TREATMENT OF BREAST CANCER: IMO STATE NIGERIA VERSUS INDIANA, USA WOMEN - COMPARATIVE ANALYTIC STUDY.

BACKGROUND: Women with breast cancer undergo multimodal treatment for best outcome. This study seeks to identify the treatment challenges for such women in Imo State, Nigeria vis-à-vis similar women in Indiana USA. We compared the treatment modalities of both groups; noting predictors of compliance for subsequent action. SETTING: Federal Medical Centre, Owerri; Imo State, Imo State University, Orlu, Nigeria and Indiana University Hospital, Indiana, USA. DESIGN: A retrospective study. METHODOLOGY: From 2000-2013, 100 randomly pulled charts of patients treated for pathologically confirmed breast cancer in Imo, Nigeria Federal Medical Centre Owerri, Imo State University Hospital; and Indiana University Hospital U.S. respectively were reviewed. The demographics, clinical and pathological data of the patients with confirmed breast cancer were obtained. The data were formatted and analyzed with SPSS version 16.0. The clinical features, management options, outcomes and specific features were compared for both groups using Wilcoxon Rank Sum tests (age, parity) and chi-square tests for all other variables. A 5% significance level was used for all tests. RESULTS: One hundred patients were included for each group. The mean/minimum ages; Imo, Nigeria 41.7/21 (SD/SE 15.3/1.5) vs. Indiana, U.S.56.4/29 (SD 12.4/SE 1.2) p<0.0001. Histology for Indiana USA women was predominantly ductal carcinoma in situ (DCIS) P<0.0001 while that of Imo, Nigeria was invasive ductal carcinoma inflammatory cancer P<0.0326. Women in both locations received chemotherapy and surgery. Imo women received less radiotherapy. Toxicity from chemotherapy remained constant features for both groups, P<0.0001. In Indiana USA, the 5year survival exceeded 85%; In Imo Nigeria it was 10%. This study showed that Women on both locations who were likely to be compliant were those receiving mastectomy; Imo, Nigeria 44(56%) <0.013 vs. Indiana, U.S. 74(80%) p<0.0186; women with cosmesis given; Imo, Nigeria 41(42%) vs. Indiana, U.S. 91 (94%) p<0.0001. Sample sizes were inadequate to perform multivariable models. CONCLUSION: The multimodal treatment regimen implied that there was need for an algorithm protocol for breast cancer women. Thus the need to improve the quality of treatment particularly in Nigeria by improved treatment documentation to overcome key barriers involving information exchange.

Video image analysis as a potential grading system for Uruguayan beef carcasses.

A study was conducted in 2 phases to evaluate the effectiveness of 1) the VIAscan Beef Carcass System (BCSys; hot carcass system) and the CVS BeefCam (chilled carcass system), used independently or in combination, to predict Uruguayan beef carcass fabrication yields; and 2) the CVS BeefCam to segregate Uruguayan beef carcasses into groups that differ in the Warner-Bratzler shear force (WBSF) values of their LM steaks. The results from the meat yield phase of the present study indicated that the prediction of saleable meat yield percentages from Uruguayan beef carcasses by use of the BCSys or CVS BeefCam is similar to, or slightly better than, the use of USDA yield grade calculated to the nearest 0.1 and was much more effective than prediction based on Uruguay National Institute of Meat (INAC) grades. A further improvement in fabrication yield prediction could be obtained by use of a dual-component video image analysis (VIA) system. Whichever method of VIA prediction of fabrication yield is used, a single predicted value of fabrication yield for every carcass removes an impediment to the implementation of a value-based pricing system. Additionally, a VIA method of predicting carcass yield has the advantage over the current INAC classification system in that estimates would be produced by an instrument rather than by packing plant personnel, which would appeal to cattle producers. Results from the tenderness phase of the study indicated that the CVS BeefCam output variable for marbling was not (P > 0.05) able to segregate steer and heifer carcasses into groups that differed in WBSF values. In addition, the results of segregating steer and heifer carcasses according to muscle color output variables indicate that muscle maturity and skeletal maturity were useful for segregating carcasses according to differences in WBSF values of their steaks (P > 0.05). Use of VIA to predict beef carcass fabrication yields could improve accuracy and reduce subjectivity in comparison with use of current INAC grades. Use of VIA to sort carcasses according to muscle color would allow for the marketing of more consistent beef products with respect to tenderness. This would help facilitate the initiation of a value-based marketing system for the Uruguayan beef industry.

Using reflectance spectroscopy to predict beef tenderness.

A study was conducted to determine if reflectance measurements made in the near-infrared region of the spectrum were additive to reflectance measurements made in the visible region of the spectrum for predicting Warner-Bratzler shear force (WBSF) values. Eighty seven strip loins were collected following fabrication over 3d at a commercial beef processing facility from heifer carcasses with Slight or Traces marbling scores. Spectroscopic measurements were made at approximately 50h postmortem using a Hunter-Lab UltraScan. Subsequently, all strip loins were aged for 14d, cooked to an internal temperature of 70°C, and sheared to obtain WBSF values. Reflectance measurements obtained in the near-infrared region of the spectrum were correlated with WBSF values, however, these measurements were not additive to the predictive ability of reflectance measurements (R(2) values did not differ) made in the visible portion of the spectrum when the use of broad-band wavelength filters were simulated. It was therefore determined, that both the visible and near-infrared spectra measure reflectance and that both methods are acceptable methods of tenderness prediction.

An evaluation of central nervous system cross-contamination due to carcass splitting in commercial beef-packing plants.

Four experiments were conducted in commercial beef-packing facilities The objectives of these experiments were to: (i) determine and validate a carcass sampling technique and location to determine if central nervous system (CNS) cross-contamination exists/occurs; (ii) determine if residual CNS tissue contamination remains on splitting saws after sanitation procedures; (iii) determine the prevalence of CNS cross-contamination in commercial slaughter facilities; (iv) determine whether washing treatments reduce or eliminate CNS tissue presence in carcass-splitting saws; (v) determine the effectiveness of commercial spray-washing systems in removing CNS tissue from beef carcasses; and (vi) compare residual CNS tissue levels on the blade and in the housings of the Jarvis Buster IX and Buster IV carcass-splitting saws. CNS tissue remained, albeit at very low levels, in the housings and on the blades of carcass-splitting saws after carcass splitting and operational sanitation. Additionally, after splitting carcasses, CNS tissue remaining in the splitting saw housings and on saw blades was found to cross-contaminate subsequent carcasses during splitting. Most splitting saw operational sanitation procedures reduced the amount of CNS tissue remaining in the splitting saw housings and on splitting saw blades, but no treatment eliminated CNS tissue from either to levels below the detection limit of the assay (6 ng/100 cm2). Washing in carcass spray-washing cabinets at three of the five commercial beef-packing facilities reduced, but did not eliminate, presence of CNS tissue in the aitch bone area of carcasses. Carcass spray washing in cabinets at three of the five facilities reduced (P < 0.05) the concentration of CNS tissue in the fourth thoracic vertebra area. While extremely low concentrations of CNS tissue remained in the splitting saw housings, on the splitting saw blades, and on carcasses, it is unknown whether these levels would pose a human food safety risk because the exact amount of bovine spongiform encephalopathy-infected spinal cord capable of transmitting the disease to humans is dependent on the infectivity titer, which is not readily known.

Central nervous system tissue in meat products: an evaluation of risk, prevention strategies, and testing procedures.

Since the outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986 and its subsequent link to the human neurological disorder variant Creutzfeldt-Jakob disease (vCJD), presence of tissues from the central nervous system (CNS) in meat products has been considered a public health concern and, thus, has been banned from entering the human food chain in many countries. Despite this, potential can exist during harvesting to contaminate or cross-contaminate edible meat products with CNS tissue that is designated as a specified risk material (SRM) in many countries. Methods used to detect CNS tissue in meat products vary greatly in their sensitivity, specificity, cost, labor and expertise needed, ease of completion, and type of results given (qualitative vs quantitative) and, within these constraints, appropriate testing methods must be selected to monitor or verify that meat products system controls are effective in removing CNS tissue from the human food chain. The extent to which monitoring procedures are needed should be based on the public health risk of CNS tissue in meat products as determined by each sovereign nation and/or third-party international organizations such as the World Organization for Animal Health (OIE). Risk associated with consumption of CNS tissue should be estimated by sovereign nations by establishing prevalence of BSE within their borders. Using this information, science-based decisions may guide international policy and trade. Using available scientific information, appropriate testing methods for monitoring or verification, and prevalence information, nations can estimate and reduce, to the extent deemed necessary, the public health risk of vCJD.

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.

PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.

A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

PURPOSE: Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. EXPERIMENTAL DESIGN: Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. RESULTS: The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. CONCLUSIONS: PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.

Matrix metalloproteinase production in regenerating axolotl spinal cord.

In urodele amphibian spinal cord regeneration, the ependymal cells lining the central canal remodel the lesion site to favor axonal regrowth. We profiled the production of matrix metalloproteinases by injury-reactive mesenchymal ependymal cells in vivo and in vitro and found that matrix metalloproteinases are involved in this remodeling process in the axolotl (Ambystoma mexicanum). The production of cell-associated matrix metalloproteinases in vivo was shown to be identical to that in our cultured ependymal cell model system. Activated and zymogen forms of matrix metalloproteinases were identified using zymography, chemical inhibitors of matrix metalloproteinases, and cleavage of propeptides by organomercurials. The principal cellular proteinases consisted of matrix metalloproteinase-2 (gelatinase A) and matrix metalloproteinase-1 (type I collagenase), which display characteristic shifts in molecular weight following proenzyme processing by organomercurials. In addition, ependymal cell conditioned medium contained secreted forms of the enzyme undetectable in situ. Matrix metalloproteinase-9 (gelatinase B) as well as matrix metalloproteinase-2 and matrix metalloproteinase-1 were secreted and casein substrate zymography showed the presence of a small amount of a very high molecular weight matrix metalloproteinase-3 (prostromelysin) secreted into the culture medium. Matrix metalloproteinases were still present at 4 weeks post-lesioning when the ependymal cells have just re-epithelialized, but decreased near the completion of regeneration (8 weeks post-lesioning). Zymography showed no detectable matrix metalloproteinases in unlesioned cord but the presence of tissue inhibitor of metalloproteinase-1 in intact cord was seen by Western blotting. This study shows that matrix metalloproteinases are associated with urodele spinal cord regeneration and validates the use of our ependymal cell tissue culture model system to evaluate ependymal cell behavior during spinal cord regeneration.

A pedigree-based study of mitochondrial D-loop DNA sequence variation among Arabian horses.

Through DNA sequence comparisons of a mitochondrial D-loop hypervariable region, we investigated matrilineal diversity for Arabian horses in the United States. Sixty-two horses were tested. From published pedigrees they traced in the maternal line to 34 mares acquired primarily in the mid to late 19th century from nomadic Bedouin tribes. Compared with the reference sequence (GenBank X79547), these samples showed 27 haplotypes with altogether 31 base substitution sites within 397 bp of sequence. Based on examination of pedigrees from a random sampling of 200 horses in current studbooks of the Arabian Horse Registry of America, we estimated that this study defined the expected mtDNA haplotypes for at least 89% of Arabian horses registered in the US. The reliability of the studbook recorded maternal lineages of Arabian pedigrees was demonstrated by haplotype concordance among multiple samplings in 14 lines. Single base differences observed within two maternal lines were interpreted as representing alternative fixations of past heteroplasmy. The study also demonstrated the utility of mtDNA sequence studies to resolve historical maternity questions without access to biological material from the horses whose relationship was in question, provided that representatives of the relevant female lines were available for comparison. The data call into question the traditional assumption that Arabian horses of the same strain necessarily share a common maternal ancestry.

Phase I and pharmacological study of CI-980, a novel synthetic antimicrotubule agent.

CI-980 (NSC 613862) is one of a novel class of 1,2-dihydropyrido[3, 4-b]pyrazines that inhibits tubulin polymerization, presumably by binding to the colchicine binding site of tubulin. In a Phase I and pharmacological study, 16 patients with advanced solid neoplasms were treated with CI-980 on a continuous 72-h infusion schedule at doses ranging from 3.0-5.4 mg/m2/day every 3 weeks. High rates of central nervous system (CNS) toxicity and neutropenia occurred in both minimally and heavily pretreated patients who were treated with CI-980 doses above 3.75 mg/m2/day, which is the maximum tolerated dose and the recommended dose for additional evaluations. CNS effects, characterized by neurocortical, mood, and cerebellar manifestations, were generally observed toward the end of the infusion and immediately posttreatment and usually resolved within 48 h after the completion of treatment. Toxicity was mild to modest at the 3.75 mg/m2/day dose level. Neither clinical nor pharmacological risk factors that may predispose patients to the development of CNS effects were evident. Although no objective antineoplastic activity was observed in this Phase I study, CI-980 steady-state plasma concentrations achieved at the recommended dose of 3.75 mg/m2/day (mean +/- SE, 5.74 +/- 0.54 nM) approached and exceeded concentrations that have been associated with significant activity in preclinical studies, indicating that additional disease-directed evaluations of CI-980 may be warranted.

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

PURPOSE: A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS: TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS: Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION: The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

A phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia.

The principal objectives of this study were to determine the feasibility of escalating doses of the hydrophilic topoisomerase I (topo I) inhibitor topotecan (TPT) as a 30-min infusion daily for 5 days in adults with refractory or relapsed acute leukemia and to study the pharmacokinetic behavior of high doses of TPT and pharmacodynamic determinants of TPT activity. Fourteen patients received 27 courses of TPT at doses ranging from 3.5 to 5.75 mg/m2/day every 3 weeks. A constellation of unusual adverse effects, consisting of high fever, rigors, precipitous anemia, and hyperbilirubinemia, was the principal dose-limiting toxicity of high doses of TPT on this schedule. These toxicities were consistently intolerable at the 5.75 mg/m2/day dose level; however, they were neither severe nor common at lower doses. Although the precise etiology of these effects is not known, high doses of TPT may induce acute hemolytic reactions in this patient population. Severe, albeit transient, mucositis was experienced by two of eight patients in 2 of 17 courses at the next lower dose level, 4.5 mg/m2/day, which was determined to be the maximum tolerated dose and the dose recommended for further trials. The pharmacokinetic behavior of TPT at high doses was not dose dependent and resembled that at lower doses. In view of preclinical data suggesting that TPT sensitivity might correlate with topo I levels, topo I content in leukemia blasts was assessed by Western blotting. Variations in topo I content were observed. Moreover, strong correlations were evident between topo I content and two markers of proliferation, proliferating cell nuclear antigen and nuclear protein B23, raising the possibility that differences in topo I content observed among various leukemia specimens might reflect differences in the proliferating fractions of cells in various leukemia samples. Although complete clearance of circulating leukemia blasts occurred in most courses, neither sustained responses nor hematopoietic recovery were observed in the heavily pretreated, poor-risk patients enrolled in this study, and it was not possible to correlate these differences in topo I content with clinical response. These results indicate that substantial dose escalation of TPT as a 30-minute infusion for a 5-day schedule above myelosuppressive doses is feasible in adults with refractory or relapsed leukemias; however, further development of alternate high-dose schedules in leukemia may be warranted in view of the nature of the dose-limiting toxicity and the lack of sustained clinical responses in this preliminary investigation.

Primary health care for children of mothers with intellectual limitations.

Intellectually impaired mothers can present a challenge to pediatric nurses. The lack of basic organizational and decision-making skills needed to provide positive nurturing can interfere with the health and development of their children. This descriptive study of the well child needs of 62 two-year-old children from low income families found that children of mothers with intellectual limitations had more frequent referrals for medical or developmental problems, accidents, and problems with hygiene and discipline than children of mothers without intellectual limitations. The needs of families with an intellectually limited mother must be recognized and evaluated if appropriate health care of children is to be accomplished.

Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors.

PURPOSE: To evaluate the feasibility of escalating doses of the topoisomerase I (topo I) inhibitor topotecan (TPT) with granulocyte colony-stimulating factor (G-CSF) in minimally pretreated adults with solid tumors and to study whether G-CSF scheduling variably affects the ability to escalate TPT doses. MATERIALS AND METHODS: Thirty-six patients received 121 courses of TPT as a 30-minute infusion daily for 5 days every 3 weeks at doses that ranged from 2.0 to 4.2 mg/m2/d. G-CSF 5 microg/kg/d subcutaneously (SC) was initiated concurrently with TPT (starting on day 1). Because the concurrent administration of TPT and G-CSF resulted in severe myelosuppression at the lowest TPT dose level, an alternate posttreatment G-CSF schedule in which G-CSF dosing began after TPT (starting on day 6) was subsequently evaluated. Plasma sampling was performed to characterize the pharmacologic behavior of high-dose TPT and to determine whether G-CSF altered the pharmacokinetic profile of TPT. RESULTS: Severe myelosuppression precluded the administration of TPT at the first dose, 2.0 mg/m2/d, with G-CSF on the concurrent schedule. However, dose escalation of TPT with G-CSF on a posttreatment schedule proceeded to 4.2 mg/m2/d. The dose-limiting toxicities (DLTs) were thrombocytopenia and neutropenia. One partial response was noted in a patient with colorectal carcinoma refractory to fluoropyrimidines. Pharmacokinetics were linear within the dosing range of 2.0 to 3.5 mg/m2/d, but TPT clearance was lower at the 4.2-mg/m2/d dose level. At 3.5 mg/m2/d, which is the maximum-tolerated dose (MTD) and recommended dose for subsequent-phase studies of TPT with G-CSF, the area under the concentration-versus-time curves (AUCs) for total TPT and lactone averaged 2.2- and 2.3-fold higher, respectively, than the AUCs achieved at the lowest TPT dose, 2.0 mg/m2/d. The pharmacologic behavior of high-dose TPT was not significantly altered by the scheduling of G-CSF. CONCLUSION: G-CSF administered after 5 daily 30-minute infusions of TPT permits a 2.3-fold dose escalation of TPT above the MTD in solid-tumor patients, whereas concurrent therapy with G-CSF and TPT results in severe myelosuppression.

The use of a shotgun for the emergency slaughter or euthanasia of large mature pigs.

The isolated heads of a Friesian bull and three large, Large White pigs were shot from various aspects with a 12-gauge shotgun using both a single 28 g solid lead projectile and buckshot, the latter consisting of nine individual lead pellets with a combined mass of 28 g. The sites of impact to the skull included the conventional frontal region, an occipital site and immediately behind the ear. A live mature Large White sow was shot with buckshot in the depression just caudal to the right ear, resulting in immediate insensibility and death. The damage caused to the isolated heads indicated that similar effects could be expected if the heads had been part of intact living animals. It is suggested that buckshot (nine lead pellets with a combined mass of 28 g) fired from a 12-gauge shotgun may be suitable for the emergency slaughter or euthanasia of a wide variety of domestic livestock and other species of animal.

The use of a shotgun for euthanasia of stranded cetaceans.

A 12-gauge shotgun, loaded with either a solid 28 g lead slug or buckshot consisting of nine individual lead pellets with a total mass of 28 g, was used to shoot the heads of one dead common dolphin (Delphinus delphis) and five dead long-finned pilot whales (Globicephala melaena) varying in length from 2.5 m to 5 m. The dolphin and the smallest pilot whale were shot with both projectiles from the dorsal surface of the head. The projectiles penetrated the head and dorsal surface of the skull, but not the base of the cranium. This site using buckshot was not effective in the larger animals. Two whales between 3 and 4 m in length were shot with buckshot through the lateral side of the head caudal to and above the eye, without penetration of the contralateral side of the head. It is concluded that shooting smaller cetaceans with a shotgun can be effective and safe. Further work is required to develop more suitable projectiles for cetaceans up to the size of mature pilot whales.

Phase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

Preliminary results of a phase I study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given by 3-hour infusion, followed by carboplatin in chemotherapy-naive patients with stage IV non-small cell lung cancer indicate that both agents can be combined at clinically relevant single-agent doses. The paclitaxel (mg/m2)/carboplatin area under the concentration-time curve (mg.min/mL) dose level of 225/7 is projected to be the maximally tolerated and recommended phase II dose level for future evaluations. Dose-limiting neutropenia, thrombocytopenia, and nausea and vomiting preclude treatment with carboplatin doses estimated to target an area under the concentration-time curve of 9 mg.min/mL when given with paclitaxel 225 mg/m2. The heterogeneous nature of the principal toxicities, as well as the ability to administer clinically relevant single-agent doses of both agents in combination, also indicate that further dose escalation of paclitaxel and carboplatin using hematopoietic growth factors would not be feasible. The preliminary antitumor activity noted to data, as well as the safety associated with the clinically relevant single-agent doses that can be given in combination, indicate that phase II/III evaluations of this regimen are warranted in patients with both advanced and early stage non-small cell lung cancer.

Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules.

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple-dosing schedules. PATIENTS AND METHODS: PZA was administered on a single-dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively. RESULTS: On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity. CONCLUSION: Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single- and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

Pretreatment H2 receptor antagonists that differ in P450 modulation activity: comparative effects on paclitaxel clearance rates and neutropenia.

Histamine-2 receptor antagonists (H2RAs) are principal components of the premedication regimen used to prevent major hypersensitivity reactions in patients receiving paclitaxel. Several different H2RAs, including cimetidine, ranitidine and famotidine, have been used in clinical trials of paclitaxel, as well as by clinicians in different geographic regions and hospitals primarily because of differences in the availability of the various H2RAs. However, H2RAs have highly variable cytochrome P450-modulating capabilities, and the P450 system appears to play a major role in paclitaxel metabolism and disposition. Therefore, the use of different H2RAs may result in different pharmacologic, toxicologic and antitumor profiles due to differential effects on paclitaxel metabolism. This study evaluated whether cimetidine and famotidine, which possess disparate P450-modulating capabilities, differentially affect paclitaxel clearance rates and the agent's principal toxicity, neutropenia. Women with advanced, platinum-refractory ovarian carcinoma received two courses of treatment with 135 mg/m2 paclitaxel over 24 h while participating in the National Cancer Institute's Treatment Referral Center Protocol. A crossover design was employed in which consecutive patients received either 300 mg cimetidine i.v. or 20 mg famotidine i.v. before their first course of paclitaxel and the alternate H2RA before their second course. In order to evaluate the differential effects of cimetidine and famotidine on pertinent pharmacologic and toxicologic parameters in the same individual, paclitaxel concentrations at steady-state (Css), paclitaxel clearance rates, and absolute neutrophil counts (ANCs) were obtained during both courses. Paclitaxel Css values were not significantly different in individual patients when either cimetidine or famotidine preceded paclitaxel (p = 0.16). Mean paclitaxel clearance rates were 271 and 243 ml/min per m2 following cimetidine and famotidine, respectively. These clearance rates were not significantly different in paired analysis (p = 0.30). The likelihood of subsequently requiring granulocyte-colony stimulating factor (G-CSF) for severe neutropenia during course 1 did not differ significantly between the two H2RAs (p = 0.9). Among patients who did not require G-CSF, mean percentage decreases in ANC were 87.7% and 84.2% after paclitaxel cycles preceded by cimetidine and famotidine, respectively. These measures of neutropenia did not differ significantly in paired analysis (p = 0.13). These results show that the H2RAs cimetidine and famotidine do not differentially affect the pharmacologic and toxicity profiles of paclitaxel when used in the premediation regimen to prevent major hypersensitivity reactions, and may be interchanged.