Patient preferences for timing and access to radiation therapy.

PURPOSE: Patient preferences for radiation therapy (rt) access were investigated. METHODS: Patients completing a course of rt at 6 centres received a 17-item survey that rated preferences for time of day; day of week; actual, ideal, and reasonable travel times for rt; and actual, ideal, and reasonable times between referral and first oncologic consultation. Patients receiving single-fraction rt or brachytherapy alone were excluded. RESULTS: Of the respondents who returned surveys (n = 1053), 54% were women, and 74% had received more than 15 rt fractions. With respect to appointment times, 88% agreed or strongly agreed that rt between 08h00 and 16h30 was preferred; 14%-15% preferred 07h30-08h00 or 16h30-17h00; 10% preferred 17h00-18h00; and 6% or fewer preferred times before 07h30 or after 18h00. A preference not to receive rt before 07h30 or after 18h00 was expressed by 30% or more of the respondents. When days of the week were considered, 18% and 11% would have preferred to receive rt on a Saturday or Sunday respectively; 52% and 55% would have preferred not to receive rt on those days. A travel time of 1 hour or less for rt was reported by 82%, but 61% felt that a travel time of 1 hour or more was reasonable. A first consultation within 2 weeks of referral was felt to be ideal or reasonable by 88% and 73% of patients respectively. CONCLUSIONS: An rt service designed to meet patient preferences would make most capacity available between 08h00 and 16h30 on weekdays and provide 10%-20% of rt capacity on weekends and during 07h30-08h00 and 16h30-18h00 on weekdays. Approximately 80%, but not all, of the responding patients preferred a 2-week or shorter interval between referral and first oncologic consultation.

Pregnancy-related uterine arteriovenous malformations: experience from a single medical center.

PURPOSE: The purpose of this article was to investigate clinical ultrasonographic findings and the outcomes of post-pregnancy patients with acquired uterine vascular abnormalities including arteriovenous malformations (AVMs). MATERIALS AND METHODS: We performed a computerized database search for all patients with ultrasonographic findings of a vascular abnormality including AVM in our referral center between 2000-2008. An ultrasound finding of vascular abnormality was defined as an area of strong hypervascularity within the myometrium and the presence of marked turbulence. The inclusion criteria for angiography were abnormal vaginal bleeding in a hemodynamically stable patient, bhCG serum levels ≤ 30 mIU/ml, and ultrasound demonstration of large (≥ 15 mm on the larger side of the vessel) or multiple vascular lesions. RESULTS: 16 women were identified, of whom 10 (63 %) underwent uterine artery embolization. Angiography confirmed the pre-interventional ultrasound diagnosis of AVM in all cases. AVM feeding arteries were on the left side of the uterus in 80 % of the cases. Residual tissue was ultrasonographically detected in five patients: 2 underwent hysteroscopy and guided curettage following embolization and three received methotrexate. All tissue samples were benign. One small vascular abnormality resolved spontaneously. CONCLUSION: An acquired uterine vascular abnormality including AVM should be considered in the work-up of post-pregnancy vaginal bleeding.

Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12.

Previous genome-wide linkage studies applied the affected sib-pair design; one investigated extended pedigrees of a genetic isolate. Here, results of a genome-wide high-density linkage scan of attention-deficit/hyperactivity disorder (ADHD) using an array-based genotyping of approximately 50 K single nucleotide polymorphism (SNPs) markers are presented. We investigated eight extended pedigrees of German origin that were non-related, not part of a genetic isolate and ascertained on the basis of clinical referral. Two parametric analyses maximizing LOD scores (MOD) and a non-parametric analysis for both a broad and a narrow phenotype approach were conducted. Novel linkage loci across all families were detected at 2q35, 5q13.1, 6q22-23 and 14q12, within individual families at 18q11.2-12.3. Further linkage regions at 7q21.11, 9q22 and 16q24.1 in all families, and at 1q25.1, 1q25.3, 9q31.1-33.1, 9q33, 12p13.33, 15q11.2-13.3 and 16p12.3-12.2 in individual families replicate previous findings. High-resolution linkage mapping points to several novel candidate genes characterized by dense expression in the brain and potential impact on disorder-relevant synaptic transmission. Our study provides further evidence for common gene effects throughout different populations despite the complex multifactorial etiology of ADHD.

Employment outcomes for recent Canadian radiation oncology graduates.

Introduction: Radiation oncology (ro) is one of several specialties identified by the Royal College of Physicians and Surgeons of Canada with employment difficulties for graduating trainees. The purpose of the present study was to determine the employment status and location of recent Canadian ro trainees within 2 years after graduation, to monitor workforce recruitment trends over time, and to capture the opinions of program directors about employment difficulty for graduates and resident morale. Visa trainee graduates were excluded. Methods: Results of the survey administered to ro program directors in 2016 and again in 2018, both with 100% response rates, are presented here. Results: In both surveys, approximately 57% of ro graduates had attained staff or locum employment in Canada or abroad within 2 years from graduation (p = 0.92). However, graduates with Canadian staff employment increased by 46% to 32 in 2018 from 22 in 2016, while the proportion of graduates with staff positions abroad decreased to 6% from 27% (p = 0.04). Most trainees without staff positions were employed as fellows. The proportion of program directors reporting employment difficulties for graduates in the Canadian labour market declined to 38% from 85% (p = 0.04), and the morale of residents in training programs remained high. Conclusions: Employment challenges for newly certified Canadian-trained radiation oncologists continue. However, compared with the situation 2 years ago, trends in the Canadian ro job market suggest a modest improvement, with more staff employment in Canada and lower emigration rates for jobs abroad.

A Phase II trial of 8 weeks of degarelix for prostate volume reduction: Efficacy and hormonal recovery.

PURPOSE: The purpose of this study was to determine the efficacy of 8 weeks of degarelix for prostate downsizing before interstitial brachytherapy. We also report associated toxicity and the time course of endocrine recovery over the following 12 months. METHODS AND MATERIALS: Fifty patients were accrued to an open-label Phase II clinical trial (www.clinicaltrials.gov ID NCT01446991). Baseline prostate transrectal ultrasound (TRUS) was performed on all patients followed by degarelix administration and a repeat TRUS at Week 8. Brachytherapy was performed within 4 weeks of the 8-week TRUS for all patients who achieved suitable downsizing. RESULTS: The median prostate volume was reduced from 65.0 cc (interquartile range [IQR]: 55.2-80.0 cc) to 48.2 cc at 8 weeks (IQR: 41.2-59.3 cc), representing a median decrease of 26.2% (IQR: 21-31%). Functional recovery of testosterone within an age-adjusted normal range occurred at a median of 34.1 weeks (IQR: 28.2-44.5 weeks) from the date of the final injection. Despite this recovery, follicle-stimulating hormone and luteinizing hormone levels remained abnormally elevated throughout 12 months. Quality-of-life implications are discussed. CONCLUSIONS: Degarelix is effective for prostate downsizing before prostate brachytherapy with a median volume decrease of 26.2% by 8 weeks. Despite the short course of treatment and eventual testosterone recovery, follicle-stimulating hormone and luteinizing hormone remain elevated beyond 12 months. Further investigation with randomized comparisons to other hormonal agents is warranted.

A study of the reliability of reported premorbid adjustment in schizophrenic patients.

A study was conducted to determine the interrater reliability and the inter-informant reliability of two rating scales commonly used with schizophrenic patients. Both scales were completed by two informants for each of 45 schizophrenics. The Levels of Functioning Scale, which measures current social functioning, gave consistent results both between raters and between informants. The Premorbid Asocial Adjustment Scale, which measures social functioning during childhood and adolescence, produced very high reliability between raters but very poor reliability between informants. This suggests that much of the data collected about premorbid adjustment of schizophrenic patients are not accurate and that attempts to correlate reported premorbid adjustment with biological measures may be invalid. Ways of increasing the reliability and validity of premorbid adjustment measures are discussed.

Held-breath self-gating technique for radiotherapy of non-small-cell lung cancer: a feasibility study.

PURPOSE: To examine the feasibility of a held-breath self-gating (HBSG) technique in the radiotherapy of lung cancer. MATERIAL AND METHODS: Sixteen consecutive eligible and consenting patients undergoing radiotherapy for non-small-cell lung cancer were accrued for this study. The patients underwent a standardized training session and were then asked to breath hold at four points in the breathing cycle (maximal and end tidal, inspiration and expiration) while under fluoroscopic visualization. Plain films and video imaging with digital image analysis were used to record and measure the movement of the diaphragm, a tumor surrogate, in the superior-inferior axis. These measurements were obtained during and between multiple separate breath holds within one session and between breath holds in sessions held at least one day apart. RESULTS: Maximal inspiration and expiration tend to provide the best positional reliability, and the standard deviation of diaphragmatic position ranged from 0.13 to 2.57 mm, with an average of 0.97 mm. During a single breath hold, the diaphragmatic movement averaged 2.62 mm with a standard deviation of 1.28 mm. The day-to-day variation of diaphragmatic positions was less than 5 mm. The held-breath self-gating technique resulted in a reduction of diaphragmatic movement by an average of 11.9 mm when compared to that seen during tidal breathing. CONCLUSION: In the radiotherapeutic management of non-small-cell lung cancer, this HBSG technique offers a simple method that provides superior immobilization of the diaphragm compared to tidal breathing. Clinical implementation of this technique should allow for a reduction of treatment margins, thus sparing more normal tissues and facilitating dose escalation.

Setup reproducibility in radiation therapy for lung cancer: a comparison between T-bar and expanded foam immobilization devices.

PURPOSE: Physiologic and non-physiologic tumor motion complicates the use of tight margins in three-dimensional (3D) conformal radiotherapy. Setup reproducibility is an important non-physiologic cause of tumor motion. The objective of this study is to evaluate and compare patient setup reproducibility using the reusable T-bar and the disposable expanded foam immobilization device (EFID) in radiation therapy for lung cancer. METHODS AND MATERIALS: Two hundred forty-four portal films were taken from 16 prospectively accrued patients treated for lung cancer. Patients were treated with either a pair of anterior and posterior parallel opposing fields (POF), or a combination of POF and a three-field isocentric technique. Each patient was treated in a supine position using either the T-bar setup or EFID. Six patients were treated in both devices over their treatment courses. Field placement analysis was used to evaluate 3D setup reproducibility, by comparing positions of bony landmarks relative to the radiation field edges in digitized simulator and portal images. Anterior-posterior, lateral, and longitudinal displacements, as well as field rotations along coronal and sagittal planes were measured. Statistical analyses of variance were applied to the deviations among portal films of all patients and the subgroup treated with both immobilization methods. RESULTS: For the T-bar immobilization device, standard deviations of the setup reproducibility were 5.1, 3.7, and 5.1 mm in the anterior-posterior, lateral, and longitudinal dimensions, respectively. Rotations in the coronal plane and the sagittal plane were 0.9 degrees and 1.0 degrees, respectively. For the EFID, corresponding standard deviations of set up reproducibility were 3.6 mm, 5.3 mm, 5.4 mm, 0.7 degrees and 1.4 degrees, respectively. There was no statistically significant difference (p = 0.22) in the 3D setup reproducibility between T-bar and EFID. Subgroup analysis for the patients who were treated with both immobilization devices did not reveal a difference either. There was no consistent systematic error from simulator to treatment unit identified for either immobilization device. CONCLUSION: Although the optimal immobilization technique and patient positioning for thoracic radiotherapy have yet to be determined, this study indicates that T-bar is comparable with EFID in its setup reproducibility. In view of the inherent advantages of T-bar, it has become a standard immobilization device at our institution. The observed range of displacements in field positioning with either immobilization device implies that one cm (two standard deviations [SD] of setup error) will be a more appropriate margin to allow for setup variability in radiation therapy for lung cancer.

Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis.

Gonadotropins play a crucial role in ovarian homeostasis and fertilization through the activation of the cAMP cascade. However, gonadotropin hyper-stimulation may be associated with higher risk for ovarian cancer development. It has been suggested, that high gonadotropin levels in peritoneal and ovarian cystic fluids of patients suffering from benign ovarian cysts, may lead to malignancy. Moreover, we have recently discovered that gonadotropin stimulation can activate the MAPK cascade in target cells. Using DNA microarray technology and RNA from human granulosa cells, we discovered that stimulation with saturating doses of gonadotropins dramatically elevates activity of genes coding for epiregulin and amphiregulin. These gene products can bind and activate the EGF receptor and ERBB4, which are associated with the development of various cancers such as ovarian, breast endometrial and other non-gynecological malignancies. Gonadotropin receptors are expressed not only in the gonads, but also in non-gonadal tissues and in cancer cells. The discovery that gonadotropins activate certain mitogenic signal transduction pathways, may serve as a guide for novel anti-cancer therapy by (1) specific interference at the receptor level to block the gonadotropic response, or arresting the receptor expression and (2) blocking downstream mitogenic signals generated by these hormones, like attenuation of the expression of epiregulin and amphiregulin that belong to the EGF family, using anti-sense and/or SiRNA techniques targeted to suppress their expression. Moreover, since amphiregulin and epiregulin act as mediators of luteinizing hormone (LH) action in the mammalian ovulatory follicles, regulation of the expression of these factors may open new possibilities in treatment of ovarian malfunction implicated with ovarian hyper-stimulation.

Expression of the p53 gene and apoptosis in gestational trophoblastic disease.

In order to understand the involvement of the p53 tumour suppressor gene in the pathogenesis of gestational trophoblastic disease (GTD), we investigated its genetic status, protein expression and its role in apoptosis in samples of complete and partial hydatidiform mole as compared with those of normal placenta. Direct sequencing of polymerase chain reaction (PCR) products of the coding and non-coding regions of the p53 gene demonstrated no mutations in any of the studied samples. Immunohistochemical studies revealed increased expression of the p53 protein predominantly in the nuclei of villous cytotrophoblasts. This over-expression of p53 was found in all samples of complete mole, in 50 per cent of partial mole samples and in about 30 per cent of normal placenta cases, although no significant difference in the staining intensity and pattern was observed. An in situ detection of DNA nicking (TUNEL) staining, demonstrating apoptosis, was also detected predominantly in villous cytotrophoblasts and in stromal areas. The per centage of apoptotic cells in all studied samples, determined by flow cytometry, demonstrated a significant increase in apoptotic cells in samples of complete and partial hydatidiform mole compared with those of normal placenta (P< 0.0003 and P< 0.004, respectively). In conclusion, the current study may provide a possible explanation to the pathogenesis of GTD, probably associated with extensive p53-dependent apoptosis to modulate excessive trophoblastic proliferation.

Regional differences in the induction of behavioral supersensitivity by prolonged treatment with atypical neuroleptics.

Some atypical neuroleptics have been shown to exert selective effects on the nigrostriatal or mesolimbic dopamine systems as assessed by behavioral, biochemical and electrophysiological measures. This specificity appears to occur using chronic or acute schedules of drug administration. This study examined the effect of chronic administration of haloperidol, clozapine, sulpiride and metoclopramide on stereotypy and locomotor activity elicited by direct injection of dopamine in to the striatum or nucleus accumbens, respectively. Each rat was pre-treated with a neuroleptic drug or vehicle control for 21 days. Five days after the termination of drug treatment, each rat was injected with 10 micrograms dopamine bilaterally, and stereotypy or locomotor activity was measured. Rats pre-treated with metoclopramide exhibited an enhanced stereotypy response, and rats pre-treated with haloperidol, clozapine or sulpiride exhibited enhanced locomotor activity compared to controls. The extent to which these results demonstrate the selective action of these drugs in sensitizing dopamine systems is discussed.

Specificity of smooth pursuit eye movement and visual fixation abnormalities in schizophrenia. Comparison to mania and normal controls.

Smooth pursuit eye movements (SPEM) were assessed in 30 schizophrenic patients, 12 lithium-free manic patients, and 20 normal controls. Compared to schizophrenic patients, manic patients evidenced less SPEM impairment in an attention enhancing, sinusoidal target motion condition and had superior performance during a visual fixation condition. SPEM and visual fixation dysfunctions may be more common in schizophrenic than in acutely manic patients, even when the latter are characterized by marked attentional dysfunction, poor interepisode psychosocial functioning, and psychosis.

Abortion at 18-22 weeks by laminaria dilation and evacuation.

OBJECTIVE: To evaluate the complications of late second-trimester abortions (18-22 weeks) by laminaria dilation and evacuation, and the obstetric outcome of subsequent pregnancies. METHODS: Dilation of the cervix was achieved by repeated laminaria tent replacement. Evacuation was carried out in the outpatient clinic using general anesthesia. After the first menstrual period, all patients were invited for examination and thereafter were asked to report the outcome of subsequent pregnancies. RESULTS: One hundred seventy-one late second-trimester abortions were performed. Cervical dilation was satisfactory in 158 women (92%). Operative sonography was required in nine (5%) women. One had uterine atony. Follow-up from 150 (88%) women indicated no infection, but one woman required repeat curettage for retained products of conception. There was no indication of cervical injury on cervical internal os measurements remote from abortion. Of the 50 patients who conceived and elected to continue the subsequent pregnancies, two had premature deliveries unrelated to cervical incompetence, and all others reached term. CONCLUSION: Late second-trimester termination by laminaria dilation and evacuation is safe and probably not associated with future adverse pregnancy outcome.

Polymorphisms of the p53 gene in women with ovarian or endometrial carcinoma.

The p53 gene is frequently mutated in various human tumors. Polymorphism is an additional genetic alteration observed in exons and introns of the p53 gene of normal tissues and tumors. Distributions of alleles of three common polymorphisms of the p53 gene; a 16 bp duplication in intron 3, codon 72 of exon 4 and a sequence in intron 6, were studied in peripheral white blood cells (WBC) of patients with ovarian or endometrial carcinomas. The analysis was performed by PCR and direct sequencing. The 100% linkage observed between the most common haplotypes of each polymorphism in healthy subjects was lower in the patients. A significant difference was observed between frequencies of genotype and haplotype combinations in patients with ovarian carcinoma and endometrial carcinoma. The incidence of heterozygosity was increased in ovarian carcinoma and decreased in endometrial carcinoma. Our results suggest that the p53 gene may be involved in susceptibility and predisposition to various cancers not only by mutations but also by preferential presentation of polymorphic alleles.

Chronic administration of three neuroleptics: effects of behavioral supersensitivity mediated by two different brain regions in the rat.

This investigation assessed the relative abilities of three neuroleptics to supersensitize behaviors mediated by the nigrostriatal and mesolimbic dopamine (DA) systems. Rats were treated with either haloperidol, thioridazine, fluotracen or vehicle for 21 days. Stereotypy, in response to DA injection to the striatum, or locomotor activity, in response to DA injection to the nucleus accumbens, were measured after the termination of drug treatment. Pre-treatment with haloperidol enhanced both behavioral responses to central DA injection, while pre-treatment with thioridazine did not enhance either behavior. Pre-treatment with fluotracen enhanced the locomotor response to DA injection to the nucleus accumbens, but did not alter stereotypy after DA injection to the striatum. Neuroleptics differ in their ability to supersensitize the same DA-related behavior, and act selectively to supersensitize behaviors mediated by different DA systems.

Relationship of adrenergic and electrical brain stimulation induced feeding responses.

Electrical and adrenergic brain stimulation can induce eating in satiated animals. This report explores the interrelationship of brain feeding systems mediating eating in response to norepinephrine and electrical stimulation of the hypothalamus in rats. It was found that simultaneous adrenergic and electrical brain stimulation resulted in a significant increase in food intake as compared to each stimulation condition alone. Furthermore, pharmacological blockade of the alpha-adrenergic receptors in the hypothalamus attenuated feeding in response to adrenergic, but not electrical brain stimulation. Results are interpreted to suggest that these feeding systems are independent at the level of the diencephalon. The role of the vagus nerve as an efferent link through which these brain systems may influence feeding behavior is discussed.

Peritoneal fluid gonadotropins and ovarian hormones in patients with ovarian cancer.

Halperin R, Hadas E, Langer R, Bukovsky I, Schneider D. Peritoneal fluid gonadotropins and ovarian hormones in patients with ovarian cancer. The aim of this study was to examine the hormonal milieu in peritoneal fluid in ovarian cancer and control patients, and to try to identify hormonal parameters specific for ovarian cancer. The study included 41 patients: 21 with ovarian cancer and 20 patients with benign disease, constituting a control group. The peritoneal fluid and serum samples from these patients were subjected to analysis of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone, testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS), and levels were compared between the two study groups. In addition, peritoneal fluid samples were subjected to cytologic examination and serum samples were assayed for CA 125. All the examined hormonal parameters in peritoneal fluid demonstrated a significant increase in ovarian cancer compared to control patients (P < 0.04). No significant difference in serum levels of the measured hormones was observed between the 2 groups. In order to further discriminate between patients with and without ovarian cancer, the sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of each parameter were calculated. Determination of LH in peritoneal fluid provided sensitivity, specificity and diagnostic accuracy of 100%. In conclusion, patients with ovarian cancer as compared to controls demonstrate significantly increased levels of gonadotropins and ovarian hormones in peritoneal fluid, thus supporting the theory of association between ovarian cancer and specific hormonal milieu. In addition, our results provide a novel hormonal marker for discrimination between patients with and without ovarian cancer.

Identification, immunoaffinity purification and initial characterization of a novel 71 kD human decidua associated protein by use of specific monoclonal antibodies.

This study is part of an ongoing attempt to identify and characterize proteins associated with the human decidual tissue. A novel decidual-associated glycoprotein with an apparent molecular weight of 71 kD named hDP71 (human decidual-protein 71), has been identified and purified by immunoaffinity technique using monoclonal antibodies. The monoclonal antibodies recognizing the hDP71 were raised against a partly purified preparation of decidual associated proteins, which was obtained by immunoabsorption of serum proteins from crude decidual extract. Although the hDP71 was copurified with another decidual-associated glycoprotein, the previously described hDP200 (Halperin et al., 1989), evidence is presented showing that the monoclonal antibodies described above are specific for hDP71.

Laminaria dilatation and evacuation for pregnancies with mid-trimester premature rupture of membranes: a retrospective cohort study.

OBJECTIVE: To assess the efficacy and risk of chorioamnionitis with laminaria tents and uterine evacuation in patients with mid-trimester premature rupture of membrane (MPROM). STUDY DESIGN: A retrospective cohort study of 34 women, admitted between January 1995 and May 1999 with confirmed mid-trimester (14-23 weeks) PROM and 34 controls matched for gestational age, undergoing elective termination. All women underwent cervical dilatation by the use of laminaria tents followed by uterine evacuation (D approximately equals E). Perioperative complications were retrieved from the medical records and long-term ones by telephone questionnaire. RESULTS: Apart from one case requiring a change in antibiotic, no short- or long-term complications were reported. Although, in 8 out of 19 study cases (42%) endocervix culture was positive. The number of laminaria tents used was similar in both groups. The future pregnancy rate was higher in the study group but included four early spontaneous abortions and one ectopic pregnancy. CONCLUSION: Evacuation of uterus following cervical dilatation by laminaria tents in patients presenting with MPROM is safe, and probably not associated with future adverse pregnancy outcome.