Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer.

BACKGROUND: Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. PATIENTS AND METHODS: Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins <1 mm, extracapsular extension, perineural or angiolymphatic invasion, or ≥2 positive lymph nodes). Postoperative treatment consisted of standard RT (60-66 Gy over 6-7 weeks) concurrent with weekly cisplatin 30 mg/m2 and weekly panitumumab 2.5 mg/kg. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-six patients were accrued; 44 were evaluable and were analyzed. The median follow-up for patients without recurrence was 49 months (range 12-90 months). The probability of 2-year PFS was 70% (95% CI = 58%-85%), and the probability of 2-year OS was 72% (95% CI = 60%-87%). Fourteen patients developed recurrent disease, and 13 (30%) of them died. An additional five patients died from causes other than HNSCC. Severe (grade 3 or higher) toxicities occurred in 14 patients (32%). CONCLUSIONS: Intensification of adjuvant treatment adding panitumumab to cisplatin CRT is tolerable and demonstrates improved clinical outcome for high-risk, resected, HPV-negative HNSCC patients. Further targeted monoclonal antibody combinations are warranted. REGISTERED CLINICAL TRIAL NUMBER: NCT00798655.

Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer.

BACKGROUND: We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). PATIENTS AND METHODS: Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). RESULTS: Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. CONCLUSIONS: RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.

ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised, phase II trial.

BACKGROUND: Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions. METHODS: In a phase II trial, patients with untreated Stage III-IVb HNSCC were randomised to cisplatin-radiotherapy with/without erlotinib. Archived primary tumours were available from 90 of 204 patients for this planned substudy. Semi-quantitative ERCC1 protein expression (H-score) was determined using the FL297, 4F9, and 8F1 antibodies. The primary analysis evaluated the relationship between continuous ERCC1 protein expression and progression-free survival (PFS). Secondary analyses included two pre-specified ERCC1 cutpoints and performance in HPV-associated disease. RESULTS: Higher ERCC1 expression was associated with inferior PFS, as measured by the specific antibodies FL297 (HR=2.5, 95% CI=1.1-5.9, P=0.03) and 4F9 (HR=3.0, 95% CI=1.2-7.8, P=0.02). Patients with increased vs decreased/normal ERCC1 expression experienced inferior PFS (HR=4.8 for FL297, P=0.003; HR=5.5 for 4F9, P=0.007). This threshold remained prognostic in HPV-associated disease. CONCLUSION: ERCC1-XPF protein expression by the specific FL297 and 4F9 antibodies is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status.

IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer.

OBJECTIVE: Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. PATIENTS AND METHODS: We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment. RESULTS: In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p=0.028, adjusted p=0.14) and improved overall survival (p=0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect. CONCLUSION: Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6.

Failure of nocturnal prolactin suppression by methysergide to entrain changes in testosterone in normal men.

In order to investigate further the postulated relationship between the secretion of PRL and testosterone, 10 normal young men were studied during polygraphically recorded sleep. Concentrations of LH and testosterone were measured in plasma every 20 min, and the results were analyzed in relation to sleep parameters and previously reported (J Clin Invest 56: 690, 1975) concentrations of PRL. All subjects were studied on a control night after placebo administration and on an experimental night after ingestion of the serotonin receptor blocker, methysergide. Analysis of variance revealed that concentrations of testosterone rose gradually during sleep on both nights, as has been noted in previous studies. Highest LH values occurred during stage 1 sleep, but were only 25% higher than the lowest values, which were seen in stage 4. As shown previously, PRL concentrations were markedly suppressed by methysergide treatment. However, no significant change in testosterone values were observed on the methysergide nights as compared to the control nights. When the data were analyzed by a correlational approach, again, no significant relation between concentrations of PRL and testosterone was found. Although these data do not support the concept that PRL-stimulated testosterone secretion occurs during the night in normal men, this study does not rule out the possibility that such a mechanism may be operative during daytime hours, or under conditions of PRL stimulation rather than PRL suppression.

Hyperprolactinemia and sexual disorders in men.

One hundred and thirty-six men, who presented at Masters & Johnson Institute for treatment of impotence, ejaculatory incompetence, and inhibited sexual desire, underwent endocrine screening. Eleven men (8.1%) were found to be hyperprolactinemic: three had a mild degree of hyperprolactinemia while eight had markedly elevated serum prolactin levels in conjunction with subnormal serum testosterone levels. The markedly hyperprolactinemic men, all of whom were subsequently found to have prolactin-secreting pituitary adenomas, presented with diverse histories of sexual disorders which were similar to those of men with psychogenic sexual dysfunctions. All eight experienced some degree of improvement of sexual function following a 2-week course of intensive psychotherapy, although full restoration of libido was contingent on reduction of circulating prolactin to normal or near-normal levels. Measurement of prolactin levels should be routinely performed in all men presenting with the above sexual disorders and depressed testosterone levels.

Deaggregation of in vitro-degranulated human platelets: irreversibility of aggregation may be agonist-specific rather than related to secretion per se.

Based on studies with thrombin, it has been proposed that human platelets exposed to strong release-inducing agents undergo irreversible aggregation and cannot be deaggregated without the use of proteolytic enzymes. We tested the hypothesis that irreversible human platelet aggregation occurs as a result of thrombin-specific platelet alterations rather than induction of the release reaction per se. Washed human platelets were exposed to either thrombin (THR) or the aminophospholipid N-(7-Nitro-2,1,3-benzoxydiazol-4-yl) phosphatidylserine (NBD-PS) for 20 seconds. Both agents caused similarly extensive release of platelet dense- and alpha-granule contents. After neutralization of thrombin and NBD-PS, and addition of PGE1 and apyrase, the platelets were sedimented, resuspended and incubated at 37 degrees C with gentle agitation. Single, disc-shaped, degranulated platelets which were recovered in both systems were capable of aggregation in response to a second exposure to aggregating and release-inducing stimuli. Deaggregation was more rapid, more extensive, and more reproducible with NBD-PS- than with THR-degranulated platelets. Platelets exposed to thrombin for longer than 20 seconds showed a progressive loss of deaggregability which was not observed after prolonged incubation with NBD-PS. These findings do not support the concept that extensive secretion per se causes irreversible aggregation of human platelets. Instead it appears that formation of irreversible linkages between platelets involves the specific, time-dependent interaction of THR with platelets, released fibrinogen and possibly one or more other substances secreted from platelets.

Lung mechanics, cellularity, and surfactant after prenatal starvation in guinea pigs.

Prenatal starvation in the guinea pig causes reduced pulmonary diffusing capacity and retarded alveolarization among neonates. To study the impact of such starvation on biochemical and mechanical properties of the neonatal lung, pregnant guinea pigs were fed ad libitum throughout gestation or starved with 50% rations during their last trimester. Neonatal body weight was 35% less due to starvation, and dry lung weight, DNA, and protein contents were decreased 26, 36, and 31%, respectively (P less than 0.001 for all). Hematological data indicated no anemia, hypoproteinemia, or altered glucocorticoid levels due to starvation. Total surfactant phospholipids in these neonates were reduced 61% in lavage and 35% in the neonatal lung tissue, although surfactant compositions were similar to controls. Specific lung compliance in the air-filled lungs was not altered, but the saline-filled lungs were more distensible over deflation pressures of 9-18 cmH2O (transpulmonary). Although starvation retarded both lung cellularity and surfactant, only that portion of lung elastic recoil attributable to tissue forces was affected.

Basal body temperature: unreliable method of ovulation detection.

Basal body temperature (BBT) charts for menstrual cycles of 98 women were evaluated by six experienced physicians. The time of ovulation as estimated from the charts by a consensus of at least five of the evaluators coincided with the luteinizing hormone (LH) peak +/- 1 day in only 17 (22.1%) of the 77 cycles that were determined by endocrine profiles to be ovulatory and to have adequate luteal phases. An additional 22.1% of these cycles were thought to have monophasic patterns by a consensus of the physicians. Extreme caution in interpretation is urged when BBT is used for clinical or research evaluations of ovulation or menstrual cycle dynamics.

PIP: This study assesses how closely basal body temperature (BBT) charts match detailed endocrine data in distinguishing ovulatory from anovulatory cycles, detecting short or inadequate luteal phase cycles, and determining the time of ovulation. 6 experienced physicians were asked to separately evaluate 104 BBT charts representing 98 women between 18-30 years of age. These physicians were to evaluate each chart for the presence of a biphasic pattern and to estimate the day of ovulation that they thought showed a biphasic BBT curve. Accuracy of estimation was judged by comparison with the day of the luteinizing hormone (LH) peak. Results indicate that: 1) the number of charts for which each physician correctly estimated the time of ovulation +or- 1 day of the LH peak ranged from 24-34, 2) although each physician correctly estimated the time of ovulation from an average of 38.1% of the charts, only 9 (22.1%) of the charts were correctly assessed by all 6 physicians, 3) an additional 22.1% of these cycles were thought to have monophasic patterns, 4) 37 (48%) of the charts drew a mixed response from the physicians, whose judgements differed regarding the presence of biphasic patterns or the correct day of ovulation, 5) in the 18 charts evaluating the short luteal phase cycles, the day of ovulation was assessed correctly in only one cycle by 2 of the 6 physicians, and 6) the anovoluntary cycles were uniformly found to have monophasic patterns by all evaluators. Extreme caution in interpretation is urged when BBT is used for clinical or research evaluations of ovualtion or menstrual cycle dynamics.

Vaginal organic acids and hormonal changes in the menstrual cycle.

Twenty-seven women not using oral contraceptives (OCs) and 22 women using OCs were studied during one complete menstrual cycle. Twenty-four-hour vaginal secretions, collected on alternate days by a tampon method, were analyzed for acetic and other short-chain aliphatic acids and for lactic acid. Daily blood samples were analyzed for estrogens, progesterone (P), and luteinizing hormone (LH). No difference was found between OC users and nonusers in either amount or variability of vaginal aliphatic acids throughout the menstrual cycle. Aliphatic acids did not correlate with estrogen of P levels. A significant positive correlation was found between vaginal lactic acid and blood estrogens in those subjects not using OCs.

Combined aspirin and sulfinpyrazone in the prevention of recurrent hemodialysis vascular access thrombosis.

We carried out a pilot study in 15 hemodialysis patients with recurrent vascular access thrombosis to examine whether the combination of low dose aspirin (85 mg once daily) and sulfinpyrazone (200 mg three times daily) is safe and effective in the prevention of vascular access thrombosis. Hemostatic measurements were performed prior to and after four weeks of starting the drug combination. Baseline values for fibrinopeptide A were elevated in all patients while those for platelet factor 4, fibrinogen, antithrombin III and protein C were generally within normal limits. A major reduction in the frequency of vascular access thrombosis from 0.114 per month to 0.04 per month was noted during combined drug treatment (p less than 0.001). Although in vitro platelet aggregation to various stimuli was markedly suppressed and platelet thromboxane B2 formation was almost completely inhibited in patients on aspirin/sulfinpyrazone, this was not associated with a significant further prolongation of the bleeding time. A relatively high rate of complications, particularly mild gastrointestinal bleeding, was noted in patients on aspirin/sulfinpyrazone that could not be predicted on the basis of pre-treatment hemostatic test results.

Platelet adhesion and aggregation in pulsatile shear flow: effects of red blood cells.

An in vitro test system was developed to examine the effects of red blood cells (RBC) on shear-induced platelet adhesion (SIPAD) and platelet aggregation (SIPAG). Suspensions of human platelets labeled with Mepacrine and suspended in citrated plasma were exposed to single, continuous or repetitive (120-300x) one second shear stress pulses of varying amplitude (15-100 dyn/cm2) in a cone-plate viscometer in the presence or absence of fresh, untreated (intact) RBC or glutaraldehyde (GLA)-fixed, rigid, adenosine diphosphate (ADP)-depleted (GLA)-RBC. SIPAG was expressed as percent loss of single platelets. SIPAD was assessed by measuring the amount of Mepacrine-related fluorescent material remaining on glass disks in the plate of the viscometer after washing with EDTA-saline to remove platelet aggregates. Intact RBC were twice as effective as GLA-RBC in potentiating SIPAG at all shear stress levels. Potentiation of SIPAD by intact RBC was markedly less than that observed with GLA-RBC at stresses below 50 dyn/cm2. These findings are consistent with the concept that while both physical and chemical (ADP) mechanisms are substantially involved in potentiation by RBC of SIPAG, RBC support SIPAD largely by enhancement of platelet transport from the bulk flow to the bounding surfaces. The findings also indicate that it is feasible to assess SIPAD and SIPAG in the same flow system simultaneously. A less complicated version of the method described here should prove useful in the evaluation of patients with platelet functional disorders, and in the evaluation and monitoring of antiplatelet agents.

A programmable, computer-controlled cone-plate viscometer for the application of pulsatile shear stress to platelet suspensions.

Described is a special purpose cone-plate viscometer that is capable of acceleration or deceleration through a step change in speed in less than 0.7s. The speed of the rotating cone is controlled by a microcomputer which can be programmed to generate speed vs time ramp functions of variable slope. Prior calibration of motor power required to shear Newtonian fluids of known viscosity at various speeds provides the basis for determination of apparent suspension viscosity and enables the viscometer automatically to compensate for changing sample viscosity during shear. The viscometer was used to carry out a series of preliminary studies in which platelet-rich plasma (PRP) was subjected to continuous and pulsatile shear stress at 37 degrees C. Shear-induced platelet aggregation (SIPAG) was significantly greater in response to pulsatile versus continuous shearing except at the lowest applied stress (10 dyn/cm2). Increases ranged from about 40 percent at a stress amplitude of 25 dyn/cm2 to nearly 55 percent at dyn/cm2. This increasing trend with stress amplitude might be interpreted as a positive correlation between SIPAG and the loading rate. Dense granule release, as indicated by serotonin release, was dependent on both stress amplitude and number of pulses even at the higher stress where SIPAG was independent of pulse number.

Protection of dogs against canine distemper by vaccination with a canarypox virus recombinant expressing canine distemper virus fusion and hemagglutinin glycoproteins.

OBJECTIVES: To evaluate the safety and efficacy of a live canarypox virus recombinant-canine distemper virus (CDV) combination vaccine against virulent CDV challenge exposure, and to document lack of interference among the other modified-live virus (MLV) components. ANIMALS: 33 specific-pathogen-free (SPF) Beagle pups (7 to 10 weeks old). PROCEDURE: A canarypox virus recombinant-CDV combination vaccine was tested for safety and efficacy along with MLV components (canine adenovirus type 2, canine coronavirus, canine parainfluenza virus, and canine parvovirus) in 26 SPF Beagle pups. The combination vaccine was rehydrated with either Leptospira canicola-L icterohaemorrhagiae combination bacterin (vaccine 1) or sterile diluent (vaccine 2). An additional group of 7 seronegative SPF pups received the control MLV components devoid of the combination vaccine (vaccine 3). Two vaccinations were administered 21 days apart, either IM or SC. The dose of the combination vaccine used to inoculate these pups was 40 times lower than the recommended commercial dose. At 21 days after the booster vaccination, all pups were challenge exposed with a virulent CDV strain, then were observed for 21 days to record morbidity and mortality. RESULTS: Adverse local or generalized reactions were not induced by vaccinations. All vaccinates seroconverted to CDV. Serum antibody titers to MLV components were not different, with or without inclusion of the combination vaccine. After challenge exposure, morbidity and mortality in vaccinates were 0% (0/26); in control dogs, values were 100% morbidity and 86% mortality (6/7). Brain impression smear slides made from all dogs that did not survive challenge exposure were CDV positive by use of a direct fluorescein isothiocyanate method. CONCLUSIONS: The canarypox virus-CDV combination vaccine, administered SC or IM, is a safe product that elicits CDV seroconversion, does not interfere with other vaccine components, and protects vaccinated pups against virulent CDV challenge exposure.

Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma.

BACKGROUND: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. METHODS: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. RESULTS: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. CONCLUSIONS: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

Motor vehicles as a site of accidental poisonings.

Although most poisonings occur within the home, the toxic agents involved are customarily transported there by motor vehicles. Over a 9-month period, all potentially toxic exposures reported to a poison information center that occurred in a motor vehicle were collected. Common toxins were identified and associated incidence and risk were assessed; 68% were pediatric exposures and the remainder were in adults. The adult exposures were dermal and via inhalation, whereas the pediatric exposures were predominantly inhalation (44%) and ingestion (36%). Inhalant toxins included carbon monoxide (CO) (13%), fire extinguishers (48%), and hydrocarbons (17%). Ingested toxins were comprised of medications (36%), automotive products (14%), and cosmetics (14%). 26% of the exposures were treated in Emergency Departments and the remainder at home. 79% of the patients were asymptomatic or had only a mild outcome; 21% suffered moderate toxicity. Toxic exposures in motor vehicles pose a significant threat to both driver and occupants. Children are at high risk from products improperly stored in the car (shopping bags, purses, glove compartment) and resulting from the care giver's inattention while driving. These results can be used to promote community awareness of this problem.

Activation of human platelets by N-substituted aminophospholipids.

N-(7-nitro-2,1,3-benzoxadiazol-4-yl) phosphatidylserine (NBD-PS), a fluorescent phospholipid synthesized from phosphatidylserine by reaction with NBD-chloride, caused platelet shape change and aggregation when added at micromolar concentrations to suspensions of washed human platelets in the absence of added fibrinogen. Platelet aggregation by NBD-PS was accompanied by thromboxane synthesis and secretion of contents from dense, alpha-, and lysosomal granules in the absence of appreciable platelet damage. Indomethacin completely inhibited NBD-PS-induced thromboxane synthesis, but platelet aggregation and [14C]serotonin secretion were only slightly inhibited. Neither inhibition of the ADP-dependent pathway with creatine phosphate/creatine kinase plus ATP, alone or in combination with indomethacin, nor maximum elevation of cyclic AMP by treatment with prostaglandin I2 and theophylline completely inhibited NBD-PS-induced platelet aggregation or [14C]serotonin secretion. Platelet effects of NBD-PS were specific in that neither phosphatidylserine nor lyso-NBD-PS were similarly active. The activation of platelets by NBD-PS is not attributable to the NBD moiety exclusively since acylation of the amino group with 5-dimethylaminonaphthalene-1-sulfonyl-chloride yielded a similarly active derivative. Dansylated phosphatidylethanolamine was also active. The findings indicate that NBD-PS and other N-substituted aminophospholipids can activate a central pathway of platelet secretion and aggregation that is independent of released ADP and thromboxane formation and is only partially controlled by platelet cyclic AMP.

Efficacy of the GnRH analogue deslorelin for suppression of oestrous cycles in cats.

The aim of this study was to develop a method for long-term but reversible inhibition of oestrous cycles in female cats by downregulation of GnRH receptors with deslorelin released from a long-acting implant. In a blind study with mature cats (n = 20), a 6 mg deslorelin implant was administered s.c. to ten cats and a placebo implant was administered to ten cats. Occurrence of oestrus and general health were observed daily, and individual faecal samples were collected at 3 day intervals for 14 months and analysed for oestradiol content. All the placebo-treated queens continued to undergo normal oestrous cycles during the study. Oestrus was accompanied by peaks in oestradiol concentrations of > or = 20 ng g-1 faeces. Treatment with deslorelin initially stimulated oestradiol release, which accompanied treatment-induced ovulations. Thereafter, oestradiol concentrations decreased to 1-10 ng g-1 faeces and remained low for extended periods. Observations of small increases in oestradiol concentrations in one cat led to a second treatment with 6 mg deslorelin in five cats on day 155 after first treatment. Faecal oestradiol concentrations remained < 20 ng g-1 faeces in the five single treatment cats for 8.0, 8.5, 11.0 and 14.0 (two cats) months. Cats receiving two implants had the first oestradiol peak > 20 ng g-1 faeces after treatment at 7.5, 11.0 (two cats), 11.5 and 14.0 months. After 14 months, two cats had returned to normal cyclic activity, two had irregular small oestrogen peaks and six showed no cyclic activity. For months 2-5, 6-10 and 11-14, oestrogen values in treated cats were significantly different from control values (P < 0.001, 0.05 and 0.02, respectively). Differences in oestrogen concentration between control cats and cats that were treated twice were significant (P < 0.001) during months 6-10 only. The general health of treated cats was unchanged throughout the study. These results confirm that deslorelin can effectively suppress ovarian activity in domestic cats, but that the duration of suppression varies among individuals.

An XX male: cytogenetic and endocrine studies.

A 3 year old black male with ambiguous genitalia had a 46, XY karyotype in a bone marrow culture and an intermediate buccal smear result, suggestive of a mosaic of chromatin positive and chromatin negative cells. Upon re-evaluation at age 15 years, he has a 30% positive buccal smear and a 46, XX karyotype in cultures of peripheral blood lymphocytes, skin fibroblasts, bone marrow, and testis. No Y-body fluorescence was detectable in interphase cells from the testicular biopsy or the various cultures. The testicular biopsy appeared similar to that of XXY males, and primary hypogonadism was documented by elevated LH (107 mIU/ml) and FSH (57 mIU/ml) levels in conjunction with low testosterone (142 ng/100 ml). Administration of hCG produced qualitatively normal acute responses of testosterone and estrogens. The cytogenetic data provide support for the theory that at least some XX males once had a Y-containing cell line which was subsequently lost.