Comparison between oral and enteral tube refeeding in hyperlipidemic acute pancreatitis.

OBJECTIVE: Hyperlipidemic acute pancreatitis (HLAP) remains one of the major digestive emergencies with increasing health risks. Oral refeeding tolerant (ORT) and enteral tube feeding tolerant (ETFT) are commonly used for nutritional management in HLAP. However, the differences between ORT and ETFT are yet to be characterized. PATIENTS AND METHODS: This study included consecutive patients admitted to the Ordos Central Hospital between January 2019 and April 2023, with predefined inclusion criteria. RESULTS: A total of 335 HLAP patients were recruited according to the inclusion criteria. 268 patients were diagnosed with moderately severe acute pancreatitis (MSAP), of which 193 were in the OFT group and 75 in the ETFT group. In the ETFT group, abdominal pain and abdominal distension were significantly higher than that in the OFT group. No significant result was identified in the laboratory data. However, the OFT group showed a higher hospitalization and cost, as well as exocrine insufficiency and newly onset diabetes, than the ETFT group. CONCLUSIONS: Based on the incidence of HLAP retrieved in this study, MSAP is the major type with increasing clinical value. From the nutritional management sense, patients who received OFT showed higher hospitalization and cost, as well as lower exocrine insufficiency and newly onset diabetes.

The clinical characteristic of alcohol-hyperlipidemia etiologically complex type of acute pancreatitis.

OBJECTIVE: The aim of our study was to elucidate the clinical characteristics of alcoholic-hyperlipidemic etiologically complex acute pancreatitis. PATIENTS AND METHODS: We reviewed complete data from 233 patients with acute pancreatitis treated in our hospital during the period January 2017-January 2022. They were divided into three groups according to etiology: alcoholic acute pancreatitis (AAP), hyperlipidemic acute pancreatitis (HLAP), and alcoholic-hyperlipidemic acute pancreatitis (AHAP). General clinical data, co-morbidities, laboratory results, imaging data, and disease severity were analyzed and compared between groups. RESULTS: The proportion of male individuals in the AHAP group was significantly higher than that in the HLAP group (p<0.001). Age of onset was lower and the number of cases with antibiotic use was higher in the AHAP group than in the AAP group (p<0.05). Additionally, the average alcohol intake each time and weekly alcohol intake were also higher in the AHAP group than in the AAP group (p<0.05). Comparison of disease severity (moderate and severe acute pancreatitis, severe acute pancreatitis, and modified computed tomography severity index score) revealed the disease condition to be more severe in the AHAP group than in the AAP and HLAP groups (p<0.05). Accordingly, patients in the AHAP group had longer hospital stays than those in the other two groups (p<0.05). There were no significant differences in alcohol consumption, severity, or length of hospital stay in the AHAP group (p>0.05). CONCLUSIONS: The clinical characteristics of patients in the AHAP, AAP and HLAP groups were different, and the patients in the AHAP group were more likely to have a moderate to severe disease course, with longer hospital stay. As a new AP classification concept, AHAP would offer high significance for diagnosis, treatment, and prognosis.

A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer.

INTRODUCTION: MEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690). METHODS: A standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype. RESULTS: Thirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months-NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1-mutated patients, the ORR was 42.8%. CONCLUSION: The addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.

A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.

BACKGROUND: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks. METHODS: Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients. RESULTS: Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment. CONCLUSIONS: AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.

Factors associated with publication of randomized phase iii cancer trials in journals with a high impact factor.

BACKGROUND: Impact factor (if) is often used as a measure of journal quality. The purpose of the present study was to determine whether trials with positive outcomes are more likely to be published in journals with higher ifs. METHODS: We reviewed 476 randomized phase iii cancer trials published in 13 journals between 1995 and 2005. Multivariate logistic regression models were used to investigate predictors of publication in journals with high ifs (compared with low and medium ifs). RESULTS: A positive outcome had the strongest association with publication in high-if journals [odds ratio (or): 4.13; 95% confidence interval (ci): 2.67 to 6.37; p < 0.001]. Other associated factors were a larger sample size (or: 1.06; 95% ci: 1.02 to 1.10; p = 0.001), intention-to-treat analysis (or: 2.53; 95% ci: 1.56 to 4.10; p < 0.001), North American authors (or for European authors: 0.36; 95% ci: 0.23 to 0.58; or for international authors: 0.41; 95% ci: 0.20 to 0.82; p < 0.001), adjuvant therapy trial (or: 2.58; 95% ci: 1.61 to 4.15; p < 0.001), shorter time to publication (or: 0.84; 95% ci: 0.77 to 0.92; p < 0.001), uncommon tumour type (or: 1.39; 95% ci: 0.90 to 2.13; p = 0.012), and hematologic malignancy (or: 3.15; 95% ci: 1.41 to 7.03; p = 0.012). CONCLUSIONS: Cancer trials with positive outcomes are more likely to be published in journals with high ifs. Readers of medical literature should be aware of this "impact factor bias," and investigators should be encouraged to submit reports of trials of high methodologic quality to journals with high ifs regardless of study outcomes.

Phase 1 study of nab-paclitaxel, cisplatin and 5-fluorouracil as induction chemotherapy followed by concurrent chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the oropharynx.

BACKGROUND: Induction chemotherapy followed by concurrent chemoradiation (CRT) (sequential therapy) has been evaluated in the treatment of locoregionally-advanced squamous cell cancer of the head and neck (LA-SCCHN), with docetaxel, cisplatin (P) and 5-flurouracil (F) shown to be superior to PF doublet. Nab-paclitaxel (A) is a novel albumin-bound paclitaxel with a superior therapeutic index to docetaxel. METHODS: A phase I trial [Clinical trials.gov identifier NCT00731380] to assess the safety and efficacy of nab-paclitaxel+cisplatin+5-fluorouracil (APF) as induction chemotherapy for three cycles, followed by concurrent carboplatin (area-under-curve (AUC) 1.5 weekly) with radiation therapy (RT) (70 Gy/35 fractions), was conducted using a 3+3 design in patients with previously untreated LA-SCCHN. Dose-limiting toxicities (DLTs) included: standard haematologic and non-haematologic toxicities, treatment delays, inability to complete ⩾95% of RT and skin/mucosal toxicity related to RT assessed from day 1 of treatment to 8 weeks after completion of CRT. RESULTS: 17 patients with oropharyngeal cancer were enrolled in three dose levels, with 15 patients evaluable for DLT. The median age was 54 years (range, 44-65 years), 14 patients were male, and 11 patients' tumours were p16 positive and four negative. Grade 3/4 adverse events during APF (%total number of cycles) were hyponatraemia (14%) neutropenia (10%), lymphopaenia (4%) and thrombocytopenia (2%) during 49 evaluable APF cycles. Febrile neutropenia occurred during one cycle of treatment. CONCLUSION: The recommended phase 2 dose of APF is nab-paclitaxel 100mg/m(2) days 1 and 8, cisplatin 75 mg/mg(2) day 1 and 5-fluorouracil 1000 mg/m(2)/day×96 h days 1-4, every 3 weeks, for three cycles prior to CRT.

Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29.

INTRODUCTION: This randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1-3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer. METHODS: Eligible patients received paclitaxel (200mg/m(2)) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4-6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽ 0.70. RESULTS: The trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66-1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71-1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69-1.30, p=0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia. CONCLUSIONS: The addition of cediranib 20mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.

NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies.

PURPOSE: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503).

BACKGROUND: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. METHODS: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. RESULTS: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. CONCLUSION: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.

In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours.

BACKGROUND: Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting. METHODS: We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration. RESULTS: Twenty-two patients were enrolled. Median progression-free survival (PFS) was 3 months (95% CI 2-10.7), and one patient had a partial response. PFS was longer among five patients who demonstrated an increase in pShift after 7 days of sorafenib compared with those who did not (14.9 months vs 2.8 months; P=0.047). However, pShift did not add value to toxicity-based dose-titration. CONCLUSION: The pharmacodynamic assessment of RAF transduction may identify selected patients with advanced NETs most likely to benefit from the combination of sorafenib plus cyclophosphamide. Further investigation of this test as a potential biomarker is warranted.

A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck.

BACKGROUND: An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck (RM-SCCHN). PATIENTS AND METHODS: Eligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate. RESULTS: Sixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 [12.7%, 95% confidence interval (CI) 5.6% to 23.5%] achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs. CONCLUSIONS: Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.

A phase II study of sunitinib in recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC.

BACKGROUND: Vascular endothelial growth factor (VEGF) and c-kit are highly expressed in adenoid cystic carcinoma (ACC) and associated with biologic aggressiveness. This study aimed to assess the antitumor activity of sunitinib, a multi-targeted inhibitor of vascular endothelial growth factor receptor, c-kit, platelet-derived growth factor receptor, ret proto-oncogene (RET) and FMS-like tyrosine kinase 3 (FLT3), in ACC of the salivary gland. PATIENTS AND METHODS: Patients with progressive, recurrent and/or metastatic ACC were treated with sunitinib 37.5 mg daily in this single-arm, two-stage phase II trial. Response was assessed every 8 weeks. RESULTS: Fourteen patients were enrolled on to the study. Among 13 assessable patients, there were no objective responses, 11 patients had stable disease (SD), 8 patients had SD ≥ 6 months and 2 patients had progressive disease as best response. Median time to progression was 7.2 months. Median overall survival was 18.7 months. Toxic effects occurring in at least 50% of patients included fatigue, oral mucositis and hypophosphatemia usually of mild to moderate severity. CONCLUSIONS: Although no responses were observed, sunitinib was well tolerated, with prolonged tumor stabilization of ≥ 6 months in 62% of assessable patients. The lack of responses is comparable with other trials of molecularly targeted agents in ACC and highlights the need for novel strategies in phase II clinical trial design.

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours.

BACKGROUND: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours. METHODS: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. RESULTS: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6-8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. CONCLUSIONS: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.

Influence of an independent review committee on assessment of response rate and progression-free survival in phase III clinical trials.

BACKGROUND: Our objective was to determine the variability in assessment between investigators (INV) and independent review committees (IRC) for response rate (RR) and progression-free survival (PFS). METHODS: Phase III trials reporting INV and IRC assessments were identified. The difference in end point assessment (IRC - INV) across all study arms was determined. A random-effects model was used to calculate the mean difference between INV and IRC RR as well as PFS. Differences in estimated benefits of treatment (experimental - control) between IRC and INV were determined. RESULTS: Twenty-one trials were included (18 RR, 8 PFS). The estimated mean difference between IRC- and INV-determined RR was 4.57% [95% confidence interval (CI) 2.95% to 6.19%]. For median PFS, the estimated mean difference was -0.19 (95% CI -0.68 to 0.29) months. The difference in estimated benefits of treatment ranged from -7.0% to 7.2% for RR and -2.0 to +2.4 months for PFS; there was no evidence of systemic bias by INV (P = 0.54 for RR and 0.31 for PFS). CONCLUSION: INV overestimate RR compared with IRC. Given the variability in assessing RR and PFS between INV and IRC, an IRC should be considered if the primary end point is on the basis of assessments of changes in tumor lesions.

In situ hybridization to detect spatial gene expression in medaka.

A whole-animal tissue section in situ hybridization (ISH) system with radio-labeled probes was developed to detect differential gene expression among tissues of the small, oviparous teleost fish, Japanese medaka (Oryzias latipes). Because of its tissue- and gender-specific expression, gonadal aromatase (CYP19a) was selected as a model gene to demonstrate the potential of the system. The ISH system was validated with a 7d exposure to the model aromatase inhibitor, fadrozole. Fadrozole did not affect the magnitude of gene expression in testes, but significantly up-regulated CYP19a gene expression in ovaries. These results were confirmed with quantitative real-time-polymerase chain reaction (RT-PCR). Histological evaluation revealed that females exposed to 100microg/L fadrozole lacked mature oocytes. Male gonadal morphology was normal in all treatments. The ISH method developed in this study allowed tissue-specific resolution of gene expression in a whole animal model, as well as the ability to analyze cellular morphological detail in the same organism.

Development of a marine fish model for studying in vivo molecular responses in ecotoxicology.

A protocol for fixation and processing of whole adult marine medaka (Oryzias melastigma) was developed in parallel with in situ hybridization (ISH) and immunohistochemistry (IHC) for molecular analysis of in vivo gene and protein responses in fish. Over 200 serial sagittal sections (5microm) can be produced from a single adult medaka to facilitate simultaneous localization and quantification of gene-specific mRNAs and proteins in different tissues and subcellular compartments of a single fish. Stereological analysis (as measured by volume density, V(v)) was used to quantify ISH and IHC signals on tissue sections. Using the telomerase reverse transcriptase (omTERT) gene, omTERT and proliferating cell nuclear antigen (PCNA) proteins as examples, we demonstrated that it is possible to localize, quantify and correlate their tissue expression profiles in a whole fish system. Using chronic hypoxia (1.8+/-0.2 mgO(2)L(-1) for 3 months) as an environmental stressor, we were able to identify significant alterations in levels of omTERT mRNA, omTERT protein, PCNA (cell proliferation marker) and TUNEL (apoptosis) in livers of hypoxic O. melastigma (p<0.05). Overall, the results suggest that O. melastigma can serve as a model marine fish for assessing multiple in vivo molecular responses to stresses in the marine environment.

Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006.

BACKGROUND: Although disease-free survival (DFS) is accepted as a valid end point in adjuvant breast cancer trials, improvement in 2-year DFS has never been formally established as an adequate correlate for 5-year overall survival (OS). We set out to ascertain if changes in 2-year DFS can be used to accurately predict 5-year OS changes. DESIGN: We conducted a systematic Medline search (1966-2006) for randomized adjuvant breast cancer trials of >100 patients per arm with 2-year DFS and 5-year OS data. A univariate regression model weighted by trial sample size was constructed to determine whether 2-year DFS differences between treatment arms within trials were predictive of 5-year OS differences. RESULTS: A total of 126 studies containing 149 treatment comparisons met the inclusion criteria. Difference in 2-year DFS was a significant predictor of difference in 5-year OS. For every 1% increase in 2-year DFS difference, the 5-year OS difference increased by 0.5%-0.55%. The proportion of variation explained ranged from 0.38 to 0.42, with a wide prediction interval. CONCLUSION: There is a statistically significant correlation, of moderate strength, between difference in 2-year DFS between treatment comparisons and difference in 5-year OS but the correlation is not strong enough to be used as a predictor.

A phase I, first in man study of OSI-7836 in patients with advanced refractory solid tumors: IND.147, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, tolerability, toxicity profile, dose-limiting toxicities (DLTs), anti-tumor activity and pharmacokinetics of OSI-7836 given IV on day 1 and day 8 every 3 weeks in patients with advanced incurable cancer. METHODS: Twenty-seven previously treated patients with advanced or metastatic solid tumors were enrolled in this phase I study conducted by the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG). OSI-7836 was administered IV on day 1 and day 8 every 3 weeks. The dose was initially escalated from 100 to 600 mg/m2 and finally de-escalated to 200 mg/m2 in seven cohorts of patients. Patients were evaluated every other cycle of treatment for radiological response. Pharmacokinetics were performed on day 1 and day 8 of cycle 1 for all patients. RESULTS: Twenty-six patients were evaluable for toxicity. All patients experienced reversible Grade 3 lymphopenia beginning at cycle 1. The maximal delivered dose was 600 mg/m2. MTD was reached at 400 mg/m2. DLTs included fever, fatigue, rash, herpes simplex infection, nausea and vomiting. The RP2D was 200 mg/m2. No objective responses were seen in 21 evaluable patients. Pharmacokinetics were dose proportional, with a mean half-life of 46.0 min and a clearance of 34 l/(h.m2). CONCLUSION: OSI-7836 given at 200 mg/m2 on day 1 and day 8 every 3 weekly is associated with manageable toxicity and is recommended for further study. While no objective responses were seen, the significant treatment related lymphopenia suggests that hematologic malignancies may warrant further investigation.

Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study.

BACKGROUND: 7-Hydroxystaurosporine (UCN-01) inhibits serine-threonine kinases including the Ca2+ and phospholipid-dependent protein kinase C (PKC), CDKs 2, 4, 6, Chk-1 and PDK1. UCN-01 mediates distinct effects in vitro/in vivo: cell cycle arrest in G1, abrogation of G2 arrest by inhibiting chk1, induction of apoptosis and potentiation of cytotoxicity of S-phase-active chemotherapeutics including the topoisomerase 1 inhibitor topotecan (T). This phase I study was designed to determine the maximal tolerated dose (MTD), recommended phase 2 dose (RPTD), toxicity profile, pharmacokinetics and antitumor activity of T and UCN-01 in patients with refractory solid tumors. DESIGN: Both agents were administered every 21 days intravenously through central venous access in escalating doses to eligible patients. On day 1, following antiemetic prophylaxis with dexamethasone and a serotonin type 3(A) receptor (5HT3) inhibitor, UCN-01 was infused over 3 h, followed by T infused over 30 min. On days 2-5, patients received T only. UCN-01 doses were reduced by 50% in cycles 2 and beyond because of its prolonged half-life. RESULTS: Thirty-three patients were entered in three cohorts: Dose Level (DL) 1 (UCN-01 70 mg/m2, T 0.75 mg/m2), three patients; DL 2 (UCN-01 70 mg/m2, T 1.0 mg/m2), 24 patients; DL 3 (UCN-01 90 mg/m2, T 1.0 mg/m2), six patients. All but three patients were PS 0 or 1, median age was 54 years (range, 29-72), 91% were female. Primary tumor types: ovary/peritoneal (23 patients), colon (three patients), salivary gland (two patients), others (five patients). All patients were eligible for adverse event (AE) analysis and 22 patients were eligible for survival and tumor response analysis. Two of six patients had dose limiting toxicity (DLT) at DL 3 (grade 3 N/V; grade 4 neutropenia with infection). One DLT was seen in one patient at DL 2, consisting of grade 4 leukopenia. This cohort was expanded and no further DLTs were observed. Most common drug-related AEs were mild (grade 1-2). Non-hematological grade 3-4 AEs consisted of transient hyperglycemia (4), infection (3), coagulation, fatigue, hypotension, nausea (2), hypomagnesemia, vomiting, headache (1). Hematologic toxicities occurred in 100% of patients. Grade 3-4 hematologic abnormalities included neutropenia (16, including three with infection), leukopenia (11), lymphopenia (7), thrombocytopenia (5). Best response for 22 evaluable patients was PD (8), SD for at least six cycles (12), PR (1: carcinoma of ovary, dose level 2) and one not assessable. Pharmacokinetic analysis confirmed the prolonged half-life of UCN-01 of approximately 15 days. CONCLUSIONS: DLT was observed at DL 3 and RPTD was determined to be DL 2. To date, this combination has been relatively well tolerated with some preliminary evidence of efficacy. A phase II study of this combination in patients with ovarian cancer is underway.