Accelerated BEP for metastatic germ cell tumours: a multicenter phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).

BACKGROUND: This Australian single-arm, multicenter, phase II trial evaluated feasibility, tolerability and activity of accelerated bleomycin, etoposide and cisplatin (BEP) as first-line chemotherapy for metastatic germ cell tumours. PATIENTS AND METHODS: Patients were planned to receive cisplatin 20 mg/m(2) and etoposide 100 mg/m(2) days 1-5, and pegfilgrastim 6 mg day 6, all repeated every 2 weeks for four cycles (three cycles for good prognosis). Bleomycin was given at 30 000 IU weekly to a total of 12 doses (9 doses for good prognosis). Primary end point was feasibility, defined as the proportion of patients able to complete the etoposide and cisplatin components of BEP and be eligible to receive a fourth cycle of BEP by day 50. RESULTS: Twelve poor, 16 intermediate and 15 good prognosis (n = 43) eligible patients were enrolled. Two patients aged >40 years were ineligible and excluded from analyses. The regimen was feasible in 86%, not feasible in 7% and not assessable in 7% of patients. Most common grade 3/4 adverse events were non-neutropenic infection (16%) and febrile neutropenia (12%). Complete response (CR) to chemotherapy and surgery was achieved in 33% poor-prognosis, 81% intermediate-prognosis and 100% good-prognosis patients. At median follow-up of 27 months (range 6-42), the 2-year progression-free survival was 50% for poor-prognosis, 94% for intermediate-prognosis and 92% for good-prognosis patients. CONCLUSION: Accelerated BEP is feasible and tolerable. Efficacy data appear to be promising. This trial and a similar UK study provide the rationale for a randomised trial comparing accelerated versus standard BEP. Australian New Zealand Clinical Trials Registry Registration number. ACTRN 12607000294459.

Testosterone deficiency and quality of life in Australasian testicular cancer survivors: a prospective cohort study.

This is the first prospective study in a contemporary Australian/New Zealand population to determine the prevalence of testosterone deficiency in testicular cancer survivors at 12 months from treatment, and any association with poorer quality of life. Hormone assays from 54 evaluable patients in a prospective cohort study revealed biochemical hypogonadism in 18 patients (33%) and low-normal testosterone in 13 patients (24%). We found no association between testosterone levels and quality of life (all P > 0.05). Hypogonadal patients should be considered for testosterone replacement to prevent long-term morbidity.

Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus.

Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was -56.8% (SD 29) and in the non-responders -27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was -49.1% (SD 44.8) in the responders and in the non-responders -27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3-6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.

Body weight and prognosis in breast cancer.

We have examined the relationship between risk factors for breast cancer incidence and the subsequent prognosis of breast cancer among patients in a randomized controlled trial of adjuvant ovarian ablation. Body weight was the only risk factor found to be associated with statistically significant differences in survival. This finding could not be explained by a disproportionate number of anatomically more advanced tumors in the heavier women. In premenopausal women aged 45 years or more, the only group to benefit from adjuvant ovarian ablation, there was an interaction of treatment and weight, suggesting that weight exerts its influence on prognosis by a hormonal mechanism. The prognostic effect of weight was generally most marked in patients with tumors whose prognostic characteristics were favorable, and in these patients weight loss as an adjuvant treatment may reduce the frequency of disease recurrence.

Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma.

Tamoxifen was evaluated as initial hormone therapy for metastatic breast cancer in 85 premenopausal patients. Tamoxifen responders continued on tamoxifen, while tamoxifen failures and initial responders who later progressed were to receive ovarian ablation next. Of 74 evaluable patients, 5 had complete responses (CR) and 15 had partial responses (PR) while 12 remained stable (ST), giving response rates of 27% (CR + PR) or 43% (CR + PR + ST). Of the 23 patients who initially responded (CR + PR + ST) to tamoxifen but then progressed and received ovarian ablation alone, 15 are assessable. Nine (60%) responded (CR + PR + ST) to ovarian ablation. Sixteen patients who failed tamoxifen had ovarian ablation alone, and of 14 assessable patients 2 had ST while 12 progressed. Thus response to tamoxifen strongly predicted response to ovarian ablation (P = 0.021). Serial follicle stimulating hormone, prolactin, and estradiol levels suggested that tamoxifen does not act by induction of a "medical ovariectomy" or by alteration of prolactin levels in premenopausal patients.

Clinical evaluation of interferons in malignant melanoma.

The evaluation of interferons in the treatment of malignant melanoma has been mainly in the treatment of advanced disease using interferons as the sole agent or in combination with other agents. Studies of the value of interferons as adjuvant therapy in high-risk primary melanoma patients are necessary, but no results have been published to date. Human interferon alpha produces low response rates as a sole agent, but in combination with cimetidine, a 30% response rate has been achieved. Recombinant alpha interferons give responses of 15%-20% in advanced melanomas, and combination with cimetidine does not enhance the response rate. Recombinant alpha interferons have been used in combination with other interferons, cimetidine, monoclonal antibodies, and cytotoxics, with either no or small improvement in response rates. DTIC with recombinant interferon alpha-2a has been shown to produce objective response rates of 26%, with low toxicity and maintenance of quality of life. A randomized trial with DTIC as the sole agent, compared with combination treatment, is being conducted to determine the significance of this finding.

Sustainable inspiratory pressures over varying flows, volumes, and duty cycles.

This study identifies the influence of flow (0.5-2.0 l/s), duty cycle (0.29-0.57), and tidal volume (1.08-2.16 liters) on sustainable inspiratory muscle pressure (Pmus) and transdiaphragmatic pressure (Pdi) development. Six normal humans performed endurance tests using an isoflow method, which allowed for measurements of maximum dynamic Pmus and Pdi, with controlled lung inflation. The subjects repeated maximum dynamic voluntary inspirations for 10 min. Pressures dropped exponentially from initial measurements at rest (Pmusi or Pdi) to sustainable values (Pmus or Pdis). As flow and tidal volume increased, maximum initial and sustainable pressures decreased significantly. However, at a constant duty cycle, the sustainable dynamic pressures remained predictable fractions of initial dynamic pressures (i.e., Pmuss/Pmusi or Pdis/Pdii), regardless of changes in flow and tidal volume. In contrast, as duty cycle increased, the sustainable fractions significantly decreased for both Pdi and Pmus. For example, at a duty cycle of 0.29, Pmuss/Pmusi was approximately 0.71, and at a duty cycle of 0.57, Pmuss/Pmusi was approximately 0.62. Calculated sustainable pressure-time indexes varied significantly between 0.16 to 0.32 for Pmus and 0.11 to 0.22 for Pdi over the breathing patterns studied. We conclude that 1) the maximum dynamic pressure that can be sustained at a given duty cycle is a predictable fraction of the maximum dynamic pressure that can be generated at rest when measured under the same conditions of inspiration and 2) the sustainable fraction of initial dynamic pressure significantly decreases with increasing duty cycle.

Survival after unexpected high serum methotrexate concentrations in a patient with osteogenic sarcoma.

An 18-year-old female patient receiving adjuvant chemotherapy for osteogenic sarcoma developed a pruritic erythematous rash during infusion of the eighth dose of methotrexate (8 g/m2) in the series. In other respects, the infusion proceeded normally but the 24-hour serum concentration of methotrexate was unexpectedly and extremely high, 574 mumols/L. Dosing error was excluded, as was the hypothesis that the high concentrations were due to the presence of methotrexate-specific antibodies. Acute oliguria and renal failure were the primary manifestations of the drug-induced toxicity and the high concentrations can be attributed to decreased renal elimination of the drug over the first 24 hours. Treatment consisted of folinic acid rescue, forced diuresis, sequential charcoal haemoperfusion and haemodialysis, and repeated oral doses of activated charcoal. After examination of the contribution of the extracorporeal procedures and the charcoal to the elimination of the drug, the relative lack of morbidity was attributed primarily to the folinic acid rescue and the intensive supportive care.

Efficacy of seven retrograde tracers, compared in multiple-labelling studies of feline motoneurones.

The labelling efficacies of 7 retrograde tracers were evaluated following cut nerve exposure or intramuscular injection into the serially compartmentalized neck muscle, biventer cervicis. Tested tracers included Fast Blue (FB), Fluorogold (FG), dextran conjugated to fluorescein (FD), dextran conjugated to rhodamine (Fluororuby (FR), 3000 and 10,000 MW), fluorescent latex microspheres, horseradish peroxidase coupled to colloidal gold, and 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI). In 2 animals, horseradish peroxidase was also employed and spinal cords were processed for peroxidase activity to evaluate its effect on the appearance of cells labelled with fluorescent tracers. Four tracers, FB, FG, FD and FR, could be observed in motoneurones under the conditions of our study. FB and FG labelled comparable numbers of motoneurones following cut nerve exposure, but dissimilar numbers following intramuscular injection. FG diffused extensively following injection and was found in motoneurones not only in the appropriate ipsilateral segment but also adjacent ipsilateral and contralateral segments. Intramuscular injections of FB usually labelled fewer cells than cut nerve exposure, but evidence for spurious labelling following intramuscular injection could also be found. FD or FR labelled motoneurones following cut nerve exposure but not following intramuscular injection. The conjugated dextrans labelled more variable numbers of cells than FB or FG, but the labelled cells had similar patterns of distribution. The remaining tracers were ineffective as retrograde markers in our study, and the possible reasons for these failures are discussed.

Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial.

Following extensive phase II trials of the combination of dacarbazine and interferon-alpha 2a we performed a prospective, randomized, controlled trial of this combination versus dacarbazine alone as systemic therapy for symptomatic, measurable metastatic malignant melanoma. The two treatment arms were well matched for age, sex, performance, status, relapse-free survival, prior therapy and sites of disease. Therapy consisted of dacarbazine given in combination in escalating doses of 200 mg/m2, 400 mg/m2 and 800 mg/m2 i.v. every 3 weeks, or alone at 800 mg/m2 i.v. every 3 weeks. Interferon was administered subcutaneously starting at 3 mU daily on days 1-3, 9 mU daily on days 4-70, then 9 mU three times per week. Therapy was continued for at least 6 months unless overt progressive disease was observed. Eighty seven patients were randomized to the combination and 83 patients to dacarbazine alone. Response rates were respectively, complete 7% and 2%, and partial 14% and 15%, for a total response rate of 21% (95% confidence limits 13-31%) and 17% (95% confidence limits 10-27%). Median duration of response was 258 and 286 days, and survival of the whole groups 229 and 269 days respectively. Toxicity was worse in the combination arm, with more patients experiencing fatigue, nausea and anorexia, flu-like symptoms and neutropenia. However quality of life was not significantly different in either group, except that fatigue, as measured at week 12 by LASA scales, and activity, as measured by the functional living index, were both improved in the combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromuscular organization of feline anterior sartorius: I. Asymmetric distribution of motor units.

The neuromuscular organization of feline anterior sartorius was examined using three experimental approaches. First, the branching pattern of the nerve supplying anterior sartorius was inspected in muscles taken from a large number of feline cadavers. All muscles were found to be supplied by two major nerve branches, one directed proximally and the other directed distally, and most muscles (42/51) had a third distinct branch that entered the muscle centrally. Second, the motoneuronal populations supplying the three nerve branches were investigated by electrophysiological techniques. Motoneurons that supplied axons to the distally-directed branch did not appear to have collaterals in more proximally-located branches. In contrast, other motoneurons supplying the proximally-directed branch also appeared to supply axon collaterals to the centrally-directed branch. This result suggested that the motoneuronal population of the distally-directed branch was largely separate from that supplying the proximally- and centrally-directed branches. Third, the motor unit territories supplied by different nerve branches were mapped using glycogen-depletion methods. Muscle fibers supplied by the distally-directed nerve branch were mostly distributed to the medial portion of anterior sartorius, whereas the fibers supplied by the other two branches were generally found more anteriorly. Further, the muscle fibers supplied by an individual nerve branch were present in greater numbers at the end of the muscle closest to the entry point of that branch. Thus, the motor units supplied by discrete nerve branches were found to be distributed asymmetrically within anterior sartorius, but were arranged neither strictly in-parallel nor strictly in-series.

Morphometry, histochemistry, and innervation of cervical shoulder muscles in the cat.

Morphometric and histochemical methods were used to estimate the force-developing capabilities and fiber-type contents of four muscle complexes (rhomboideus, levator scapulae, trapezius, and sternomastoideus) that link the shoulder girdle to the skull and cervical vertebrae. Each complex contained at least two member muscles that were distinctive architecturally and often had specialized innervation patterns. Trapezius and sternocleidomastoideus were innervated by both cranial nerve XI and cervical spinal nerves. Glycogen depletion of trapezius suggested that the nerves derived from cervical roots might be entirely sensory. Muscles within each complex varied in physiological cross-sectional area from less than 0.1 cm2 to greater than 1 cm2. They showed differences in fiber-type composition that suggested specialized roles for different behaviors. The morphometric features of the cervical shoulder muscles suggest that they have considerable potential to produce head movements and should be incorporated into feline head-movement models.

Suboccipital muscles in the cat neck: morphometry and histochemistry of the rectus capitis muscle complex.

The morphometry, histochemistry, and biomechanical relationships of rectus capitis muscles were examined in adult cats. This family of muscles contained six members on the dorsal, ventral, and lateral aspects of the upper cervical vertebral column. Three dorsal muscles (rectus capitis posterior major, medius, and minor) formed a layered complex spanning from C1 and C2 to the skull. Rectus capitis posterior major was composed predominantly of fast fibers, but the other two deeper muscles contained progressively higher proportions of slow fibers. One ventral muscle, rectus capitis anterior major, was architecturally complex. It originated from several cervical vertebrae and appeared to be divided into two different heads. In contrast, rectus capitis anterior minor and rectus capitis lateralis were short, parallel-fibered muscles spanning between the skull and C1. The ventral muscles all had nonuniform distributions of muscle-fiber types in which fast fibers predominated. Dorsal and ventral muscle groupings usually had cross-sectional areas of 0.5 cm2 or more, reflecting a potential capacity to generate maximal tetanic force in excess of 9 N. Biomechanical analyses suggested that one muscle, rectus capitis lateralis, had its largest moment in lateral flexion, whereas the other muscles had large, posturally dependent moment arms appropriate for actions in flexion-extension. The observation that most rectus muscles have relatively large cross-sectional areas and high fast-fiber proportions suggests that the muscles may have important phasic as well as postural roles during head movement.

Sagittal-plane mobility of the cat cervical spine.

The present study was conducted to evaluate the nature of sagittal-plane motion across cervical vertebral joints and to identify the centers of rotation for each joint in anaesthetized cats X-rayed in a range of head-neck postures. Relative positions of adjacent pairs of vertebrae were assessed by constructing transparent templates for each vertebra that could be overlaid onto different X-rays, and then by digitizing the locations of three markers attached at a distance from each template. The finite centers of rotation for each joint were estimated using a rigid-body method. The errors associated with the estimates were quantified further by using a method in which the positions of digitized markers were fitted to concentric circles using a least-squares approach. The center of rotation between the skull and C1 was located at the cranial articular facets between the two bones. The center of rotation between C1 and C2 was situated near the tip of the odontoid process close to the site of attachment of the transverse ligaments. Centers of rotation for the other cervical vertebral joints were located in the region of the intervertebral disc. A similar range of values was obtained for centers of rotation when extended or flexed postures were used for the calculations, suggesting that the centers of rotation may not move markedly throughout a range of sagittal-plane rotations of approximately 90 degrees at the skull-C1 joint and about 15-30 degrees at the other cervical joints. These results showed that all cervical joints rotated during sagittal-plane motion. A minimal representation of the musculoskeletal mechanics of the feline neck probably requires multiple segments, each corresponding to a single vertebral bone.

Neuromuscular organization of feline anterior sartorius: II. Intramuscular length changes and complex length-tension relationships during stimulation of individual nerve branches.

The feline anterior sartorius is a long strap-like muscle composed of short muscle fibers. Nerve branches that enter this muscle contain the axons of motor units whose constituent muscle fibers are distributed asymmetrically within the muscle. In the present study, twitch and tetanic isometric contractions were evoked by stimulating individual nerve branches while muscle force was recorded and intramuscular length changes were monitored optically by the movement of reflective markers on the muscle. Contractions elicited by stimulating the parent nerve produced little change in the positions of the surface markers. Contractions elicited by stimulating the proximally or distally directed nerve branches caused the muscle to shorten at the end closest to the nerve branch and lengthen at the opposite end. Some muscles were supplied by a centrally directed nerve branch whose stimulation produced variable effects: in some cases a portion of the muscle shortened whereas the rest lengthened, but in other cases, the positions of the surface markers showed little change. The intramuscular length changes produced by stimulating single nerve branches were greater during isometric contractions at short whole-muscle lengths than at long whole-muscle lengths. The twitch and tetanic length-tension relationships obtained by stimulating the individual nerve branches were not congruent with the length-tension relationship produced when the parent nerve was stimulated. At short whole-muscle lengths, stimulation of a single nerve branch generated only a small fraction of the force that could be generated by the muscle when the parent nerve was stimulated. As whole-muscle length increased, an increased fraction of total muscle force could be generated by stimulating a single nerve branch. The results suggest that a complex relationship between passive and active elements contributes to the total muscle force and depends on the distribution of active and passive muscle units throughout the muscle.

A simple dosimeter for bronchial provocation testing using a solid-state electronic timing module.

In conducting inhalational challenge tests of airway responsiveness to methacholine, we prefer to deliver the challenge aerosol intermittently, using a dosimeter that turns the nebulizer on for about 0.5 to 0.6 second to deliver each "puff." To avoid the considerable expense of commercially available dosimeters, we constructed our own electronically controlled device, which, in conjunction with a DeVilbiss Model 646 nebulizer, is easily calibrated and permits reproducible and precise timing of challenge puffs. The device was constructed of readily available components and cost us only $100. An experienced technician can use it to trigger on the nebulizer within 0.5 second of the start of inspiration, and in more than one year's experience we have found the system to be completely satisfactory and reliable.

Plasma fibronectin concentrations in dogs with disseminated intravascular coagulation.

Plasma fibronectin concentrations were significantly (P less than 0.001) below the reference range in dogs with disseminated intravascular coagulation (DIC) secondary to nonlymphomatous neoplasia, acute necrotizing pancreatitis, sepsis, chronic active hepatitis, and heat stroke. There was no statistical evidence of a group effect. Decrease in fibronectin concentration was associated with severe DIC, although no attempt was made to correlate fibronectin concentration with prognosis. These findings parallel those reported for severely ill human beings with diseases associated with DIC. They exemplify the potential of spontaneous diseases in animals as models for the study of human disease.