Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

Response of immune response genes to adjuvants poly [di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP), CpG oligodeoxynucleotide and emulsigen at intradermal injection site in pigs.

Understanding the mechanisms by which adjuvants mediate their effects provide critical information on how innate immunity influences the development of adaptive immunity. Despite being a critical vaccine component, the mechanisms by which adjuvants mediate their effects are not fully understood and this is especially true when they are used in large animals. This lack of understanding limits our ability to design effective vaccines. In the present study, we administered polyphosphazene (PCEP), CpG oligodeoxynucleotides (CpG), emulsigen or saline via an intradermal injection into pigs and assessed the impact on the expression of reported 'adjuvant response genes' over time. CpG induced a strong upregulation of the chemokine CXL10 several 'Interferon Response Genes', as well as TNFα, and IL-10, and a down-regulation of IL-17 genes. Emulsigen upregulated expression of chemokines CCL2 and CCL5, proinflammatory cytokines IL-6 and TNFα, as well as TLR9, and several IFN response genes. PCEP induced the expression of chemokine CCL2 and proinflammatory cytokine IL-6. These results suggest that emulsigen and CpG may promote recruitment of innate immune cells and Th1 type cytokine production but that PCEP may promote a Th-2 type immune response through the induction of IL-6, an inducer of B cell activity and differentiation.

Evaluation of a large-scale donation of Lifebox pulse oximeters to non-physician anaesthetists in Uganda.

Pulse oximetry is widely accepted as essential monitoring for safe anaesthesia, yet is frequently unavailable in resource-limited settings. The Lifebox pulse oximeter, and associated management training programme, was delivered to 79 non-physician anaesthetists attending the 2011 Uganda Society of Anaesthesia Annual Conference. Using a standardised assessment, recipients were tested for their knowledge of oximetry use and hypoxia management before, immediately following and 3-5 months after the training. Before the course, the median (IQR [range]) test score for the anaesthetists was 36 (34-39 [26-44]) out of a maximum of 50 points. Immediately following the course, the test score increased to 41 (38-43 [25-47]); p < 0.0001 and at the follow-up visit at 3-5 months it was 41 (39-44 [33-49]); p = 0.001 compared with immediate post-training test scores, and 75/79 (95%) oximeters were in routine clinical use. This method of introduction resulted in a high rate of uptake of oximeters into clinical practice and a demonstrable retention of knowledge in a resource-limited setting.

A paradigm shift towards low-nitrifying production systems: the role of biological nitrification inhibition (BNI).

BACKGROUND: Agriculture is the single largest geo-engineering initiative that humans have initiated on planet Earth, largely through the introduction of unprecedented amounts of reactive nitrogen (N) into ecosystems. A major portion of this reactive N applied as fertilizer leaks into the environment in massive amounts, with cascading negative effects on ecosystem health and function. Natural ecosystems utilize many of the multiple pathways in the N cycle to regulate N flow. In contrast, the massive amounts of N currently applied to agricultural systems cycle primarily through the nitrification pathway, a single inefficient route that channels much of this reactive N into the environment. This is largely due to the rapid nitrifying soil environment of present-day agricultural systems. SCOPE: In this Viewpoint paper, the importance of regulating nitrification as a strategy to minimize N leakage and to improve N-use efficiency (NUE) in agricultural systems is highlighted. The ability to suppress soil nitrification by the release of nitrification inhibitors from plant roots is termed 'biological nitrification inhibition' (BNI), an active plant-mediated natural function that can limit the amount of N cycling via the nitrification pathway. The development of a bioassay using luminescent Nitrosomonas to quantify nitrification inhibitory activity from roots has facilitated the characterization of BNI function. Release of BNIs from roots is a tightly regulated physiological process, with extensive genetic variability found in selected crops and pasture grasses. Here, the current status of understanding of the BNI function is reviewed using Brachiaria forage grasses, wheat and sorghum to illustrate how BNI function can be utilized for achieving low-nitrifying agricultural systems. A fundamental shift towards ammonium (NH4(+))-dominated agricultural systems could be achieved by using crops and pastures with high BNI capacities. When viewed from an agricultural and environmental perspective, the BNI function in plants could potentially have a large influence on biogeochemical cycling and closure of the N loop in crop-livestock systems.

Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC. PATIENTS AND METHODS: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS). RESULTS: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months). CONCLUSIONS: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy.

BACKGROUND: Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. PATIENTS AND METHODS: Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. RESULTS: Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a > or =50% prostate-specific antigen (PSA) decline and seven (21.2%) had a > or =30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score > or =2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. CONCLUSION: Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials.

BACKGROUND: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane-estramustine-carboplatin (TEC) chemotherapy may be greatest. PATIENTS AND METHODS: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as > or = 50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram. RESULTS: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival. CONCLUSIONS: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.

Evidence for biological nitrification inhibition in Brachiaria pastures.

Nitrification, a key process in the global nitrogen cycle that generates nitrate through microbial activity, may enhance losses of fertilizer nitrogen by leaching and denitrification. Certain plants can suppress soil-nitrification by releasing inhibitors from roots, a phenomenon termed biological nitrification inhibition (BNI). Here, we report the discovery of an effective nitrification inhibitor in the root-exudates of the tropical forage grass Brachiaria humidicola (Rendle) Schweick. Named "brachialactone," this inhibitor is a recently discovered cyclic diterpene with a unique 5-8-5-membered ring system and a gamma-lactone ring. It contributed 60-90% of the inhibitory activity released from the roots of this tropical grass. Unlike nitrapyrin (a synthetic nitrification inhibitor), which affects only the ammonia monooxygenase (AMO) pathway, brachialactone appears to block both AMO and hydroxylamine oxidoreductase enzymatic pathways in Nitrosomonas. Release of this inhibitor is a regulated plant function, triggered and sustained by the availability of ammonium (NH(4)(+)) in the root environment. Brachialactone release is restricted to those roots that are directly exposed to NH(4)(+). Within 3 years of establishment, Brachiaria pastures have suppressed soil nitrifier populations (determined as amoA genes; ammonia-oxidizing bacteria and ammonia-oxidizing archaea), along with nitrification and nitrous oxide emissions. These findings provide direct evidence for the existence and active regulation of a nitrification inhibitor (or inhibitors) release from tropical pasture root systems. Exploiting the BNI function could become a powerful strategy toward the development of low-nitrifying agronomic systems, benefiting both agriculture and the environment.

Influence of hen age and molting treatments on shell egg exterior, interior, and contents microflora and Salmonella prevalence during a second production cycle.

The objective of this study was to determine if increasing hen age and 3 different molting treatments influenced the total microflora counts or the prevalence of Salmonella spp. on the exterior of the egg shell, within the interior shell, or in the contents. Eggs from Hy-Line W-98 and Bovans White layer strains were sampled approximately every 28 d from 70 to 114 wk of age, with the molting period from 66 to 70 wk of age. Layers were utilized from the 35th North Carolina Layer Performance and Management Test and managed under identical husbandry practices. This study consisted of nonfasted, nonmolted, and feed-restricted treatments with the use of 135 eggs per layer strain, for a total of 270 eggs sampled per period. The exterior, interior shell, and contents were spiral plated onto plate count agar to calculate the total aerobic counts. Additional preenrichment, enrichment, conformational, and biochemical procedures were performed to test for the presence of Salmonella spp. Hen age and molting treatment significantly (P < 0.05) affected the microbial loads on all 3 egg components. Exterior, interior, yolk, and albumen counts increased during the molt period to as much as 1 log unit higher than the highest countable plate, which was 10(5). Exterior, interior, and contents counts significantly increased (P < 0.05) during period 15, with a significant increase (P < 0.05) in the interior also in period 14, and in the contents in periods 14 and 17. There were a total of 360 egg pools, and of those, 4 were positive Salmonella samples. Both the interior and exterior shell components and 2 of the 3 molting treatments had positive samples. Of these positives, 4 were confirmed as Salmonella Braenderup. Three positives were associated with the interior component, whereas 1 positive was associated with the exterior shell component. Three of the 4 samples were related to the nonfasted treatment, whereas the remaining positive was found in the non-molted treatment.

Spontaneously occurring fibroid tumors of the laying hen oviduct.

Spontaneously occurring benign uterine leiomyomas (fibroids) are the most common tumors of reproductive-age women. It is estimated that more than 70% of all women will develop uterine fibroids, and the presence of these tumors is a primary cause of hysterectomies. Research into the causes and treatment of uterine fibroids is hampered by a lack of reliable animal models for the disease. Leiomyomas that appear to be outwardly similar to human uterine fibroid tumors are known to occur on the oviducts of laying hens over 2 yr of age. The objective of this study was to characterize these tumors and compare them to human uterine fibroids to determine the suitability of the aging hen as a model system for the study of the disease. In this study, hens at 5 yr of age were examined for the presence of oviduct-associated fibroid tumors. Tumors were found attached to the internal surface of the oviduct, embedded in the oviduct wall, or attached to the exterior of the magnum and isthmus. Tumor and normal oviduct samples were frozen or fixed in formalin for histological analyses or immunohistochemistry for estrogen and progesterone receptors, proliferating cell nuclear antigen and Bcl-2 protein expression. Human uterine fibroid samples were acquired and evaluated compared with hen oviduct fibroids. The results indicate that laying hen fibroid tumors are similar to human fibroid tumors with respect to estrogen and progesterone receptors, localized cellular proliferation, and expression of the Bcl-2 protein.

Enteric drainage pancreatic transplantation.

Enteric drainage is currently the preferred method of pancreatic transplantation. This technique results in long-term good control of diabetes. In this report we discuss the postoperative radiologic anatomy and complications.

Effects of injected gluconeogenic supplementation on the performance of broilers from young breeders.

Previous research has shown that administering carbohydrates to late-term embryos increases chick hatching weight and liver glycogen content and that supplementing broiler chicks from young hens at day of hatch with subcutaneously injected hydrolyzed casein and thiamine enhances their early performance. It was hypothesized that other practical and readily available gluconeogenic energy sources, including hydrolyzed casein, may similarly be given to hatchlings from immature breeder hens to increase the availability of liver glycogen reserves and augment growth. In addition to physiological saline (sham) and hydrolyzed casein treatments, 2 other treatments containing practical gluconeogenic energy sources (chicken egg crude albumin or albumin hydrolysate) were tested in the current study using hatchlings that were subsequently provided adequate brooding and nutrition. Added biotin was included in the crude albumin treatment. There were no treatment effects on mortality, BW gain, feed or water consumption, feed conversion, body temperature, hematocrit, plasma refractive index, relative liver weight, or liver glycogen content at any of the ages or age intervals examined through d 16 posthatch. These results suggest that under proper brooding conditions and timely feed provision, growth is not facilitated by injected casein hydrolysate, chicken egg crude albumin, or chicken egg albumin hydrolysate during the early transition from fat to carbohydrate-based nutrient uptake in posthatch chicks from young breeder hens.

Herpes zoster infection in the post-hematopoietic stem cell transplant pediatric population may be preceded by transaminitis: an institutional experience.

Herpes zoster (HZ), a varicella-zoster virus reactivation, frequently complicates hematopoietic stem cell transplantation (HSCT). Its incidence, complications, and associated risk factors in 310 children undergoing HSCT were reviewed. In all, 61 of 201(32%) patients who had undergone allogeneic and 10 of 109 (9%) patients who had undergone autologous HSCT developed HZ. Of 90 VZV seropositive allogeneic patients, 50 (53%) developed HZ. Seven (17%) of 41 VZV seropositive autologous patients developed HZ. Although a substantial number of patients develop HZ in the early post-HSCT period, risk for HZ persists and HZ can occur up to 5 years post-HSCT. Risk factors for HZ included age >10 years (P<0.0001), allogeneic HSCT (P<0.001), and total body irradiation (TBI) (P<0.059) in allogeneic recipients. Of 37, 22 (59%) patients experienced an elevated alanine aminotransferase (ALT), unassociated with GVHD, in the month preceding HZ. Of the 48/64 patients (75%) hospitalized for treatment (median stay, 6 days; range, 2-39), length of stay was unaffected by donor type but increased by cutaneous dissemination and visceral involvement (P=0.023 and 0.034, respectively) in allogeneic patients. Consideration of HZ infection particularly in patients >10 years of age with elevated ALT after TBI-conditioned allogeneic HSCT may permit earlier diagnosis and therapeutic intervention.

Differential expression of iodothyronine deiodinase type 2 in growth plates of chickens divergently selected for incidence of tibial dyschondroplasia.

Tibial dyschondroplasia (TD) is a genetic leg defect in broilers with a lesion of avascular, non-calcified cartilage below the growth plate of the proximal tibiatarsus. This disease is considered to result from the inability of chondrocytes to undergo terminal differentiation. Thyroid hormones are required for chondrocyte differentiation. The thyroid gland produces and secrets mostly L-thyroxine or T4 and T4 plays most of its biological activities through conversion to triiodothyronine or T3 in local tissues by iodothyronine deiodinases type 1 or type 2, which are tissue specific. In this study, no differences were found in the plasma concentrations of total T3 and T4 between two chicken lines divergently selected for the incidence of TD. Plasma T4 was higher than T3, especially in older chickens. Younger birds had much higher T3 than older birds, but there were no significant age differences in T4. The expression level of deiodinase type 2 in the growth plates of broilers with TD was one-eighth of those birds without the disease. The expression levels of deiodinase type 2 (DIO2) in commercial broilers without the disease were much higher than those with TD and lower than those without the disease in the susceptible and resistant lines, respectively. These results indicate that the inadequate expression of DIO2 in the growth plates contributes to the pathogenesis of TD in broilers and that TD is a tissue-specific hypothyroidism.

Precision of dialysis (peeper) sampling of cadmium in marine sediment interstitial water.

Isolating and analyzing interstitial water (IW) during sediment toxicity tests enables researchers to relate concentrations of contaminants to responses of organisms, particularly when IW is a primary route of exposure to bioavailable contaminants by benthic dwelling organisms. We evaluate here the precision of sampling IW with the dialysis or 'peeper' method using sediments spiked with five different concentrations of cadmium. This method is one of several that are commonly used for collecting IW. Seven consecutive ten-day toxicity tests were conducted on these sediments and IW samples were collected at the end of each of these tests. Prior to each test initiation and insertion of IW samplers, sediments were allowed to equilibrate for seven days under flow-through conditions with filtered seawater. At the end of each ten-day testing period, peepers were retrieved, and IW cadmium measured. Data sets were organized by treatment and test number. Coefficients of variation (CV) for the six replicates for each sediment and testing period and for each sediment across testing periods (42 replicates) was used as a measure of sampling precision. CVs ranged from 25 to 206% when individual testing periods were considered, but ranged from 39 to 104% when concentrations for all testing periods were combined. However, after removal of outliers using Dixon's Criteria, the CVs improved and ranged from 6 to 88%. These levels of variability are comparable to those reported by others. The variability shown is partially explained by artifacts associated with the dialysis procedure, primarily sample contamination. Further experiments were conducted that support our hypothesis that contamination of the peeper causes much of the variability observed. If method artifacts, especially contamination, are avoided the dialysis procedure can be a more effective means for sampling IW metal.

The physiology of induced molting.

The initiation of seasonal feather molting in wild avian species frequently coincides with incubation of eggs and brooding of offspring. A period of natural inappetence or anorexia usually accompanies this molt. This is particularly true of the jungle fowl, the wild ancestor of the domestic chicken. Brooding of eggs by the jungle fowl is accompanied by spontaneous anorexia, with little food or water consumed throughout the period of egg incubation. During this time, the reproductive tract regresses, and feather molting is initiated. Selective breeding for a high rate of egg production has blunted the response of the commercial laying hen to exogenous environmental cues and reduced or eliminated the endogenous biological cues that coordinate initiation of seasonal molting. However, commercial layers retain in their physiological repertoire the ability to tolerate prolonged fasting and to undergo a spontaneous regression of the reproductive tract and feather molting. Induction of a coordinated molt, by manipulation of environmental and nutritional cues, or endocrine manipulation, can be used in domestic hens to regress and regenerate the reproductive tract. This improves subsequent egg production and eggshell quality. This process also induces temporary recrudescence of lymphoid tissues and may alter immune function in hens. The process of molting, and the subsequent recovery from the molt, may be viewed as a complex physiological constellation, induced by environmental and nutritional cues, involving endocrine systems, reproductive tissue structure and function, lymphoid structure, and immune function.

The expression of calbindin in chicks that are divergently selected for low or high incidence of tibial dyschondroplasia.

Three experiments were conducted with broiler chicks that were divergently selected for low or high incidence of tibial dyschondroplasia (LTD and HTD, respectively) to determine if the expression of intestinal calbindin-28 kD mRNA and protein differed between the 2 strains. In addition, levels of intestinal vitamin D receptor mRNA and plasma thyroid hormone concentrations were also examined. In experiment 1, LTD and HTD chicks were fed a corn-soybean meal diet that was adequate in all nutrients except cholecalciferol (D3), which was titrated to 5 or 40 microg/kg diet in a completely randomized 2 x 2 factorial arrangement. At 4 and 8 d of age, HTD chicks fed 5 microg of D3/kg of diet had a lower (P < 0.05) expression level of calbindin-28 kD mRNA than the LTD chicks fed the same diet. At 4 and 8 d of age, HTD chicks fed 5 microg of D3 had the lowest intestinal expression of calbindin-28 kD protein. Expression of vitamin D receptor mRNA did not differ for broiler strains at either level of D3 supplementation. In experiment 2, there was no significant difference in the expression of calbindin-28 kD mRNA or vitamin D receptor mRNA between day-of-hatch LTD, HTD, and commercial broiler chicks. Experiment 3 was similar in design to the first experiment except that the birds were fed for 18 d. Calbindin-28 kD and vitamin D receptor mRNA expression levels at 18 d were similar to those observed in experiment 1. Plasma triiodothyronine and free-triiodothyronine concentrations were greater for LTD chicks, regardless of dietary D3 supplementation levels. These results suggest that divergent selection of broilers for LTD or HTD alters the physiological response to nutritionally inadequate levels of dietary D3.

Extradural spinal synovial cysts in nine dogs.

Nine dogs presenting for investigation of cervical or thoracolumbar myelopathies were diagnosed with extradural spinal synovial cysts. Degenerative disease affecting the articular facets or intervertebral discs was present on plain spinal radiographs in all cases. Myelography was consistent with dorsolateral, extradural spinal cord compression. Two groups of dogs were identified: (1) young, giant breed dogs with multiple cysts involving one or more levels of the cervical spinal cord; and (2) older, large breed dogs with solitary cysts involving the thoracolumbar spinal cord. The synovial cysts constituted the major compressive lesions in four of the dogs. Analysis of lumbar cerebrospinal fluid demonstrated albuminocytological dissociation, consistent with chronic compressive myelopathy, in six dogs. All dogs underwent decompressive surgery and the diagnosis of synovial cysts was confirmed histologically. The mean follow-up period was 17 months (range four to 36 months). At the time of follow-up, all dogs were fully ambulatory with improved neurological function compared with that at initial presentation.

Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate.

The purpose of this study was to assess the efficacy of weekly administration of docetaxel as a single agent in patients with hormone-refractory, symptomatic, metastatic prostate cancer with respect to symptom palliation, tumor response, time to progression, and survival. Sixty men with progressive metastatic prostate cancer that had progressed on at least one hormonal regimen were enrolled in this multicenter phase II study. Twenty-one percent of patients had received prior palliative radiotherapy, and 25% had received prior chemotherapy for hormone-refractory disease. Patients were scheduled to receive three 8-week cycles of docetaxel (36 mg/m(2) on days 1, 8, 15, 22, 29, and 36) with 2-week intervals between cycles. The docetaxel dose could be decreased in the event of toxicity, but no dose escalation was permitted. A > or =50% decrease in serum prostate-specific antigen (PSA) levels from baseline with stabilization or improvement of performance status lasting 2 months or longer occurred in 24 (41%) patients, of whom 16 (27%) had a > or =80% decrease for 2 months or more. The median time to progression for all patients was 5.1 months (range, 0.9 to 18.2 months). The estimated median time to progression for patients who had and those who did not have a > or =50% reduction in serum PSA level with stable or improved performance status was 6.65 and 4.3 months, respectively. The median overall survival was 9.4 months (range, 1.6 to 18.2 months). Treatment toxicity was considered acceptable. Single-agent docetaxel at 36 mg/m(2) weekly was associated with a PSA response rate of 41%, increased time to progression and survival, and minimal myelosuppression in patients with hormone-refractory metastatic prostate cancer.