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The emergence, spread, and persistence of antimicrobial resistance (AMR) remains a pressing global concern. Increased promotion of commercial small-scale agriculture within low-resource settings has facilitated an increased use in antimicrobials as growth promoters globally, creating antimicrobial-resistant animal reservoirs. We conducted a longitudinal field study in rural Ecuador to monitor the AMR of Escherichia coli populations from backyard chickens and children at three sample periods with approximately 2-month intervals (February, April, and June 2017). We assessed AMR to 12 antibiotics using generalized linear mixed effects models (GLMM). We also sampled and assessed AMR to the same 12 antibiotics in one-day-old broiler chickens purchased from local venders. One-day-old broiler chickens showed lower AMR at sample period 1 compared to sample period 2 (for 9 of the 12 antibiotics tested); increases in AMR between sample periods 2 and 3 were minimal. Two months prior to the first sample period (December 2016) there was no broiler farming activity due to a regional collapse followed by a peak in annual farming in February 2017. Between sample periods 1 and 2, we observed significant increases in AMR to 6 of the 12 antibiotics in children and to 4 of the 12 antibiotics in backyard chickens. These findings suggest that the recent increase in farming, and the observed increase of AMR in the one-day old broilers, may have caused the increase in AMR in backyard chickens and children. Small-scale farming dynamics could play an important role in the spread of AMR in low- and middle-income countries.

In the food industry, oil blending represents a simple method for the generation of products with desired nutritional and technological properties. The objective of this work was to blend anchoveta oil (AO) with virgin olive oil (VOO) to modify the ω-6/ω-3 ratio of the product for nutritional purposes and to evaluate its oxidative stability index (OSI) for technological purposes. Four AO/VOO blends were formulated: 50/50, 40/60, 30/70 and 20/80 (w/w), generating a ω-6/ω-3 ratio between 0.610–2.129, nutritionally recommendable. The Rancimat method allowed determining the OSI of the formulations at temperatures of 100, 110 and 120 °C, finding OSI ranges between 0.963–3.410 h, 0.430–1.730 h and 0.183–0.813 h, respectively. The kinetic behavior of the formulations with respect to activation energy (89.622 to 93.414 kJ/mol), entropy (−13.248 to −17.657 kJ/mol), enthalpy (86.455 to 90.248 kJ/mol), Gibbs energy (91.928 to 96.348 kJ/mol) and Q10 (2.090 to 2.153) has been described. The formulations are proposed as an alternative to increase the shelf life of AO and increase the nutritional value of VOO.

This paper provides an overview of plant system studies to establish a common technical view for Sodium-cooled Fast Reactor (SFR) concept (the common SFR concept) between France and Japan based on ASTRID 600 and the new concept with downsized output (ASTRID150). One of important issues on a reactor structure design is to enhance seismic resistance to be tolerable against strong earthquake such that postulated in Japan. A concept of High Frequency Design (HFD) is shared, in which the natural frequency of the reactor structure should be higher than that of peak acceleration of vertical floor seismic response with a horizontal seismic isolation system. The design options related to HFD have been examined and design recommendations are established. ASTRID 600 adopted a gas power conversion system to strictly eliminate the chemical reaction risks due to the proximity of sodium and water in the steam generator units. On the other hand, a steam generator (SG) is thought to be a concept with high technical readiness level and is a reference option in Japan and a backup option in France. Then, design comparison of the SG with single-walled helical coil tubes was mainly conducted in this study from the viewpoint of safety and so on. A common concept of a decay heat removal system is discussed to achieve practical elimination of loss of decay heat removal function. A fuel handling system studies are performed to eliminate and ex-vessel storage of spent fuels in sodium to reduce a construction cost. An adequate confinement system is investigated to achieve practical mitigation of large radiological release to the environment even under the condition of core destructive accident.

In the frame of the France-Japan agreement on nuclear collaboration, a bilateral collaboration agreement on nuclear energy was signed on March 21st, 2017, including a topic dedicated to Sodium-cooled Fast Reactor (SFR). This agreement has set the framework to start a bilateral discussion on a joint view of an SFR concept. France (CEA and FRAMATOME) and Japan (JAEA, MHI and MFBR) have carried out these studies from 2017 to 2019. Based on the beginning of the basic design phase of ASTRID project − ASTRID − 600 MWe (ASTRID for Advanced Sodium Technological Reactor for Industrial Demonstration), the two countries performed a common work to examine ways to develop a feasible common design concept, which could be realized both in France and in Japan. The subject was then extended and extrapolated with the ASTRID − 150 MWe data (reduced power reactor and enhanced experimental capabilities) in a second phase of this study. France and Japan first focused on design requirements. Common requirements were identified, as well as differences in the safety approach and the structural design requirements, according to national standards and respective site conditions, in particular considering seismic hazards. The teams developed common Top-Level design Requirements (TLRs) to allow common specification data, then joint design. This collaborative work was carried out through the implementation of twelve France-Japan Working Groups, working jointly. This paper is providing a review of this joint synthesis on Sodium Fast Reactor design concept. It is summarizing the context and objectives, then the definition and approaches of the Top Level Requirements. This paper is then dealing with the major design features: the core design and their related safety aspects, and the nuclear island design. Thus, this paper is providing a comprehensive review of this joint work gathering French and Japan nuclear design teams during two full years.

From 2010 to 2019, the French Alternative Energies and Atomic Commission (CEA) associated with industrial partners realized the Basic Design of a prototype Sodium Fast Reactor. This project was called ASTRID (ASTRID for Advanced Sodium Technological Reactor for Industrial Demonstration). ASTRID design studies were financed through governmental funds until the end of the basic design. These funds covered also the design studies for the core manufacturing workshop, the refurbishment or construction of large test loops. One year before the term of this Basic Design phase (in 2018), industrial partners, CEA and the French State conducted a review of fast neutrons reactors and fuel cycle strategy. The review which is now translated into the Multiannual Energy Program concluded that the perspective of industrial deployment of Fast Reactors is more distant. Yet it has been concluded to keep this option open, requiring to maintain competences, and to progress on technological barriers and further develop know-how. The strategy for complete closure of nuclear fuel cycle is maintained as a long-term sustainability objective (in the second half of the 21st century). Therefore, as a direct consequence of this decision, the ASTRID project stopped at the end of 2019 at its Basic Design phase. Quickly the question raised on the Knowledge Management (KM) and Know-How capitalization of the huge amount of studies and results realized during ten years (around 23 000 technical documents). Moreover the challenge was to realize this KM process in less than one year, before the ASTRID project team definitive split. The paper is presenting an innovative KM methodology which has been created and specifically performed on the ASTRID project. It is based on a series of interviews and video recordings, all transformed into some New KM tools called “MOOK” (MOOK for Management of Organized Online Knowledge). All these MOOKs considered as “data rich contents” are then inter-connected and linked by the ASTRID Product Breakdown Structure to some fundamental documents, for a comprehensive and quick mapping of the project. They finally form an efficient KM tool recorded in a PLM Software (PLM for Product Lifecycle Management). Thus the ASTRID project team has realized a high level and easy-to-use “GPS” (Global Positioning System) tool to keep the ASTRID history, context, knowledge and know-how for years. This KM methodology can be easily adapted to other nuclear projects and needs.

Workplace violence is a significant problem in industry, especially among rank-and-file workers, known as "blue-collar workers". This systematic review and meta-analysis aim to evaluate the suitability of the reduced Negative Acts Questionnaire (NAQ-R) as an instrument to measure workplace violence in this type of population and synthesize the results of studies that have used it in different industrial sectors. A systematic review was conducted in accordance with the PRISMA 2020 statement. Publications describing populations of industrial workers were identified and included in the meta-analysis. For meta-analysis, we extracted data that allowed us to estimate the effect size of the included studies. We used a random-effects model to estimate the overall effect size and assessed heterogeneity between studies using the I² statistic. The global effect size test showed that the overall effect size was significantly different from zero (3.00, t=22.28, p<0.001), indicating an overall effect in relation to workplace violence measured by the NAQ-R in industrial workers. Our results support the claim that the NAQ-R is an effective tool for assessing workplace violence among industrial workers. These findings have important implications for practitioners and researchers working in the field of industrial psychology and occupational health.

The use of antimicrobial growth promoters in chicken farming has been commonly associated with high levels of antimicrobial resistance (AMR) in humans. Most of this work, however, has been focused on intensive large-scale operations. Intensive small-scale farming that regularly uses antibiotics is increasing worldwide and has different exposure pathways compared with large-scale farming, most notably the spatial connection between chickens and households. In these communities, free-ranging backyard chickens (not fed antibiotics) can roam freely, whereas broiler chickens (fed antibiotics) are reared in the same husbandry environment but confined to coops. We conducted an observational field study to better understand the spatial distribution of AMR in communities that conduct small-scale farming in northwestern Ecuador. We analyzed phenotypic resistance of Escherichia coli sampled from humans and backyard chickens to 12 antibiotics in relation to the distance to the nearest small-scale farming operation within their community. We did not find a statistically significant relationship between the distance of a household to small-scale farming and antibiotic-resistant E. coli isolated from chicken or human samples. To help explain this result, we monitored the movement of backyard chickens and found they were on average 17 m (min-max: 0-59 m) from their household at any given time. These backyard chickens on average ranged further than the average distance from any study household to its closest neighbor. This level of connectivity provides a viable mechanism for the spread of antimicrobial-resistant bacteria and genes throughout the community.

Purpose: Ixabepilone is a microtubule stabilizer with activity in taxane-refractory metastatic breast cancer and low susceptibility to taxane-resistance mechanisms including multidrug-resistant phenotypes and high β-III tubulin expression. Since these resistance mechanisms are common in triple-negative breast cancer (TNBC), ixabepilone may have particular advantages in this patient population. This study evaluated the substitution of ixabepilone for paclitaxel following doxorubicin/cyclophosphamide (AC) in the adjuvant treatment of early-stage TNBC., Methods: Patients with operable TNBC were eligible following definitive breast surgery. Patients were randomized (1:1) to receive four cycles of AC followed by either four cycles (12 weeks) of ixabepilone or 12 weekly doses of paclitaxel., Results: 614 patients were randomized: 306 to AC/ixabepilone and 308 to AC/paclitaxel. At a median follow-up of 48 months, 59 patients had relapsed (AC/ixabepilone, 29; AC/paclitaxel, 30). The median time from diagnosis to relapse was 20.8 months. The 5-year disease-free survival (DFS) rates of the two groups were similar [HR 0.92; ixabepilone 87.1% (95% CI 82.6-90.5) vs. paclitaxel 84.7% (95% CI 79.7-88.6)]. The estimated 5-year overall survival (OS) rates were also similar [HR 1.1; ixabepilone 89.7% (95% CI 85.5-92.7) vs. paclitaxel 89.6% (95% CI 85.0-92.9)]. Peripheral neuropathy was the most common grade 3/4 event. Dose reductions and treatment discontinuations occurred more frequently during paclitaxel treatment., Conclusions: Treatment with AC/ixabepilone provided similar DFS and OS in patients with operable TNBC when compared to treatment with AC/paclitaxel. The two regimens had similar toxicity, although treatment discontinuation, dose modifications, and overall peripheral neuropathy were more frequent with AC/paclitaxel., Trial Registration: Clinical Trials.gov Identifier, NCT00789581.

Purpose: Adding antiangiogenic therapy to standard chemotherapy has improved response rates and progression-free survival in metastatic breast cancer (BC) patients. This phase II study evaluated cardiac safety of bevacizumab with/without trastuzumab with two docetaxel-based regimens in early BC., Methods: 127 women with non-metastatic node-positive or high-risk node-negative BC were enrolled. Women with human epidermal growth factor receptor 2 (HER2)-negative BC (n = 93) received docetaxel/doxorubicin/cyclophosphamide (TAC) + bevacizumab, while women with HER2-positive disease (n = 34) received docetaxel/carboplatin/trastuzumab (TCH) + bevacizumab, every 3 weeks for six cycles. Maintenance therapy with bevacizumab alone or bevacizumab plus trastuzumab, respectively, was given every 3 weeks for 52 weeks. The primary objective was to evaluate cardiac safety, as measured by the incidence of ≥ grade 3 clinical congestive heart failure (CHF); the secondary objective was assessment of safety and toxicity., Results: At least one cardiac adverse event (AE; CHF, cardiomyopathy, or left ventricular dysfunction) was reported in 26.1% of TAC (n = 92) and 17.6% of TCH subjects (n = 34); there were no cardiac deaths. ≥ Grade 3 clinical CHF was observed in 4.3% in the TAC plus bevacizumab stratum and 0% in the TCH plus bevacizumab stratum. A ≥ grade 3 treatment-emergent AE (any kind) related to study treatment was observed in 59.8% in the TAC with bevacizumab and 52.9% in the TCH plus bevacizumab stratum., Conclusion: Adding bevacizumab to a docetaxel-based regimen with trastuzumab did not appear to increase cardiotoxicity., Trial Registration: ClinicalTrials.gov Identifier: NCT00446030, registered March 8, 2007.

Purpose: The American Society of Clinical Oncology (ASCO) published a study in 2007 that anticipated a shortage of oncologists by 2020. This study aims to update and better assess the market for chemotherapy and radiation therapy and the impact of health reform on capacity of and demand for oncologists and radiation oncologists., Methods: The supply of oncologists and radiation oncologists, by age, sex, and specialty, was projected through 2025 with an input-output model. The Medical Expenditure Panel Survey, commercial claims, and Medicare claims were analyzed to determine patterns of use by patient characteristics such as age, sex, health insurance coverage, cancer site, physician specialty, and service type. Patterns of use were then applied to the projected prevalence of cancer, using data from the SEER Program of the National Cancer Institute., Results: Beginning in 2012, 16,347 oncologists and radiation oncologists were active and supplying 15,190 full-time equivalents (FTEs) of patient care. Without consideration of the Affordable Care Act (ACA), overall demand for oncologist services is projected to grow 40% (21,255 FTEs), whereas supply may grow only 25% (18,997 FTEs), generating a shortage of 2,258 FTEs in 2025. When fully implemented, the ACA could increase the demand for oncologists and radiation oncologists by 500,000 visits per year, increasing the shortage to 2,393 FTEs in 2025., Conclusion: Anticipated shortages are largely consistent with the projections of the ASCO 2007 workforce study but somewhat more delayed. The ACA may modestly exacerbate the shortage. Unless oncologist productivity can be enhanced, the anticipated shortage will strain the ability to provide quality cancer care.

Stenoma catenifer Walsingham is the major pest in avocado groves (Persea americana Mill.) in the Neotropical region. Management has been difficult for many reasons related to the reduced knowledge on its bioecology and the avocado growing systems. The goal of this work was to study the vertical distribution of S. catenifer in avocado plants, the gagging effect of infested fruit on its survival, and the losses caused. The experiments were conducted in a commercial grove located at the São Tomás de Aquino, State of Minas Gerais, Brazil, during the 2001/2002 and 2002/2003 growing season. S. catenifer was observed especially at the lower and central part of the plant, and the inner canopy was the least attacked in comparison with the north, south, east and west quadrants. These results may be important indicators for the use of am adequate sampling procedure. The highest percentage of attacked fruit had one to four larvae; in some cases up to eight individuals per fruit were found. The losses caused by the borer varied during the agricultural season, with figures close to 5% in a single evaluation, and the harvest loss may reach 27%. The bagging of infested fruit caused mortality of S. catenifer, as observed through the evaluation carried out four days later.

Human sulfotransferase 1A1 (SULT1A1) is involved in the metabolism of a number of substances including 4-hydroxytamoxifen. It has been shown that patients who are homozygous for the variant SULT1A1 *2/*2 have lower catalytic activity. Previous data has suggested that patients with this particular genotype may be at a greater risk of developing breast cancer or not responding to tamoxifen therapy. To date, there is no data within the Hispanic population on the genotypic and allelic frequencies of the SULT1A1 gene. Two hundred and ninety-six patients were genotyped by either restriction fragment length polymorphism (RFLP) or Pyrosequencing for the SULT1A1 exon 7 polymorphism. The genotypic frequency was 0.47 (*1/*1), 0.40 (*1/*2) and 0.13 (*2/*2) in Caucasians and 0.37 (*1/*1), 0.45 (*1/*2) and 0.18 (*2/*2) in Hispanics. Although Hispanics have a higher genotypic frequency of variant genotypes this difference was not statistically significant (p=0.26). SULT1A1 genotype did not correlate with any prognostic or predictive markers associated with breast cancer. Future evaluations will assess the functional significance of this polymorphism on survival.

Purpose: To evaluate the efficacy and toxicity of the sequential administration of paclitaxel (Taxol; Bristol-Myers Squibb; Princeton, NJ), carboplatin (Paraplatin; Bristol-Myers Squibb), and oral etoposide (VePesid; Bristol-Myers Squibb) followed by gemcitabine (Gemzar; Eli Lilly; Indianapolis, IN) and irinotecan (Campostar; Pfizer Pharmaceuticals; New York, NY) in the first-line treatment of patients with carcinoma of unknown primary site., Patients and Methods: One hundred thirty-two patients were treated with sequential combination chemotherapy for a maximum of six cycles. All patients had relatively poor prognostic features. Fifty-nine patients had well-differentiated adenocarcinoma, 73 patients had poorly differentiated carcinoma, and 121 patients had performance status scores of 0 or 1., Results: Thirty-three (30%) of 111 assessable patients (95% confidence interval 27%-33%) had objective responses to treatment (26 partial responses, seven complete responses). The combination of gemcitabine and irinotecan was associated with significantly less toxicity than the triple-drug regimen and improved the responses in several patients (10%). The response rates were similar in the two major histologic tumor types, but were lower for patients with liver-dominant tumors (13%) and higher for patients with lymph-node-dominant tumors (50%). The median progression-free survival time, median survival time, and actuarial survival rates at 1 and 2 years were 5.7 months, 9.1 months, 35%, and 16%, respectively., Conclusions: Sequential combination chemotherapy with paclitaxel/carboplatin/oral etoposide and gemcitabine/irinotecan is an active treatment for patients with carcinoma of unknown primary site, but overall toxicities are greater than those seen with other combinations of new drugs and survival appears similar to that observed in 264 other patients treated in our four previous phase II trials. A better understanding of the biology of these heterogeneous tumors will likely lead to improved therapy for these patients.

This study was designed to evaluate the feasibility, toxicity, and efficacy of rituximab added to the VNCOP-B (etoposide/mitoxantrone/cyclophosphamide/vincristine/prednisone/bleomycin) combination regimen for the treatment of elderly patients with large B-cell lymphoma. Previously untreated patients > or = 65 years of age with stage II, III, or IV large B-cell non-Hodgkin's lymphoma were treated with a modified VNCOP-B regimen with weekly chemotherapy for 8 weeks. In addition, patients received rituximab 375 mg/m2 intravenously on weeks 1, 2, 3, 4, 6, and 8. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) during the 8 weeks of treatment. Between August 1999 and February 2002, 41 patients entered this multicenter phase II trial. The median age was 74 years, and 54% of patients had high-risk tumors (age-adjusted International Prognostic Index scores of 2 or 3). Sixty-eight percent of patients completed the 8 weeks of therapy. Overall response rate was 66%; actuarial progression-free survival rate at 2 years was 59%, with a 57% actuarial overall 2-year survival rate. Patients > or = 75 years of age had similar treatment outcomes compared with younger patients. Toxicity with this regimen was predominantly related to chemotherapy; rituximab was well tolerated. Grade 3/4 neutropenia occurred in 83% of patients even with routine use of prophylactic G-CSF or GM-CSF. Treatment-related death occurred in 4 patients (10%). VNCOP-B plus rituximab is efficacious, producing 2-year progression-free survival rates that compare favorably with those of other active regimens in this patient group. Hematologic toxicity was increased compared with previous reports with VNCOP-B alone, as evidenced by the treatment-related mortality rate of 10% in the present study. Differences in toxicity may have been caused by the addition of rituximab, the modified etoposide schedule, or the differences in patient characteristics. This regimen provides a treatment option for elderly patients who are not considered candidates for standard CHOP/rituximab chemotherapy.

Purpose: To evaluate safety, tolerability, and pharmacokinetics of a new nucleoside analogue, tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC)] in patients with refractory solid tumors., Experimental Design: Seventy patients were enrolled in four separate Phase I trials. Patients had metastatic or relapsed cancer of the colon, breast, pancreas, gastrointestinal tract, lung, and other sites. FMdC was administered by i.v. infusion over 30 min in one of four dose schedules--from once every 3 weeks to twice a week for 3 weeks, with dose escalation in each. Maximum doses ranged from 630 to 16 mg/m(2)., Results: Myelotoxicity, especially neutropenia, was the dominant toxicity and was generally dose-related. Grade 3 or 4 neutropenia occurred in 53% of patients but was of relatively short duration (1-8 days) in all of the patients. One patient experienced grade 3 thrombocytopenia and one patient grade 4 (duration 15 and 11 days, respectively). Transient febrile episodes were reported in 82% of patients with drug administration but were easily controlled. Drug-related gastrointestinal events were mild and appeared unrelated to dose. Pharmacokinetics were linear with dose, not appreciably affected by schedules, and not different after single or multiple doses. Terminal half-life was 3-4 h, and 23% of the administered drug was recovered in the urine as unchanged drug. The uridine analogue (FMdU), the deaminated metabolite of FMdC, was the primary metabolite. Objective antitumor activity was observed in eight patients: one exhibited a partial response and seven exhibited stable disease., Conclusions: In general, FMdC was well tolerated. On the basis of the time to recovery from neutropenia, the recommended schedule for Phase II studies is one treatment every 2 weeks, at a minimum dose of 270 mg/m(2).

Objectives: This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule., Patients and Methods: CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2. The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and of SN-38 glucuronide (SN-38G)., Results: Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level. When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-II, respectively The harmonic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia, nausea, or vomiting. Across the range of doses studied, mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2., Conclusions: When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF. This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-week single-agent CPT-11 therapy.

An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.

Purpose: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies., Patients and Methods: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d., Results: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response., Conclusion: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.

The authors evaluated the activity and toxicity of docetaxel given as a 1-hour infusion every 21 days in patients with unresectable cholangiocarcinoma. Seventeen patients with cytologically or histologically confirmed cholangiocarcinoma received intravenous docetaxel over 1 hour, repeated every 21 days. The initial dose of docetaxel was 100 mg/m2, with a subsequent 25% dose reduction for patients experiencing grade 3 or 4 toxicities. Treatment was continued until disease progression or occurrence of intolerable side effects. All patients received premedication with dexamethasone 8 mg by mouth twice daily for 5 days, starting 1 day before docetaxel infusion. Sixteen of the 17 patients were assessable for response and toxicity; one patient was removed from the trial for intercurrent illness. Thirty-eight cycles of docetaxel were delivered (median, two cycles). No complete or partial responses were noted. Fourteen patients had progressive disease, one patient had stable disease, and one patient died of septic shock shortly after starting treatment. Granulocytopenia was the dose-limiting toxicity. Thirteen patients had grade 4 granulocytopenia, 11 of whom required antibiotics for neutropenic fever. Granulocytopenia was the only grade 4 toxicity observed. Grade 3 toxicities included stomatitis, anemia, fatigue, vomiting, and hypotension. Grade 1 or 2 toxicities included alopecia, diarrhea, peripheral edema, myalgias, and anorexia. Administered on this dose and schedule, docetaxel lacked activity in patients with cholangiocarcinoma. The toxicity profile, including dose-limiting granulocytopenia, has been previously described in patients receiving docetaxel.

A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials.

Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Totals of 109, 48, 64, and 59 courses were given, respectively. Dose-limiting toxicity consisted of granulocytopenia for the o.d. x 5-day dosage, a combination of myelosuppression and diarrhea in both of the 10-day schedules, and only diarrhea in the 21-day schedule. Pharmacokinetics revealed a substantial variation of the area under curve (AUC) of topotecan lactone in all of the dose schedules with a mean intrapatient variation of 25.4 +/- 31.0% (o.d. x 5), 34.5 +/- 25.0% (o.d. x 10), 96.5 +/- 70.1% (b.i.d. x 10), and 59.5 +/- 51.0% (b.i.d. x 21). Significant correlations were observed between myelotoxicity parameters and AUC(t) day 1 and AUC(t) per course of topotecan lactone. In all of the studies, similar sigmoidal relationships could be established between AUC(t) per course and the percentage decrease of WBCs. At maximum-tolerated dose level, no significant difference in AUC(t) per course was found [AUC(t) per course was 107.4 +/- 33.7 ng x h/ml (o.d. x 5), 145.3 +/- 23.8 ng x h/ml (o.d. x 10), 100.0 +/- 41.5 ng x h/ml (b.i.d. x 10), and 164.9 +/- 92.2 ng x h/ml (b.i.d. x 21), respectively.] For oral topotecan, the schedule rather than the AUC(t)-per-course seemed to be related to the type of toxicity. Prolonged oral administration resulted in intestinal side effects as a dose-limiting toxicity, and short-term administration resulted in granulocytopenia. On the basis of this pharmacokinetic study, no schedule preference could be expressed, but based on patient convenience, administration once daily for 5 days could be favored.

Purpose: Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors., Patients and Methods: A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75-175 mg/m2 administered over three hours followed by gemcitabinc 1500-3500 mg/m2 administered over 30-60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant., Results: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m2 and gemcitabine 3500 mg/m2 in the form of grade 4 neutropenia lasting for > or = 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m2 and gemcitabine 3500 mg/m2. Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary., Conclusions: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2.

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.

Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days) was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day, and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity (DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2 for the b.i.d. schedule.

Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2, 000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19. 5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration-36. 84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels ( 14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 1/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 1/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.

Vinorelbine (Navelbine) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m2. Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m2. Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m2 on days 1 and 8 and mitoxantrone 10 mg/m2 on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.

Purpose: Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies., Patients and Methods: Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods., Results: Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function., Conclusion: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

The purpose of this study was to evaluate the feasibility of chronic oral administration of etoposide with granulocyte-macrophage colony-stimulating factor (GM-CSF) [sargramostim (Immunex)] coadministration or premedication; to estimate and compare the frequency of toxicities accompanying etoposide administration alone, etoposide/GM-CSF coadministration and etoposide with GM-CSF premedication. Thirty-nine patients with advanced treatment-refractory malignancies were enrolled to this study. Eligible patients were randomized to one of three treatment arms: daily oral etoposide alone for 21 days (arm A); daily oral etoposide for 21 days with GM-CSF, 250 micrograms/m2, s.c. twice daily for the first 10 days of etoposide administration (arm B); or daily oral etoposide for 21 days with GM-CSF twice daily for the sixth through second days preceding etoposide administration (arm C). Courses of treatment were repeated every 28 days. Etoposide dosages for each arm were 25, 50, 75 and 100 mg/m2/day. At least three patients were treated at each dosage level until dose-limiting toxicity was observed. Patients had twice weekly blood counts and weekly clinical examinations to assess toxicity. Patients with measurable or evaluable evidence of cancer were assessed for antitumor response after every other course of therapy. Nadir neutrophil counts at each dosage level were compared between treatment arms by non-parametric Wilcoxen rank sum tests. GM-CSF coadministration (arm B) or premedication (arm C) with daily chronic oral etoposide was feasible and did not lead to excessive hematological toxicity. Pairwise comparisons of neutrophil nadirs for the first course of therapy for each treatment arm did not demonstrate any significant differences and, at most, a slight trend favoring improved neutrophil nadirs was shown for arm C compared to arm A (p = 0.07). Dose intensity as measured by mean days of etoposide administered per patient for each arm suggested only slight improvement in etoposide tolerance for treatment arms B and C. The conclusion, GM-CSF can be safely administered to patients receiving chronic daily oral etoposide. It appears that GM-CSF provides no clinically useful improvement in granulocyte tolerance of therapy.

Purpose: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy., Patients and Methods: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response., Results: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case., Conclusion: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

We have conducted a study of ilmofosine (1-hexadecylthio; 2-methoxyethyl-rac-glycero-3-phosphocholine) in non-small cell bronchogenic carcinoma, using a schedule of continuous infusion for 5 days and a dose of 300 mg/m2/day. Toxicities were gastrointestinal (nausea, vomiting, diarrhea), fatigue and liver function abnormalities. These were severe and resulted in the removal of some patients from study. No consistent pattern of bone marrow suppression was seen. No tumor regressions occurred in 14 evaluable patients including 5 with no prior therapy. We conclude that ilmofosine is inactive in this tumor at this dose and schedule.

Twenty-nine patients with persistent, recurrent and/or metastatic squamous cell carcinoma of the head and neck were treated daily for five days at three-week intervals with topotecan 1.5 mg/m2. Four patients received prior chemotherapy, 23 prior surgery and 29 prior radiation therapy. Of the 29 eligible patients, 8 patients were not evaluable for response and were assumed to be non-responders. Of the remaining 21 evaluable patients, there were zero responses (0%, 95% confidence interval [0,.12]). The most common toxicities were myelosuppression, dyspnea and malaise/fatigue/lethargy. Topotecan has limited activity in advanced head and neck cancer with this dose and schedule.

Background: Recurrent cancer of the head and neck after primary therapy is almost always fatal. The combination of 5-fluorouracil (5-FU) and cisplatin is considered the best available therapy but complete response rates remain too low to affect survival. This study was designed to evaluate the complete response rate and toxicity of 5-FU, cisplatin, and alpha-interferon (alpha-IFN) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)., Methods: Fifty eligible patients with recurrent or metastatic SCCHN and no prior chemotherapy (40 men, 10 women; age range, 26-77 years; median, 59 years; 82% white; 88% had prior surgery and 92% had prior radiation therapy) were treated every 21 days with 96-hour infusion of 5-FU 1000 mg/m2/day; cisplatin 100 mg/m2, day 1; and alpha-IFN 5 x 10(6) units/day, days 1-4., Results: One hundred fifty-seven courses of chemotherapy were administered, with a median of three courses. Thirty-seven patients experienced Grade 3 or 4 toxicity. Of the 17 patients with Grade 4 toxicity; 12 had hematologic toxicity, 3 stomatitis, and 2 vomiting. Two additional patients died of myelosuppression-related sepsis. Of the 50 patients, 3 (6%) achieved a complete response, five (10%) had a partial response, 3 (6%) had unconfirmed response (1 complete and 2 partial), 10 (20%) had stable disease, 17 (34%) progressed, and 12 (24%) were considered nonresponders owing to early death (6) or inadequate assessment (6). The median survival was 5 months., Conclusion: The complete response rate of patients with recurrent or metastatic SCCHN treated with 5-FU, cisplatin, and alpha-IFN does not appear to be superior to that observed for 5-FU and cisplatin. Alpha-interferon appears to augment hematologic and gastrointestinal toxicities associated with this combination.

Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (< 1,000/microliters) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Non-hematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37 degrees-40 degrees C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies.

Context: Liposomal encapsulation of drugs can potentially ameliorate toxicities and improve acute and chronic tolerance. The increased uptake of liposomes by colon adenocarcinoma cell lines may enable DaunoXome to circumvent the p-glycoprotein-mediated anthracycline resistance of colon cancer cells., Purpose: To determine if DaunoXome, liposome-encapsulated daunorubicin, has clinical activity in patients with adenocarcinoma of the colon who failed treatment with a 5-fluorouracil containing regimen., Method: In a Phase II trial, patients with metastatic adenocarcinoma of the colon, whose disease has progressed after receiving one 5-fluorouracil-containing regimen, were treated with DaunoXome 100 mg/m2 repeated every 3 weeks., Results: In this trial 16 patients received 45 courses of therapy. No objective tumor responses were seen. Hematologic toxicities consisted of neutropenia (grade 3 and 4), grade 2 anemia, and grade 2 thrombocytopenia. Nonhematologic toxicities were mild and manageable. Of the 16 patients, 5 experienced flushing, shortness of breath, chest tightness, and back pain during DaunoXome infusion, which resolved with infusion interruption, diphenhydramine, and meperidine., Conclusions: DaunoXome is generally well tolerated at a dose of 100 mg/m2 every 3 weeks. Toxicities are mild and reversible. On this schedule DaunoXome does not have significant clinical activity in patients with metastatic adenocarcinoma of the colon who have progressed after one 5-fluorouracil-containing regimen.

Purpose: We conducted a phase I and pharmacokinetic trial of CPT-11 (irinotecan) to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetic profile, and antitumor effects in patients with refractory solid malignancies., Patients and Methods: We treated 32 patients with CPT-11 administered as a 90-minute intravenous infusion every week for 4 consecutive weeks followed by a 2-week rest period. Dose levels ranged from 50 to 180 mg/m2/wk. We determined concentrations of the lactone (active) and total (lactone plus carboxylate) forms of CPT-11 and its metabolite, SN-38, in the plasma and urine of selected patients during and after drug infusion., Results: Grade 4 diarrhea was the dose-limiting toxicity (DLT) at the 180-mg/m2/wk dose level. Other toxicities attributed to CPT-11 included dehydration, nausea, vomiting, and asthenia. Hematologic toxicity was mild in most patients. The terminal plasma half-life for CPT-11 (total) was 7.9 +/- 2.8 hours, for CPT-11 (lactone) 6.3 +/- 2.2 hours, for SN-38 (total) 13.0 +/- 5.8 hours, and for SN-38 (lactone) 11.5 +/- 3.8 hours. We observed significant correlations between drug dose and peak plasma concentration (Cpmax) and between drug dose and area under the concentration curve (AUC) for CPT-11, but not for SN-38., Conclusion: The MTD for CPT-11 in this patient population was 150 mg/m2/wk when administered on a weekly-times-four schedule repeated every 6 weeks. At dose levels greater than 150 mg/m2/wk, diarrhea is dose-limiting.

To examine the effects of ingested snakeweed foliage (SW) on male fertility and reproduction, SW collected at prebloom stage was dried, ground, and mixed with ground commercial rat feed (CRF) as 0, 12.5, and 25% of total diets. Male rats fed SW for 20 d impregnated females as successfully as did dietary controls, but males fed 12.5 or 25% SW for 40 d had seemingly impaired fertility and apparently increased mortality of offspring. Males fed SW for an additional 30 and 42 d showed no differences (P > .05) in serum testosterone or LH concentrations after a GnRH challenge compared with controls. Semen samples collected from the vas deferens revealed that total sperm concentrations were similar (P > .10) between rats fed 12.5 or 25% SW and controls. The percentage of abnormal sperm was higher (P < .01) in rats fed 12.5 or 25% SW for 102 d, compared with the percentage of abnormal sperm in controls (11.5 and 17.8 vs 10.4%), and weight of testes was decreased (P < .05). Dietary SW increased (P < .01) activities of alkaline phosphatase and gamma-glutamyl transpeptidase over those in controls at d 20 (but not at d 98) and hepatomegaly was evident at d 50 and 98. Ingestion of snakeweed foliage by male rats increased abnormal sperm counts, impaired reproduction, and caused hepatotoxicosis.

Twenty-five children with serious Gram-negative infections were treated in a prospective study with amikacin 20 mg/kg administered in a single daily dose as a 30 min iv infusion for 4 to 12 days. In nine cases the amikacin was combined with beta-lactam antibiotics. Escherichia coli were the most frequent bacteria isolated followed by K. pneumoniae, Providencia and Enterobacter spp. and Pseudomonas aeruginosa with MICs ranging from 1 to 16 mg/l. Mean (+/- S.D.) peak and trough concentrations of days 1 and 4 of therapy ranged from 49 +/- 13.5 to 53.6 +/- 13.4 mg/l and 6 + 1.4 to 7.7 +/- 4.1 mg/l respectively. All patients were clinically and bacteriologically cured. No significant adverse reactions were observed. The results suggest that administration of a single daily dose of 20 mg/kg amikacin should be considered practical and safe in children. Further studies are needed.