, further development of BAY 12-9566 has been abandoned.

Background: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. Patients and methods: Starting doses were Tomudex 2.5 mg/m2 i.v. bolus day 1 and Doxorubicin 30 mg/m2 i.v. bolus day 1, repeated every 3 weeks. Doxorubicin was escalated in increments of 10 mg/m2 to 60 mg/m2, followed by escalation of Tomudex in increments of 0.5 mg/m2 to 3.5 mg/m2, on six dose levels. Twenty-five patients received 127 cycles of therapy, with at least 3 patients treated at each dose level. Results: There was no dose limiting toxicity (DLT) observed in the first five dose levels. Three of six patients on dose level six had DLT. Further dose escalation was not warranted and this was declared the MTD. Grade 3 or 4 granulocytopenia was observed in 16/25 patients, with associated fever in 3/25 patients. Responses were seen in this study with one complete response (duration 12.8 months) and 3 partial responses (median duration 8 months) in 21 evaluable patients. Fourteen patients had stable disease (median duration 2.5 months). All 4 responding patients and 10 patients with stable disease had gastric cancer. Conclusions: The recommended phase-II dose for this combination in future studies is Tomudex 3 mg/m2 and doxorubicin 60 mg/m2 given every 3 weeks.

Purpose: The epidermal growth factor receptor (EGFR) appears relevant in the pathogenesis and progression of colorectal cancer. After completing a phase I pharmacodynamic trial of ZD1839, we undertook a dose expansion trial to examine the antitumour efficacy and adverse effect profile of this agent in a homogeneous group of patients with metastatic colorectal cancer (CRC). Experimental design: Eligible patients with metastatic or recurrent CRC received ZD1839 750 mg daily by mouth. This dose was selected based on a phase I trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Treatment was continued until unacceptable toxicity or disease progression. Results: Twenty-eight patients were enrolled at three NCIC CTG centers. Twenty-three patients had received prior chemotherapy; 12 patients had received three or more regimens. No objective responses were observed in 24 evaluable patients, although 8 patients had stable disease (median duration of 2.2 months). The most frequent drug related adverse events were diarrhea, rash and nausea. Eleven patients required dosing modification (hold or reduction), while 3 patients discontinued therapy because of toxicity. There were no treatment related deaths. Conclusions: ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.

Purpose: A multi-institution phase II study was undertaken by National Cancer Institute of Canada–Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. Patients and Methods: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. Results: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. Conclusion: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

Subungual exostosis is an acquired, benign, and solitary bone tumor of the distal phalanx occurring beneath or adjacent to nail. A 18-year-old man presented with a lump, ulceration, and pain on his right big toe. This complaint was present for the past 2 years. Initially, lump and pain were present, and since the past 6 months ulceration and superadded infection occurred. Plain radiograph showed a calcified lesion that was continuous with the phalangeal cortical surface in the distal dorsal aspect of the big toe. Excisional biopsy with complete nail removal and reconstruction of the tip of the toe were done. Histopathology confirmed the diagnosis of subungual exostosis. Clinical or radiological recurrence was not observed after 26 months of follow-up. The case is reported to present the tumor overview and to highlight that the diagnosis of this benign lesion should not be missed. Clinical and radiological features allow early diagnosis and treatment thus preventing the lesion to progress to the stage of onycholysis. Level of Evidence: Therapeutic, Level IV

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

A rapid, simple and sensitive isocratic High Performance Liquid Chromatography (HPLC) method was developed to measure the concentration of etoposide in plasma samples with UV detection at 220 nm. The method uses a Bondapac C18 column at 60 degrees C. The mobile phase consists of Methanol: water (45:55 v/v) at a flow rate of 2.8 ml/min. Phenacetin was used as an internal standard. The plasma samples were extracted using ether with the organic layer evaporated under nitrogen. The residue was dissolved in 200 microl methanol with 20 microl injected into the HPLC column. The extraction method showed a recovery of 91.5+/-3% for etoposide. In this system, the retention time of phenacetin and etoposide were 3.3 and 4.4 min, respectively. The limit of detection of etoposide in plasma is 20 ng/ml and the limit of quantitation is 40 ng/ml. This analytical method has very good reproducibility (8.1% between-day variability at a concentration of 50 ng/ml). It is a fast, sensitive and economic method applicable for clinical and pharmacokinetic studies.

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

Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150-300mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%: median duration (MD) 20 months; range 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months: range 3.5-38): 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1,839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

The objective of this phase I-II study was to determine the efficacy and toxicity of combination chemotherapy with 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and oral etoposide (FLAME) in patients with measurable unresectable or metastatic gastric cancer. Starting doses on the phase I study were as follows: methotrexate 50 mg/m 2 intravenous bolus day 1; leucovorin 20 mg/m 2 intravenous bolus days 2 through 4, starting 24 hours after the methotrexate dose; 5-fluorouracil 325 mg/m 2 intravenous bolus 15 minutes after leucovorin days 2 through 4; doxorubicin 25 mg/m 2 intravenous bolus day 8; and oral etoposide 50 mg/day for 14 days, starting on day 8. A new cycle started on day 28. A total of 42 patients were treated-10 patients in the phase I study and 32 patients in the phase II study. Dose-limiting toxicity was encountered in the phase I study on the second escalation step, when doxorubicin was escalated to 30 mg/m 2 and 5-fluorouracil was escalated to 350 mg/m 2 . In the phase II study 28 patients (109 courses) were evaluable for toxicity. Neutropenia grade 3 or more was dose limiting and was documented in 12 patients (43%) during 22 treatment courses (20%). Neutropenia was associated with febrile neutropenia requiring hospitalization in four patients during five courses of therapy. Grade 3 stomatitis and grade 3 diarrhea was infrequent, documented in two patients (two courses) and three patients (four courses), respectively. All other toxicity was grade 1 and grade 2. The combined objective response rate in 38 evaluable patients entered in both studies was 23.3% (six partial responses and one complete response). Stable disease was documented in 15 patients (39.5%). The median survival for the 42 patients entered in both trials was 6.9 months (95% confidence interval, 5.9-8.5 months). The objective response rate and median survival for the combined group is comparable with that reported for the etoposide, leucovorin, and 5-fluorouracil (ELF), and 5-fluorouracil and methotrexate (FMTX) regimens in a recently reported, multicenter, phase III study.

We studied the toxicity and efficacy of adding to epirubicin five resistance modulators in the treatment of resistant solid tumors. Additional drugs were added in successive cohorts of patients, such that cohort 1 patients received two drugs along with their epirubicin, while cohort 4 patients received five modulators along with their epirubicin. Metronidazole, tamoxifen (cohort 1), dipyridamole (cohort 2), ketoconazole (cohort 3) and cyclosporin (cohort 4) were administered with epirubicin. A total of 22 patients were treated. Nausea and vomiting was usually mild to moderate. There was an unexpectedly high incidence of possible cardiac toxicity associated with treatment, although in some patients it was uncertain whether or not observed cardiac events were related to treatment. Granulocytopenia was significant in all four cohorts, but it was unclear whether it was increased by the modulators. There were two febrile neutropenic events in cohorts 1 and 2 successfully treated with antibiotics, and three septic deaths (one in each of cohorts 1, 2 and 4). It was elected to discontinue enrollment on the study prematurely in light of cardiac and other toxicity seen in the first two patients accrued in cohort 4. A single response was observed. While this approach is feasible, the observed toxicity and the difficulty patients experienced in ingesting the large number of prescribed pills will make further exploration of this approach difficult.

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.

195Pt and 15N nuclear magnetic resonance (NMR) was used to study the chemical equilibria of cisplatin in water and plasma ultrafiltrate (PUF). Cisplatin was found to be stable for at least 2, but no longer than 5 months in a reconstituted clinical formulation, as determined by 195Pt NMR. In aqueous solution, the cis-PtCl2(NH3)2 195Pt and 15N NMR signal intensities decreased with time and the formation of [PtCl(H2O)(NH3)2]+ at PH values of 3.0, 6.5, 7.5 and 9.5 was observed within 24 h of sample preparation. In addition, [Pt(H2O)2(NH3)2]++ was observed at pH 3.0, and [PtCl(OH)(NH3)2] and [Pt(OH)2(NH3)2] were observed at pHs 7.5 and 9.5. During incubation of PUF with cisplatin for 35 h, 15N NMR signals for at least eight cisplatin derivatives appeared at different times, whereas only four were observed by 195Pt NMR. With our NMR protocols, the detection limit for quantifiable cisplatin derivatives is estimated at 500 microM using 195Pt NMR andor = 200 microM using 15N NMR. In addition to providing useful information about the chemical stability of cisplatin and derivatives formed in aqueous solution, these magnetic resonance techniques, particularly 15N NMR, can provide useful information about the metabolism of cisplatin in biological regimes.

This study investigated the status of Solute carrier 27A1 (SLC27A1) polymorphism in Indian cattle breeds (n = 102) using PCR-RFLP assay and its association with milk production and reproduction traits. Two region of SLC27A1 gene consisting of exon 3 and exon 4 revealed 261 and 160 bp products, respectively. The digestion of 261 bp product using SacII restriction enzyme (RE) resulted in monomorphic pattern; only GG genotype. The BsaHI/PCR-RFLP assay revealed three types of genotypes, namely, TT (160 bp), CC (106 and 54 bp) and heterozygous CT (160, 106 and 54 bp) genotypes with frequencies 18.62, 59.80 and 21.56 %, respectively. The allelic frequency of C and T alleles were 0.71 and 0.29, respectively. Association study revealed that lactation period (LP), milk yield in 300 days (MY300), calving interval (CI), peak yield (PY) and days to reach peak yield (DRPY) had non-significant difference among all the three genotypes in first and second lactations. while, significant difference was (P=0.028) observed for total milk yield (TMY), where TMY of CC genotype was significantly higher than CT and TT genotypes in only first lactation. Results indicated that C allele for SLC27A1 gene can be used as candidate gene for marker assisted selection in Sahiwal and Hariana cattle.

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.

4032Background: Metastatic gastric and GEJ cancer is a leading cause of cancer-related mortality. Systemic chemotherapy remains the primary treatment but optimal agents and schedule remain controve...

In this paper, we present measurements of CO and NO emissions and the fraction of the heat of reaction emitted as radiation for a two stage burner. The fuel-air mixtures of different equivalence ratios were burned in two separate porous ceramic sections. The primary radiating surface in this burner is the outer cylindrical surface of the porous media. We compared the two stage results to those obtained by burning the entire mixture in a single stage. The emissions of NO and CO from the two stage burner were lower than those from the single stage burner. In addition, the emissions of the two stage burner could be minimized by proper choice of the equivalence ratios in the two stages without significantly affecting the radiant fraction. Typical values of NO and CO emissions from the two stage burner were l7-30 ppm and 10-75 ppm (corrected to 0% O2), respectively, for an overall equivalence ratio of 0.75-0.95. Typical radiant fractions were 35-45% for an energy input of 3.9-7.1 kW. For the two stage...

192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m2. The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.

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.