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Biomedical subjects

P Whelan

Publications and source records attributed to P Whelan.

At least 19 recordsLinked to original sources
PubMed2003

Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma.

OBJECTIVE: To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to clinical progression. Finally to compare TPS with prostate-specific antigen (PSA) measurements in terms of prognostic impact in patients with metastatic prostatic carcinoma. METHODS AND PATIENTS: TPS and PSA measurements were performed before start of and monthly during intermittent MAB in 68 patients participating in EORTC protocol 30954. Both TPS and PSA were measured in serum. Fifty-six patients from eight centers were included in the final analysis because at least three TPS values were available. TPS and PSA values were correlated with clinical course of the disease. Median follow-up was 21.3 months. Three patient groups were defined on clinical grounds: (a) clinically progressive disease (n=18); (b) clinically stable disease (n=33); and (c) patients who did not reach a predefined nadir PSA value following 9 months of treatment (n=5). RESULTS: Pretreatment TPS was significantly higher in the clinically progressive patients than in the other patient groups (p=0.0041). When grouping patients according to their pretreatment TPS values (cut-off value of 100 U/l) the pretreatment TPS value (>100 U/l) proved to be a statistically significant prognostic factor with respect to time to progression: elevated TPS was associated with a 3.8 increased risk for progressive disease (p=0.0055). Pretreatment PSA (>100 ng/ml) was of no prognostic value for time to progression. In five patients increase of TPS coincided with or preceded clinical progression during treatment, whereas PSA remained normal. CONCLUSION: Additional value of pretreatment TPS measurements in metastatic prostate cancer patients is found in defining the patients with rapid clinical progression. Following MAB an increase in TPS signifies clinical progression even if PSA is found to remain normal.

Androgen Antagonists↗
PubMed2001

Management of persistent or locally recurrent epidermoid cancer of the anal canal with abdominoperineal resection.

We retrospectively evaluated the outcome of 22 patients with epidermoid cancer of the anal canal who underwent surgical salvage after failure of primary chemoradiotherapy. Patients who required surgery had significantly more advanced T-stage than those who did not fail chemoradiotherapy. Eighteen patients failed surgical salvage. Invasion through the muscle wall of the bowel was present in 16 of 18 patients compared with two of four patients who have no evidence of disease (follow-up 5-10 years). Failure occurred only in the pelvis in 13 of the patients who died of disease. The mean time to death after surgery was 19 months. We confirm the overall poor results of conventional abdominoperineal resection in those patients who have failed previous therapy. Most failures occur in the pelvis. Transanorectal ultrasound and magnetic resonance imaging (MRI) may allow better selection of patients for exenterative procedures and identify those not amenable to successful salvage.

Abdomen↗
PubMed2000

Prostate cancer treated by anti-androgens: is sexual function preserved? EORTC Genitourinary Group. European Organization for Research and Treatment of Cancer.

This paper reports on results of the EORTC protocol 30892, an open, prospective, randomized study of 310 patients with previously untreated metastatic prostate cancer with favourable prognostic factors who were treated by either flutamide (FLU) or cyproterone acetate (CPA) monotherapy. The final analysis with regard to the main end points, time to progression and survival are still pending. Final results related to the evaluation of sexual functioning prior to and under treatment are reported here. Of 310 randomized patients 294 were eligible for evaluation within this side study. The median age was 71 years (range 48-85). Potential risk factors related to age, general health and prostate cancer were evaluated. For evaluation of sexual functions a five-item questionnaire was used which was administered by the investigator. The protocol allowed time dependent observations at 3-monthly follow-up visits. Sexual functioning was dependent on age but not on prostate cancer-related parameters. Sexual functions at entry were similar within the two treatment groups, spontaneous (nightly) erections and sexual activity were seen in 43-51% and 29-35% of cases. Under treatment, sexual functions under FLU and CPA declined slowly with median times of 12.9 and 5.8 months versus 13.7 and 8.9 months respectively for spontaneous erections and sexual activity. Eventually, with an average observation time in excess of 2 years, loss of spontaneous erections and of sexual activity occurred in 80% versus 92% and in 78% versus 88% of men under FLU versus CPA treatment respectively. None of these differences reached statistical significance. Maintenance of potency under treatment with FLU as reported in the literature is not confirmed in this study. However, loss of sexual functions under monotherapy with both antiandrogens is slow and 10-20% of men retain sexual activity after 2-6 years of treatment. This observation can be exploited in new treatment schemes and is likely to lead to improved quality of life. The advantage of FLU in time and total preservation of sexual functions is statistically not significant and must be balanced against the side effects of FLU and other pure antiandrogens, which may exceed those of CPA especially with respect to gynaecomastia. Hepatic toxicity may limit the long-term use of both drugs.

Aged↗
PubMed2000

Properties of rhythmic activity generated by the isolated spinal cord of the neonatal mouse.

We examined the ability of the isolated lumbosacral spinal cord of the neonatal mouse (P0-7) to generate rhythmic motor activity under several different conditions. In the absence of electrical or pharmacological stimulation, we recorded several patterns of spontaneous ventral root depolarization and discharge. Spontaneous, alternating discharge between contralateral ventral roots could occur two to three times over a 10-min interval. We also observed other patterns, including left-right synchrony and rhythmic activity restricted to one side of the cord. Trains of stimuli delivered to the lumbar/coccygeal dorsal roots or the sural nerve reliably evoked episodes of rhythmic activity. During these evoked episodes, rhythmic ventral root discharges could occur on one side of the cord or could alternate from side to side. Bath application of a combination of N-methyl-D,L-aspartate (NMA), serotonin, and dopamine produced rhythmic activity that could last for several hours. Under these conditions, the discharge recorded from the left and right L(1)-L(3) ventral roots alternated. In the L(4)-L(5) segments, the discharge had two peaks in each cycle, coincident with discharge of the ipsilateral and contralateral L(1)-L(3) roots. The L(6) ventral root discharge alternated with that recorded from the ipsilateral L(1)-L(3) roots. We established that the drug-induced rhythm was locomotor-like by recording an alternating pattern of discharge between ipsilateral flexor and extensor hindlimb muscle nerves. In addition, by recording simultaneously from ventral roots and muscle nerves, we established that ankle flexor discharge was in phase with ipsilateral L(1)/L(2) ventral root discharge, while extensor discharge was in phase with ipsilateral L(6) ventral root discharge. Rhythmic patterns of ventral root discharge were preserved following mid-sagittal section of the spinal cord, demonstrating that reciprocal inhibitory connections between the left and right sides of the cord are not essential for rhythmogenesis in the neonatal mouse cord. Blocking N-methyl-D-aspartate receptors, in both the intact and the hemisected preparation, revealed that these receptors contribute to but are not essential for rhythmogenesis. In contrast, the rhythm was abolished following blockade of kainate/AMPA receptors with 6-cyano-7-nitroquinoxalene-2,3-dione. These findings demonstrate that the isolated mouse spinal cord can produce a variety of coordinated activities, including locomotor-like activity. The ability to study these behaviors under a variety of different conditions offers promise for future studies of rhythmogenic mechanisms in this preparation.

Animals↗
PubMed1999

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer.

Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.

Adult↗
PubMed1999

Changing trends in prostatic cancer.

OBJECTIVES: To examine the diagnosis and treatment of prostatic cancer in a population-based study, reporting incidence trends and survival, in the decade before the introduction of prostate-specific antigen (PSA) testing, and thus determine whether the overall incidence of prostatic cancer is increasing or not. PATIENTS AND METHODS: The study included all men registered as having prostatic cancer in the Yorkshire region between 1981 and 1990. The Northern and Yorkshire Cancer Registry and Information Service has an active registration policy and after notification, the information received is validated by histopathology reports and case-note review. Of the patients registered, 68% were over 70 years old at the time of diagnosis (mean age 74 years). Prostatic cancer was often diagnosed incidentally, after prostatectomy for presumed benign disease. Indications for treatment were not recorded, but most patients had treatment which was designed to control outlet bladder symptoms rather than with intent to cure cancer. RESULTS: In all, 8118 patients with prostatic cancer were registered, of whom 6587 had histological confirmation. There was a 30% increase in the age-standardized incidence of prostatic cancer during the study period (P<0.001). The mortality from prostatic cancer increased by 35% (P<0.001) and the percentage of patients known to have metastases at the time of presentation increased from 18% to 24%. These changes were seen in all age groups. The overall survival was 49% at 5 years and 34% at 10 years. CONCLUSIONS: There has been a real increase in the incidence of prostatic cancer which pre-dates the use of serum PSA testing. The percentage relative survival of patients with prostatic cancer in Yorkshire during the study period is similar to that seen in other parts of the UK, but compares badly with reported survival in other countries.

Adult↗
PubMed1999

In vivo resistance to bacterial biofilm formation on tympanostomy tubes as a function of tube material.

Adherent bacterial biofilms have been implicated in the irreversible contamination of implanted medical devices. We evaluated the resistance of various tympanostomy (pressure equalization [PE]) tube materials to biofilm formation using an in vivo model. PE tubes of silicone, silver oxide-impregnated silicone, fluoroplastic, silver oxide-impregnated fluoroplastic, and ion-bombarded silicone were inserted into the tympanic membranes of 18 Hartley guinea pigs. Staphylococcus aureus was then inoculated into the middle ears. An additional 8 guinea pigs were used as controls; the PE tubes were inserted without middle ear inoculation. All PE tubes were removed on day 10 and analyzed for bacterial contamination using culture, immunofluorescence, and scanning electron microscopy (SEM). All infected ears developed otitis media with otorrhea, but none of the animal control ears drained. Fluorescence imaging of the animal control tubes showed large cellular components consistent with inflammation. The infected tubes showed heavy DNA fluorescence consistent with bacteria and inflammatory cells. All animal control tubes except the ion-bombarded silicone tubes showed adherent inflammatory film on SEM. Also, all tubes placed in infected ears except the ion-bombarded silicone tubes showed adherent bacterial and inflammatory films on SEM. Nonadherent surface properties such as the ion-bombarded silicone may be helpful in preventing chronic PE tube contamination.

Animals↗
PubMed1999

Orchiectomy and orchiectomy plus mitomycin C for metastatic prostate cancer in patients with poor prognosis: the final results of a European Organization for Research in Cancer Therapy Genitourinary Group Trial.

PURPOSE: The outcome of patients with symptomatic metastatic prostate cancer is poor and improved treatment regimens are urgently needed. Theoretically, the combination of orchiectomy and chemotherapy could reduce androgen sensitive and insensitive cells in the prostate. This European Organization for Research in Cancer Therapy Genitourinary Group randomized, multicenter phase III trial demonstrates the outcome of orchiectomy alone versus orchiectomy followed by intravenous mitomycin C. MATERIALS AND METHODS: A total of 189 patients with metastatic prostate cancer and poor prognostic factors were randomized in this trial by 42 institutions. Of these patients 184 (97%) were eligible for study, including 90 treated with orchiectomy alone (orchiectomy only arm) and 94 treated with orchiectomy followed by 15 mg./m.2 mitomycin C in 1 week (combined treatment arm). Mitomycin C was administered every 6 weeks and treatment was continued as long as tolerance and patient compliance allowed, and no progression was observed. Objective and subjective criteria for progression were clearly defined in the protocol. RESULTS: Patient and tumor characteristics were well balanced between the 2 treatment arms. At a median followup of 4.2 years 144 patients had died, including 112 of prostate cancer. No significant differences for time to overall (p = 0.17), subjective (p = 0.25) and objective (p = 0.08) progression were found between the 2 treatment groups. For progression-free survival no difference was noted (p = 0.67) between the 2 treatment groups but a trend in favor of orchiectomy alone was observed for overall survival (p = 0.04). Mitomycin C induced considerable hematological, gastrointestinal, renal and pulmonary toxicity leading to discontinuation in 31% of patients with pulmonary toxicity and 7% with renal deterioration. In addition, the quality of life evaluation revealed significant reduction in the combined treatment arm. CONCLUSIONS: Based on the results of this randomized phase III study orchiectomy plus mitomycin C for metastatic prostate cancer in patients with poor prognostic factors cannot be recommended due to failure of improvement in survival and reduced quality of life parameters.

Antibiotics, Antineoplastic↗
PubMed1999

Retinoids in chemoprevention.

Over several decades, in vitro experimental studies have demonstrated that retinoids effect the process of carcinogenesis and tend towards the alteration of cells back to more normal differentiation. This hypothesis has formed the basis of several chemopreventive studies in breast cancer, cervical cancer, head and neck cancer and lung cancer. Experimental evidence exists to suggest that chemoprevention with retinoids may well have a beneficial effect in patients at high risk of acquiring prostate cancer. None of the studies, however, in any of the cancers have yet been definitive, but opportunities exist with newer retinoids that appear to be able to be given on a long-term basis with minimal toxic side effects, to explore this exciting potential treatment pathway.

Breast Neoplasms↗
PubMed1998

A presumptive case of fatal Murray Valley encephalitis acquired in Alice Springs.

A presumptive case of Murray Valley Encephalitis (MVE) acquired in Alice Springs in March 1997 is reported. The patient subsequently died in Mackay. The diagnosis of Murray Valley Encephalitis was supported by the detection of flavivirus IgM in cerebrospinal fluid. Low titres of IgM specific to Murray Valley Encephalitis and Alfuy were detected in a single serum sample. The patient's travel movements indicate that his infection was acquired in the Alice Springs vicinity. This conclusion was further supported by the detection of Murray Valley Encephalitis activity in sentinel animals in the area and by the presence of large numbers of the principal mosquito vector of Murray Valley Encephalitis in the Northern Territory.

Antibodies, Viral↗
PubMed1998

Dengue or Kokobera? A case report from the top end of the Northern Territory.

In early April 1998, the Centre for Disease Control in Darwin was notified of a possible case of dengue which appeared to have been acquired in the Northern Territory. Because dengue is not endemic to the Northern Territory, locally acquired infection has significant public health implications, particularly for vector identification and control to limit the spread of infection. Dengue IgM serology was positive on two occasions, but the illness was eventually presumptively identified as Kokobera infection. This case illustrates the complexity of interpreting flavivirus serology. Determining the cause of infection requires consideration of the clinical illness, the incubation period, the laboratory results and vector presence. Waiting for confirmation of results, before the institution of the public health measures necessary for a true case of dengue, was ultimately justified in this case. This is a valid approach in the Northern Territory, but may not be applicable to areas of Australia with established vectors for dengue.

Adult↗
PubMed1998

Use of intravenous fosfestrol tetrasodium (Honvan) infusion in treatment of symptomatic advanced prostate cancer.

Fosfestrol tetrasodium (Honvan) is a synthetic oestrogen-based compound. Studies have suggested its use in the treatment of localised, advanced and hormone-refractory prostate cancer. This series of 17 patients with advanced disease documents the response, both subjective and objective, to standard dose intravenous Honvan infusion. Infusions were well tolerated, with no cardiovascular side-effects. Twelve patients received Honvan as de novo therapy, of whom 10 (83%) described subjective improvement and 11 (92%) had objective evidence of improvement, 11 (92%) had documented falls in prostate-specific antigen (PSA) levels. Nine patients received Honvan infusions as secondary treatment for hormone-escaped disease (1 patient received Honvan for a second time and another for a second and third time). Of these, 1 (11%) had a documented fall in PSA; 3 (33%) reported a subjective symptomatic improvement, and 2 (22%) demonstrated objective evidence of improvement. Patients with symptoms from bulk abdomino-pelvic disease seemed to fare better than those with bony metastases. This may suggest a specific indication for Honvan in a subgroup of patients with acute obstructive events of the ureters, urethra or circulatory vessles, in particular its value as a de novo therapy. In those patients who received Honvan as secondary therapy, some response was seen in a third, but overall these patients remained hormone-refractory.

Journal Article↗
PubMed1998

A pilot study of intermittent androgen deprivation in advanced prostate cancer.

OBJECTIVE: To assess the feasibility of intermittent hormone therapy for metastatic prostate cancer. PATIENTS AND METHODS: Sixteen patients with metastatic carcinoma of the prostate were treated using a protocol of intermittent hormone therapy with the luteinizing hormone-releasing hormone (LHRH) analogue leuprorelin at a dose of 3.75 mg every 4 weeks. The protocol required that hormone therapy be stopped when the response was stable, and was designed to assess the duration of the unmaintained response and the probability of a second response to re-initiation of leuprorelin. RESULTS: Eleven of the 16 patients had a stable hormone response and stopped therapy 3-9 months (mean 5.5) from the start of treatment. The mean (range) duration of the unmaintained response, as judged by monitoring symptoms and serum prostate specific antigen (PSA) levels every month was 4 (2-8) months in the seven patients who had bone metastases and was 3, 3 and 6 months in the three with only loco-regional disease (one patient temporarily discontinued follow-up). As the immediate re-induction of hormone therapy was not mandatory in asymptomatic patients at the time of progression, the mean (range) period off hormone therapy was 8 (3-13) months in those eight patients with bone metastases and was 3, 36 and 42 + months in the three presenting with loco-regional disease. All 10 patients who re-initiated hormone therapy had a second hormone response, in six of which led to a decline in PSA level to < 2 ng/mL. During the period off hormone therapy no patient developed irreversible symptoms. CONCLUSIONS: The temporary cessation of hormone therapy early during the response in patients with metastatic carcinoma of prostate is associated with biochemical evidence of relatively early progression in most cases, but can be associated with significant periods off therapy and with a high chance of a second hormone response. The value of this approach to the quality and duration of patients' lives requires a prospective comparative evaluation.

Androgen Antagonists↗