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Biomedical subjects

W Walsh

Publications and source records attributed to W Walsh.

At least 19 recordsLinked to original sources
PubMed2006

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

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

Adult↗
PubMed2005

A phase I study of oral ZD 1839 given daily in patients with solid tumors: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To define the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), the biological active (BA) dose and the pharmacokinetics (PK) of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa) when administered continuously as a once daily dose in patients with advanced, incurable solid tumours. PATIENTS AND METHODS: Twenty-eight patients were enrolled in cohorts of three from three National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) centers. ZD1839 was given at doses from 150 to 800 mg daily orally and patients underwent a pretreatment and a 28 day post treatment tumor biopsy, while PK sampling was performed on days 8, 15, 22, 29, and a toxicity assessment every 28 days. RESULTS: All twenty-eight patients were evaluable for non-hematological and hematological toxicity. Twenty-seven were evaluable for response. The MTD was not reached but DLT included reversible rash and diarrhea. One patient with urachal cancer had a transient 55% decrease in tumor size and two other patients (breast and non-small cell lung cancer) had minor responses; three additional patients had pharmacodynamic evidence of target effect. PK demonstrated steady state within the first 2 weeks of dosing and dose dependent exposure. CONCLUSION: It appears that ZD 1839 at a dose of 800 m/day was tolerable, although some patients required dose modification for diarrhea. Doses above 250 m/day demonstrate biologic activity and could be consider for future study in a variety of EGFR positive tumor types.

Administration, Oral↗
PubMed2005

An NCIC CTG phase I/pharmacokinetic study of the matrix metalloproteinase and angiogenesis inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin.

BACKGROUND: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin in patients with advanced solid tumours, and to identify the maximum tolerated dose and the dose for use in future studies. PATIENTS AND METHODS: BAY 12-9566 and 5-fluorouracil/leucovorin were administered to 17 patients in 3 cohorts. Each patient served as his/her own control, with 5-fluorouracil being given alone on days 1-5 of cycle 1. In cohort 1, BAY 12-9566 at 800 mg p.o. b.i.d. was given with 350 mg/m2 5-fluorouracil/20 mg/m2 leucovorin x 5 days q28 days. In cohort 2, the BAY 12-9566 dose was reduced to 400 mg p.o. b.i.d., with the 5-fluorouracil/leucovorin doses remaining unchanged. Finally, in cohort 3, BAY 12-9566 400 mg bid was given with 5-fluorouracil 400 mg/m2/day. Patients were continued on therapy until unacceptable toxicity or tumour progression occurred. Pharmacokinetic analyses for both BAY 12-9566 and 5-fluorouracil were performed. RESULTS: The maximum tolerated dose was 400 mg p.o. b.i.d. BAY 12-9566 plus 5-fluorouracil/leucovorin at 400 mg/m2/day and 20 mg/m2/day, respectively. Thrombocytopenia necessitated a decrease of the dose of BAY 12-9566 by 50% from cohort 1 to cohort 2. Two dose-limiting toxicities occurred in cohort 3 consisting of neutropenic fever, and ileitis, causing severe diarrhea. Of 17 patients treated on study, 7 of 14 patients evaluable for response achieved stable disease. Pharmacokinetic analysis suggested there was no interaction between BAY 12-9566 and 5-fluorouracil. CONCLUSIONS: BAY 12-9566 400 mg bid and 5-fluorouracil 350 mg/m2 plus leucovorin 20 mg/m2 can be co-administered. Although there is some evidence of a clinical interaction, there is no apparent pharmacokinetic interaction. Future studies with these 2 types of agents administered in combination are warranted.

Angiogenesis Inhibitors↗
PubMed2004

A phase 1 study of OSI-211 given as an intravenous infusion days 1, 2, and 3 every three weeks in patients with solid cancers.

PURPOSE: To define the maximum tolerated dose (MTD), recommended phase II dose (RD) and dose limiting toxicity (DLT) of liposomal lurtotecan, OSI-211 (formerly known as NX211), given as a short intravenous infusion on days 1, 2, and 3 every three weeks. EXPERIMENTAL DESIGN: Thirty-seven patients were enrolled and treated in a dose escalation study from a starting dose of 0.15 mg/m(2) daily x 3 to 2.1 mg/m(2) daily x 3. Detailed pharmacokinetic analyses of blood were done on both days 1 and 3 of the first cycle and toxicity was monitored. RESULTS: Two MTDs were defined; one for patients defined as minimally pretreated and one for those heavily pretreated. Dose limiting toxicity was myelosuppression: primarily thrombocytopenia although neutropenia was also noted. The MTD was 2.1 mg/m(2)/d (total dose of 6.3 mg/m(2)) in minimally pretreated patients and 1.8 mg/m(2)/d (5.4 mg/m(2) total dose) in heavily pretreated patients. Pharmacokinetics revealed that AUC and C (max) increased with dose and were significantly higher than that of free lurtotecan (AUC approx. 100 fold higher). The half life and duration of the active lactone form were also significantly longer than historical data on free drug. Two partial responses were seen, one each in a patient with breast and ovarian cancer. CONCLUSIONS: Two Phase II recommended doses were established for OSI-211 given as a daily x 3 schedule every three weeks. The recommended phase II dose is 1.8 mg/m(2) daily x 3 for minimally pretreated patients and 1.5 mg/m(2) for those heavily pretreated. Phase II studies should be initiated in sensitive tumours.

Adult↗
PubMed2004

A phase I study of AMD473 and docetaxel given once every 3 weeks in patients with advanced refractory cancer: a National Cancer Institute of Canada-Clinical Trials Group trial, IND 131.

BACKGROUND: AMD473 (previously ZD0473) is a new-generation platinum compound with activity against a wide range of human tumour cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. To assess its potential combined with a taxane, a phase I study of AMD473 and docetaxel in advanced cancer was initiated by the National Cancer Institute of Canada-Clinical Trials Group. PATIENTS AND METHODS: Patients with advanced cancer, measurable disease, performance status Eastern Cooperative Oncology Group 0-2, no major organ dysfunction, and one or no previous taxane regimen received escalating doses of AMD473 and docetaxel every 3 weeks, with a starting dose of AMD473 80 mg/m(2) and docetaxel 60 mg/m(2). RESULTS: Thirty-three patients enrolled on four dose levels were evaluable for toxicity and 25 patients were evaluable for response. The maximum tolerated dose was dose level 4 (AMD473 120 mg/m(2) and docetaxel 75 mg/m(2)), with grade 4 neutropenia in both minimally and heavily pretreated patients causing dose-limiting toxicity. As well at dose level 4, one patient had grade 3 vomiting despite premedication. Dose level three was expanded for both groups of patients and was defined as the recommended phase II dose at AMD473 100 mg/m(2) and docetaxel 75 mg/m(2). Non-hematologic toxicities included fatigue, diarrhoea and other mild toxicities. There was one partial response in a patient with prostate cancer and stable disease in 15 patients. No apparent pharmacokinetic interaction was noted. CONCLUSION: AMD473 and docetaxel can be combined with a recommended phase II dose level of 100 mg/m(2) and 75 mg/m(2), respectively, given intravenously every 3 weeks. The combination has activity and should be explored in responsive tumour types.

Adenocarcinoma↗
PubMed2003

Mechanical properties of urogynecologic implant materials.

Synthetic suburethral slings have recently become popular despite the risk of erosion commonly associated with synthetic implants. Some of these materials seem to have unexpectedly low erosion rates. Based on the hypothesis that erosion is due, in part, to biomechanical properties, we undertook an in vitro study. The biomechanical properties of eight non-resorbable synthetic implant materials, stiffness (slope, N/mm) and peak load (N) were determined from load vs. displacement curves. Open-weave Prolene mesh showed unique biomechanical properties compared to other tested materials. The tension- free vaginal tape had the lowest initial stiffness (0.23 N/mm), i.e. low resistance to deformation at forces below the elastic limit, whereas the stiffest implant tested, a nylon tape, reached 6.83 N/mm. We concluded that the TVT and other wide-weave Prolene tapes have unique biomechanical characteristics. These properties may be at least partly responsible for the apparent clinical success of the implants.

Biocompatible Materials↗
PubMed2003

A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129.

BACKGROUND: ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group. PATIENTS AND METHODS: Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m(2) every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m(2) on the basis of emergent data from studies ongoing at the time. RESULTS: Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m(2) and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m(2). Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m(2) and two patients (10%) at 120 mg/m(2). Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients. CONCLUSION: ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.

Adult↗
PubMed2003

Surgical management of large rotator cuff tears combined with instability in elite rugby football players.

Large rotator cuff tears are extremely uncommon in young people and when they occur they may be associated with shoulder instability. This paper reports on a series of six elite rugby union and rugby league footballers who presented with shoulder instability and large rotator cuff tears. They were treated with a two stage procedure: an open rotator cuff repair followed by an open shoulder stabilisation some 10 weeks later. All had successful outcomes. The paper also highlights the risk of tearing the rotator cuff when a patient continues to play contact sport with an untreated unstable shoulder.

Adult↗
PubMed2002

Single vs. dual vessel porcine extracorporeal liver perfusion.

BACKGROUND: The use of porcine extracorporeal liver perfusion (PECLP) to provide temporary hepatic support for patients in fulminant hepatic failure has been limited by the fact that individual perfusions can be sustained for only a few hours. Inadequate liver function and/or hemodynamic instability are the major contributing factors for early interruption of PECLP. Recent reports suggest that the choice of single (portal vein only) vs dual (portal vein and hepatic artery) vessel perfusion may influence the duration of perfusion. We hypothesize that PECLP with single vessel perfusion (SVP) is associated with worse liver function and greater hemodynamic instability than PECLP with dual vessel perfusion (DVP). MATERIALS AND METHODS: To eliminate the potentially confounding influences of liver failure and xenograft rejection, liver isografts procured from White-Landrace pig donors were perfused by either SVP or DVP via an extracorporeal circuit established with normal White-Landrace pig recipients. The function of perfused livers was evaluated by measuring production of bile and Factors V and VIII, clearance of ammonia and lactate, and extraction of O(2) at baseline and at 0, 1, 3, 6, 12, and 24 h after initiation of PECLP. The impact of PECLP on recipient hemodynamic status was assessed by monitoring BP, heart rate, urine output, O(2) saturation, etc. Among other parameters evaluated were serum albumin and total protein and hepatic release of IL-1beta and nitric oxide to assess their possible contributions to hemodynamic instability. RESULTS: DVP and SVP livers cleared ammonia and lactate similarly. Both approaches were associated with progressive hypoalbuminemia and hypoproteinemia. DVP livers produced more bile and Factor V and were associated with less recipient hypotension and IL-1beta and NO release than SVP livers. CONCLUSIONS: Livers with DVP function better than livers with SVP. The duration of PECLP can be limited by recipient hypotension, although this complication is less severe with DVP than with SVP.

Ammonia↗
PubMed2002

Total hip arthroplasty for arthrodesed hips.

The benefits of converting an ankylosed or arthrodesed hip to total hip arthroplasty have been reported in the literature as have the technical difficulties associated with this procedure. This review, however, outlines the experience of a single surgeon (WJMB) at a single institution using uncemented prostheses. Between November 1991 and June 1996, 5 arthrodesed hips underwent uncemented total hip arthroplasty in 4 males and 1 female. Clinical and radiological follow-up review was for at least three years in all patients. In general, patients were satisfied with the outcome of their surgery with Harris Hip scores improving from an average of 62 preoperatively to an average of 72 postoperatively. The surgical outcome in these difficult cases was not as satisfactory as for routine total hip arthroplasty. Meticulous preoperative planning is required to aim toward leg length restoration and restoration of the abductor moment arm. A modular prosthesis allows versatility at surgery.

Adult↗
PubMed2002

Salvaging unstable or recurrent dislocating total hip arthroplasty with the constrained acetabular component.

PURPOSE: To review cases of implantation of constraining acetabular components for unstable or recurrent dislocating total hip arthroplasty at the Department of Orthopaedics, Concord Hospital, Sydney. METHODS: A retrospective analysis was performed on prospectively collected data of 13 consecutively enrolled patients. RESULTS: From 1989 to 2000, 13 constraining acetabular components were implanted into 13 patients as a revision procedure. The surgical approach for the implantation of the constrained liner was posterolateral in 11 cases; a modified Hardinge approach was applied in 2 cases. The mean clinical follow-up duration was 43 months (range, 14-121 months) and the mean age at the time of surgery was 73 years (range, 52-84 years). No patients were lost to follow-up. Indications for using the constrained acetabular component were recurrent dislocation in revision hip replacements (n=8), and intra-operative instability (n=5). There were no episodes of dislocation of the constrained arthroplasty. In 7 cases, the constrained component was implanted into a previously well-fixed shell. CONCLUSION: We recommend the judicious use of the constrained component in cases of hip instability during or after total hip arthroplasty when other methods are not successful.

Acetabulum↗
PubMed2001

Identification and characterization of a novel family of pneumococcal proteins that are protective against sepsis.

Four pneumococcal genes (phtA, phtB, phtD, and phtE) encoding a novel family of homologous proteins (32 to 87% identity) were identified from the Streptococcus pneumoniae genomic sequence. These open reading frames were selected as potential vaccine candidates based upon their possession of hydrophobic leader sequences which presumably target these proteins to the bacterial cell surface. Analysis of the deduced amino acid sequences of these gene products revealed the presence of a histidine triad motif (HxxHxH), termed Pht (pneumococcal histidine triad) that is conserved and repeated several times in each of the four proteins. The four pht genes (phtA, phtB, phtD, and a truncated version of phtE) were expressed in Escherichia coli. A flow cytometry-based assay confirmed that PhtA, PhtB, PhtD and, to a lesser extent, PhtE were detectable on the surface of intact bacteria. Recombinant PhtA, PhtB, and PhtD elicited protection against certain pneumococcal capsular types in a mouse model of systemic disease. These novel pneumococcal antigens may serve as effective vaccines against the most prevalent pneumococcal serotypes.

Amino Acid Sequence↗
PubMed2001

Use of a whole genome approach to identify vaccine molecules affording protection against Streptococcus pneumoniae infection.

Microbial targets for protective humoral immunity are typically surface-localized proteins and contain common sequence motifs related to their secretion or surface binding. Exploiting the whole genome sequence of the human bacterial pathogen Streptococcus pneumoniae, we identified 130 open reading frames encoding proteins with secretion motifs or similarity to predicted virulence factors. Mice were immunized with 108 of these proteins, and 6 conferred protection against disseminated S. pneumoniae infection. Flow cytometry confirmed the surface localization of several of these targets. Each of the six protective antigens showed broad strain distribution and immunogenicity during human infection. Our results validate the use of a genomic approach for the identification of novel microbial targets that elicit a protective immune response. These new antigens may play a role in the development of improved vaccines against S. pneumoniae.

Amino Acid Sequence↗
PubMed2001

Quantification of third body damage to the tibial counterface in mobile bearing knees.

Fourteen pairs of explanted low contact stress (LCS) tibial interface components: six rotating platform (RP), six meniscal (MN) and two anterior-posterior (AP) glide designs, have been analysed with particular attention paid to the condition of the tibial counterfaces. The average surface roughness, Ra, for the tibial trays ranged from 0.01 to 0.087 micron, significantly greater than the unworn control measurement of 0.008 micron. The scratch geometry analysis showed that the scratch peaks were found to be consistently of a lower aspect ratio than the scratch valleys and under 1 micron in height (average asperity height Rp = 0.52 micron, aspect ratio delta p = 0.01, average asperity depth Rv = 1.10 microns, delta v = 0.05). The largest scratches were 3-4 microns in both Rp and Rv. In vitro tests have shown that ultra-high molecular weight polyethylene (UHMWPE) wear increases in the presence of counterface scratches perpendicular to the direction of motion. In these explants, the unidirectional motion produced scratches parallel to the direction of sliding which is predicted to produce a smaller increase in UHMWPE wear. Other designs in mobile bearing knees have less constrained motion at the tibial counterface and this has been shown to accelerate wear; it may also lead to a further increase in wear in the presence of third body scratches. It may be possible in future knee designs to reduce this type of wear damage by introducing alternative materials or coatings which are more resistant to scratching and surface roughening.

Aged↗
PubMed2000

A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours.

BACKGROUND: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies. PATIENTS AND METHODS: BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred. RESULTS: A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements. CONCLUSIONS: The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.

Administration, Oral↗
PubMed1999

Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2', 2'-difluorodeoxycytidine) plus cisplatin in previously untreated patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Thirty-one patients with measurable advanced transitional-cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 70 mg/m(2) over 1 hour on day 2 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed more than 1 year before study entry. RESULTS: There were six complete responses and 10 partial responses in 28 assessable patients, for an overall response rate of 16 of 28 (57%). The response rate on an intent-to-treat basis was 16 of 31 patients (52%). The median survival is 13.2 months, with 18 patients still alive at this time. Toxicity was primarily hematologic, with 12 of 31 patients (39%) having > or = grade 3 granulocytopenia and 17 of 31 (55%) having > or = grade 3 thrombocytopenia. Two patients had febrile neutropenia. All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. CONCLUSION: Gemcitabine plus cisplatin is an active regimen for the treatment of urothelial cancer.

Adult↗
PubMed1997

Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB).

The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms in the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance-seeking behaviors (ethanol, drugs, tobacco, and food) and other related behaviors (pathological gambling, Tourette's disorder, attention-deficit/hyperactivity disorder). This is the first study supporting a strong association between the dopamine D2 receptor Taq A1 allele with schizoid/avoidant behavior (SAB). Additionally, an albeit weaker association between the 480-bp VNTR 10/10 allele of the dopamine transporter (DAT1) gene with SAB was similarly found.

Adult↗