Systematic analysis of early phase clinical studies for patients with breast cancer: Inclusion of patients with brain metastasis.

PURPOSE: This systematic review aims to better define the limitations and patterns with which patients with MBC and CNS metastasis are enrolled into early phase developmental therapeutics trials. METHODS: In June 2016, PubMed search was conducted using the following keywords: "Breast cancer". Drug-development phase 1, phase 2 or phase 1/2 trials for patients with MBC were included. Multiple-histology trials and trials without an efficacy endpoint were excluded. RESULTS: In total, 1474 studies were included; Inclusion criteria for 423 (29%) allowed for CNS metastasis, 770 (52%) either excluded or did not document eligibility of patients with CNS disease. Trials accruing patients with HER2-positive MBC and including targeted therapies had higher odds of allowing for patients with CNS disease (adjusted OR 1.56, 95% CI 1.08-2.2.6; p=0.019 and 1.49, 95% 1.08-2.06; p=0.014, respectively). There were also higher odds of accrual of patients with CNS involvement into clinical trials over time (odds ratio=1.10, 95% CI 1.07-1.12; p<0.0001). CONCLUSION: Most published early phase clinical trials either did not clearly document or did not allow for accrual of patients with CNS disease. Early phase trials with targeted agents or enrolling HER2+ MBC had higher odds of permitting CNS metastases.

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.

Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/ß and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/ß or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number: NCT01782313.

KLF13 regulates the differentiation-dependent human papillomavirus life cycle in keratinocytes through STAT5 and IL-8.

High-risk strains of human papillomavirus (HPV) are the causative agents of cervical and anogenital cancers and are associated with 5% of all human cancers. Although prophylactic vaccines targeting a subset of HPV types are available, they are ineffective in HPV-infected individuals. Elucidation of the mechanisms controlling HPV replication may allow development of novel anti-HPV therapeutics. Infectious HPV virions are produced during terminal differentiation of host cells. The process of viral maturation requires synergistic interactions between viral and cellular proteins that leads to amplification of the viral genome and expression of late viral genes. Here we show that the transcription factor Kruppel-like factor 13 (KLF13) has a critical role in the HPV life cycle. KLF13 is overexpressed in HPV-positive keratinocytes and cervical cancer cell lines. Expression of KLF13 in normal cervical epithelium is low but increases significantly in cervical intraepithelial neoplasia and invasive squamous cervical cancer. After HPV infection, the E7 protein suppresses ubiquitin ligase FBW7 expression leading to an increase in KLF13 expression. Reduction of KLF13 with short hairpin RNA in differentiating HPV-positive cells resulted in diminished levels of viral gene expression and genome amplification. Knockdown of KLF13 also reduced the level of the transcription factor signal transducer and activator of transcription 5, which led to the downregulation of the ataxia-telangiectasia mutated DNA damage pathway and the chemokine interleukin-8 (IL-8). In addition, neutralization of IL-8 diminished viral genome amplification in differentiating HPV-positive cells. Thus, KLF13 is critical for the activation of the HPV productive life cycle and is likely involved in initiation and progression of cervical cancer.

Elevated incidence of fractures in women with invasive breast cancer.

UNLABELLED: This study evaluates the incidence of bone fractures in women with BC.We found that women with invasive breast cancer are at an increased risk for bone fractures, with fractures most commonly occurring at lower extremity and vertebral sites. The risk is further increased in women undergoing cancer therapy. INTRODUCTION: Bone loss and fractures in breast cancer have generally been attributed to aromatase inhibitor use. This study assessed the incidence of fractures after invasive breast cancer diagnosis and evaluated bone density and FRAX risk calculation at time of fracture occurrence. METHODS: Retrospective cohort study of women with invasive breast cancer [June 2003-December 2011] who participated in an academic hospital based genetic biobank. Demographic and clinical characteristics were abstracted from the electronic medical record (EMR). RESULTS: A total of 422 women with invasive breast cancer were assessed; 79 (28 %) sustained fractures during the observation period; fractures occurred at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40 per 1000 person-years. Women who sustained fractures were mostly white and had a family history of osteoporosis (36.9 %, p = 0.03) or history of a prior fracture (6/79, p = 0.004). Fractures occurred 4.0 years (range 0-12 years) after cancer diagnosis. Fracture cases had femoral neck bone mineral density (BMD) of 0.72 + 0.12 g/cm(2), T-score of -1.2, that is, within the low bone mass range. Fractures most commonly occurred in lower extremities, vertebral, and wrist sites. Hip fractures accounted for 11 % of fractures, occurring at a median age of 61 years. CONCLUSIONS: Fractures occur shortly after commencing cancer therapy. Rapid bone loss associated with cancer therapy may precipitate fractures. Fractures occur at relatively higher BMD in BC. Occurrence of fractures in invasive breast cancer raises the possibility of cancer-induced impairment in bone quality.

Higher severity grade of erlotinib-induced rash is associated with lower skin phototype.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) are associated with a characteristic papulopustular rash, an adverse event considered to be a class effect of these agents. Erlotinib, a small-molecule EGFRI, causes a papulopustular rash in 68-75% of patients. The limited reported data suggest that deleterious effects of ultraviolet radiation (UVR) may enhance the development of EGFRI-induced rash. Because the level of the biological pigment melanin correlates with increased protection against UVR, we hypothesized that lighter levels of skin pigmentation are associated with greater severity of rash. AIM: To characterize the relationship between skin phototype (SPT) and rash severity. METHODS: A retrospective chart review was conducted of 40 patients on erlotinib. Skin sensitivity to UVR was categorized using the Fitzpatrick SPT classification scheme. Grading of rash was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3. RESULTS: There was an inverse relationship between SPT and rash severity. Grade 0 was seen in the majority of patients with SPT V/VI, grade 1/2 in the majority of patients with SPT III/IV, and grade 3/4 rash in the majority of patients with SPT I/II (grade 0: 7% SPT I/II, 32% SPT III/IV and 50% SPT IV/V; grade 1/2: 33%, 63% and 50%, respectively; grade 3/4: 60%, 5% and 0%, respectively) (P < 0.01, Fisher exact test). CONCLUSIONS: Prevention and management of cutaneous side-effects from EGFR inhibitors is important to achieve maximum patient compliance and therapeutic benefit. The results of this study suggest that SPT may be an independent predictive factor for EGFRI-induced papulopustular rash, thus pre-therapy counselling and early intervention are important.

Alloantibodies to factor VIII in haemophilia.

Up to one-third of haemophilia A patients develop factor VIII (FVIII) alloantibodies (inhibitors). The Bethesda assay detects inhibitors but is relatively insensitive. Recently, a new fluorescence-based immunoassay (FLI) was developed for antibody detection. The aim of this study was to assess the prevalence of inhibitors as measured by FLI. Assays of FVIII, FVIII inhibitor by Bethesda assay with Nijmegen modification, and FVIII inhibitor by FLI were performed on adult patients with haemophilia A. Data were complete for 46 patients (median age 39), of whom 72% were severe, 7% moderate and 22% mild. The Bethesda assay was positive in only two patients (4%), while FLI was positive in 23 of 46 patients (50%), with values ranging from 0.4 to 33.7 nm (median 3.5 nm). FLI titres exceeded 7.0 nm in 19.5% of patients, all but one of whom had severe haemophilia. FLI antibody-positive patients were less likely to be HIV positive (30% vs. 70%, P = 0.02). The use of a prophylaxis regimen was associated with a lower incidence of antibody; only two of 23 patients with detectable antibody and none of those with antibody >7 nm were on a prophylaxis regimen, while nine of 23 patients without antibody were on prophylaxis, (P = 0.03). There was no difference in inhibitor presence in patients using recombinant versus plasma-derived factor. Antibodies detected by FLI are frequent in patients with haemophilia A, but are less common in those who are HIV positive or are receiving regular FVIII prophylaxis.

Accelerated resolution of laser-induced bruising with topical 20% arnica: a rater-blinded randomized controlled trial.

BACKGROUND: Dermatological procedures can result in disfiguring bruises that resolve slowly. OBJECTIVES: To assess the comparative utility of topical formulations in hastening the resolution of skin bruising. METHODS: Healthy volunteers, age range 21-65 years, were enrolled for this double (patient and rater) blinded randomized controlled trial. For each subject, four standard bruises of 7 mm diameter each were created on the bilateral upper inner arms, 5 cm apart, two per arm, using a 595-nm pulsed-dye laser (Vbeam; Candela Corp., Wayland, MA, U.S.A.). Randomization was used to assign one topical agent (5% vitamin K, 1% vitamin K and 0·3% retinol, 20% arnica, or white petrolatum) to exactly one bruise per subject, which was then treated under occlusion twice a day for 2 weeks. A dermatologist not involved with subject assignment rated bruises [visual analogue scale, 0 (least)-10 (most)] in standardized photographs immediately after bruise creation and at week 2. RESULTS: There was significant difference in the change in the rater bruising score associated with the four treatments (anova, P=0·016). Pairwise comparisons indicated that the mean improvement associated with 20% arnica was greater than with white petrolatum (P=0·003), and the improvement with arnica was greater than with the mixture of 1% vitamin K and 0·3% retinol (P=0·01). Improvement with arnica was not greater than with 5% vitamin K cream, however. CONCLUSIONS: Topical 20% arnica ointment may be able to reduce bruising more effectively than placebo and more effectively than low-concentration vitamin K formulations, such as 1% vitamin K with 0·3% retinol.

Clusterin as a possible predictor for biochemical recurrence of prostate cancer following radical prostatectomy with intermediate Gleason scores: a preliminary report.

Disease recurrence following radical prostatectomy is a major concern in prostate cancer patients. Gleason scores are useful in predicting recurrence. Low Gleason scores are usually associated with long disease-free intervals, while high Gleason scores are suggestive of early recurrence. However, prediction of recurrence has been difficult with intermediate Gleason scores. Clusterin is a ubiquitous secretory sulfated glycoprotein. It is also an antiapoptotic mediator in prostate cancer. The objective of the present study is to determine if clusterin can serve as a predictive biomarker for recurrence of prostate cancer with intermediate Gleason scores in patients following radical prostatectomy. Prostatic specimens with Gleason score of 6 (3+3) or 7 (3+4) were obtained from the archival bank. Three groups of specimens were investigated. The first group was from nine patients who developed recurrent disease according to a persistent rise of serum PSA within 3 years following radical prostatectomy. Those in the second group and the third group were from patients who showed no evidence of disease recurrence for at least 5 y (11 patients) and 10 y (eight patients), respectively following the surgery. Histological sections were subjected to immunohistochemical staining using a monoclonal antibody specific for clusterin. The staining intensity was scored as 0, 1, 2, and 3, with 0 being no staining, 1 showing less than 25% positive staining, 2 being 25-50% positive, and 3 showing greater than 75% positive staining. One-way ANOVA with Bonferroni correction was used for statistical analysis. Evaluation of the scores of clusterin staining was carried out according to four specific areas in each specimen. They were (a) benign epithelial cells, (b) malignant epithelial cells (cancer epithelia), (c) stromal cells surrounding benign cells, and (d) stromal cells surrounding malignant cells (cancer stroma). Staining score in prostatic epithelial cells, benign as well as malignant, showed no significant relationship among the three patient groups. However, when staining scores in stromal cells were compared, there was a significant difference between patients with recurrent disease and those showed no evidence of disease recurrence for at least 10 y. Results of this preliminary study support the important role of clusterin in the stromal component for prostate cancer progression. Clusterin immunostaining may be useful to aid the prediction of chance of disease recurrence in patients with Gleason score 6 or 7 prostate cancer following radical prostatectomy. Further studies with a large number of cases are warranted to verify this preliminary finding.

Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience.

BACKGROUND: Locoregionally advanced, stage IV head and neck cancer has traditionally carried a poor prognosis. We sought to assess changes in patterns of failure, prognostic factors for recurrence, and overall outcome, using two different strategies of chemoradiotherapy conducted in prospective, multi-institutional phase II trials. PATIENTS AND METHODS: Three hundred and thirty-seven stage IV patients were treated from 1989 to 1998. We compared locoregional and distant recurrence rates, overall survival and progression-free survival from two different treatment strategies: intensive induction chemotherapy followed by split-course chemoradiotherapy (type 1, n=127), or intensified, split-course, hyperfractionated multiagent chemoradiotherapy alone (type 2, n=210). Univariate and multivariate analyses of 12 chosen covariates were assessed separately for the two study types. RESULTS: The pattern of failure varied greatly between study types 1 and 2 (5-year locoregional failure of 31% and 17% for study types 1 and 2, respectively, P=0.01; 5-year distant failure rate of 13% and 22% for study types 1 and 2, P=0.03). Combined 5-year overall survival was 47% [95% confidence interval (CI) 41% to 53%) and progression-free survival was 60% (95% CI 55% to 66%). Both treatment strategies yielded similar survival rates. Poor overall survival and distant recurrence were best predicted by advanced nodal stage. Locoregional recurrence was extremely rare for patients with T0-T3 tumor stage, regardless of lymph-node stage. CONCLUSIONS: This analysis suggests that pattern of failure in primary head and neck cancer may be dependent upon treatment strategy. Randomized clinical trials of induction chemotherapy are warranted as a means to determine if a decrease in distant metastases can lead to an increase in survival rates in the setting of effective chemoradiotherapy for locoregional control. Additionally, this analysis provides impetus for randomized clinical trials of organ preservation chemoradiotherapy in sites outside the larynx and hypopharynx.

Osteopontin contributes to hepatocyte growth factor-induced tumor growth and metastasis formation.

The cytokine hepatocyte growth factor (HGF)/scatter factor-1 and its cognate receptor, Met, are involved in the etiology and progression of many types of cancer. Despite recent advances in understanding the signal transduction pathways activated by HGF, the mechanism by which HGF exerts its tumorigenic effect is not well understood. To identify proteins that may be involved in mediating HGF-induced cell motility, invasiveness, and tumorigenesis, we used two separate differential display screening methods to identify changes in gene expression that are initiated by HGF in an epithelial cell culture system. Among several known and unknown genes whose expression was modified, osteopontin (OPN), a protein previously associated with tumorigenesis, was found to be upregulated within 6 h following HGF stimulation. OPN expression was dependent on activation of the PI-3 kinase pathway. Autocrine secretion of HGF resulted in sustained expression of OPN. Downregulation of opn expression by stable antisense transfection attenuated OPN expression and repressed HGF-induced invasiveness in vitro and decreased HGF-mediated tumor growth and metastasis formation in vivo. Constitutive expression of OPN in itself exerted partial invasiveness in vitro, but its expression itself was not sufficient to initiate tumor growth or metastasis formation in vivo. Thus, together with other molecules, OPN activity contributes to HGF-induced tumor growth and invasiveness.

Swallowing and voice effects of Lee Silverman Voice Treatment (LSVT): a pilot study.

OBJECTIVE: To define the effects of Lee Silverman Voice Treatment (LSVT on swallowing and voice in eight patients with idiopathic Parkinson's disease. METHODS: Each patient received a modified barium swallow (MBS) in addition to voice recording before and after 1 month of LSVT. Swallowing motility disorders were defined and temporal measures of the swallow were completed from the MBS. Voice evaluation included measures of vocal intensity, fundamental frequency, and the patient's perception of speech change. RESULTS: before LSVT, the most prevalent swallowing motility disorders were oral phase problems including reduced tongue control and strength. Reduced tongue base retraction resulting in residue in the vallecula was the most common disorder in the pharyngeal stage of the swallow. Oral transit time (OTT) and pharyngeal transit time (PTT) were prolonged. After LSVT, there was an overall 51% reduction in the number of swallowing motility disorders. Some temporal measures of swallowing were also significantly reduced as was the approximate amount of oral residue after 3 ml and 5 ml liquid swallows. Voice changes after LSVT included a significant increase in vocal intensity during sustained vowel phonation as well as during reading. CONCLUSIONS: LSVT seemingly improved neuromuscular control of the entire upper aerodigestive tract, improving oral tongue and tongue base function during the oral and pharyngeal phases of swallowing as well as improving vocal intensity.

Effects of xerostomia on perception and performance of swallow function.

BACKGROUND: Head and neck cancer treatment with high-dose chemoradiation may cause xerostomia and affect the patient's perception of swallowing ability. METHOD: Whole saliva production was measured in 36 patients with advanced-stage cancer of the oropharynx before treatment and 3 months after treatment by weighing a 4 x 4 inch gauze before and after a 2-minute chewing period. Presence of multiple eating difficulties was measured by patient interview. Swallowing was examined videofluorographically (VFG). RESULTS: Saliva weight decreased from a mean (SEM) of 5.1 (0.5) g pretreatment to 1.4 (0.5) g after treatment (p<.0001). At 3 months, significantly more patients perceived difficulty swallowing, dry mouth, needing water while eating, food stuck in the mouth or throat, and change in taste. Saliva weight was not correlated with VFG measures of bolus transit or observations of residue. CONCLUSIONS: Chemoradiation treatment results in xerostomia and a significant increase in patient perception of swallowing difficulties. Saliva weight in patients who perceive swallowing problems was lower. Xerostomia did not affect the physiologic aspects of bolus transport. Xerostomia affected the sensory process and comfort of eating more than bolus transport.

Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: possible role in AP-1-mediated proliferation of ER-negative endometrial cancer.

OBJECTIVE: Tamoxifen is the most widely used antiestrogen to treat all stages of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen acts as a partial estrogen in the uterus and is known to increase the risk of endometrial cancer by two- to threefold. Recent evidence indicates that there is a connection between tamoxifen resistance and activation of the activator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKCalpha), an upstream activator of the AP-1 pathway, in hormone-independent breast cancer and antiestrogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormone-independent breast cancer and determine whether specific PKC isozyme alterations correlated with known clinicopathological features of endometrial cancer. METHODS: The PKC isozyme profile of endometrial carcinomas from 42 patients who were not previously exposed to antiestrogens was examined by Western blot. The relationship between PKC isozyme expression and key prognostic factors for endometrial carcinoma including hormone receptor status, tumor grade, stage, size, and depth of myometrial invasion was examined using the Spearman's rho correlation coefficient. RESULTS: As previously found in breast cancers, PKCalpha and estrogen receptor alpha (ERalpha) expression are inversely related (r(s) = -0.35, P = 0.046). We report significant inverse correlations among ER/progesterone receptor (PR) expression and tumor grade (r(s) = -0.49, P = 0.001 and r(s) = -0.44, P = 0.004, respectively), ER, and depth of myometrial invasion (r(s) = -0.40, P = 0.009). There were no other significant correlations between PKC isozyme expression and other key prognostic factors examined. CONCLUSION: This study indicates that, similar to what was previously observed in breast cancer, PKCalpha and ER expression is inversely related in endometrial cancer. PKCalpha expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCalpha overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.

Ultrasonic quantification of geniohyoid cross-sectional area and tissue composition: a preliminary study of age and radiation effects.

BACKGROUND: This study developed and used a new, noninvasive approach to quantify cross-sectional area and tissue composition within the geniohyoid (GH) muscle in normal adults and head and neck cancer patients. METHODS: B-mode ultrasound was used to measure GH cross-sectional area at rest and during four speech gestures and GH tissue composition at rest in normal young adults, patients with SCC head and neck cancer treated with primary radiotherapy, and normal older adults age matched with the patients. RESULTS: Patients exhibited significantly greater GH cross-sectional area than young subjects at rest and in effortful conditions. Significantly greater muscle tissue variability across GH quadrants was observed in patients compared with normal subjects and in older compared with younger subjects. CONCLUSIONS: B-mode ultrasound area analyses and tissue classification techniques can be used to quantify muscle changes, such as those resulting from age, radiotherapy, or rehabilitation for head and neck cancer.

Effects of lingual gestures on blood flow into the tongue: a pilot study.

BACKGROUND: Reduced blood flow has been hypothesized to be a major factor in the formation of postradiation fibrosis. This study examined Doppler ultrasonography as a technique to detect changes in blood flow into the tongue during selected lingual gestures, /t/ and /k/. METHODS: Six normal subjects, three young men (mean age, 26 years) and three older men (mean age, 66 years) were examined in an upright position using Doppler ultrasound imaging of the external carotid artery just below the lingual artery. Measurements were made with a standardized segmentation technique before and after three repetitions of four speech production gestures /t/ and /k/, each with natural and maximal force. RESULTS: Blood flow peak systole increased significantly after the speech gestures (p < .001). Pooled before and after gesture values for older subjects were significantly lower than those for younger subjects (p < or = .05). CONCLUSIONS: Ultrasonography is a clinically useful technique for measuring blood flow during a dynamic gesture and may be useful for measuring effects of tumor treatment and in a lingual exercise program.

Temporal and biomechanical characteristics of oropharyngeal swallow in younger and older men.

As the U.S. population ages, there is increasing need for data on the effects of aging in healthy elderly individuals over age 80. This investigation compared the swallowing ability of 8 healthy younger men between the ages of 21 and 29 and 8 healthy older men between the ages of 80 and 94 during two swallows each of 1 ml and 10 ml liquid. Videofluoroscopic studies of these swallows were analyzed to confirm the absence of swallowing disorders. Biomechanical analysis of each swallow was completed, from which data on temporal, range of motion, and coordination characteristics of the oropharyngeal swallow were taken. Position of the larynx at rest, length of neck, and pattern of hyoid bone movement were also compared between the two groups. None of the younger or older men exhibited any swallowing disorders. The C2 to C4 distance of older men was significantly shorter than that of younger men, and laryngeal position at rest was lower than in younger men but not significantly so. Older men had a significantly longer pharyngeal delay than younger men and significantly faster onset of posterior pharyngeal wall movement in relation to first cricopharyngeal opening. The older men exhibited significantly reduced maximum vertical and anterior hyoid movement as compared to the younger men even when accounting for the difference in C2 to C4 distance in older men. These data support the hypothesis of reduced muscular reserve in the swallows of older men as compared to younger men. Older men also exhibited less width of cricopharyngeal opening than younger men at 10 ml volume, indicating less upper esophageal sphincter flexibility in the swallows of older men. The potential for exercise to improve reserve is discussed. Significant changes in extent of hyoid elevation and duration of cricopharyngeal opening were seen as liquid bolus volume increased.

Effectiveness of four hours of education in interpretation of radiographic studies.

Clinicians working with oropharyngeal swallowing disorders often use videofluoroscopy to define their patients' swallowing abnormalities. This study examined the effect of 4 hours of training in the identification of head and neck anatomy and oropharyngeal swallowing disorders viewed radiographically. Ninety clinicians participated in a 5-hour session which included 30-minute pre- and post-tests requiring identification of head and neck anatomy and oropharyngeal swallowing disorders and a 4-hour training period. Results showed significant improvement in identification of both radiographic anatomy and swallowing disorders. The change in pre- and post-test measures was negatively correlated with extent of prior experience in dysphagia. Similar studies are needed with clinicians or students inexperienced in dysphagia to define the number of hours of education needed in order for students to reach a desired accuracy level in their identifications.

Pretreatment swallowing function in patients with head and neck cancer.

BACKGROUND: Few objective data characterizing the pretreatment swallow function of patients with head and neck cancer are available. METHODS: Pretreatment swallowing function in 352 patients with various lesions was evaluated with videofluoroscopy and compared with control subjects. RESULTS: Patients had significantly longer oral and pharyngeal transit times, greater amounts of oral and pharyngeal residue, shorter cricopharyngeal opening durations, and lower swallow efficiencies. Swallow function worsened significantly with increased tumor stage, and patients with oral or pharyngeal lesions had worse swallow function than patients with laryngeal lesions. Frequency of complaint of swallow difficulty before treatment was 59%. Patients with lower stage tumors had fewer complaints of swallowing, as did patients with oral cavity lesions. CONCLUSIONS: Despite demonstrating significant differences from control subjects, patients had highly functional swallows before treatment. The tendency for patients not to perceive a swallowing problem is consistent with the highly functional nature of their pretreatment swallow.

Testosterone supplementation for erectile dysfunction: results of a meta-analysis.

PURPOSE: To our knowledge a causal relationship between altered levels of androgens and erectile dysfunction has not yet been established. We reviewed the literature to assess the usefulness of androgen replacement for erectile dysfunction. MATERIALS AND METHODS: Meta-analysis was chosen as the method of evaluating the literature. Study inclusion criteria were testosterone given as the only therapy for erectile dysfunction and a clearly stated definition of response for evaluating treatment success or failure. RESULTS: We evaluated 73 articles obtained by a MEDLINE search of 1966 to 1998 and included 16 in our study. The overall response rate was 57%. In the 9 series with response rate by etiology patients with primary versus secondary testicular failure had a response rate of 64% versus 44% (p <0.001). Intramuscular and oral methods of delivery were equivalent with a response rate of 51.3% and 53.2%, respectively. However, the response to transdermal therapy was significantly different from that of intramuscular and oral treatment (80.9% versus 51.3% and 53.2%, respectively, p <0.001). The mean confidence level response for testosterone treatment was 16. 7% in the placebo and 65.4% in the treated group (p <0.0001). CONCLUSIONS: Our meta-analysis of the usefulness of androgen replacement therapy for erectile dysfunction indicates that the response rate for a primary etiology was improved over that for a secondary etiology, transdermal testosterone therapy was more effective than intramuscular or oral treatment, and intramuscular and oral treatments were equivalent. In addition, there was a statistically significant difference in favor of testosterone over placebo, implying a role for supplementation in select groups.

Tumor size and pretreatment speech and swallowing in patients with resectable tumors.

The pretreatment relationship of tumor burden to speech and swallowing function in 230 patients with oral or oropharyngeal cancer before surgery was assessed. Reduced articulation, reduced conversational understandability, or self-reported dysphagia were present in at least 34% of patients before treatment. Videofluoroscopy showed at least 9% of patients had reduced swallowing efficiency on liquid, paste, or cookie boluses. By use of regression techniques, the percentages of the oral tongue and of the anterior floor of mouth affected by neoplasm were found to be significantly related to reduced articulation; T stage and the percentage of the oral tongue affected with tumor were mildly related to reduced understandability; tumor volume and having soft palate affected by neoplasm were significantly related to self-reported dysphagia; and percentages of affected oral tongue and of affected tongue base were significantly related to reduced swallowing efficiency. Tumor burden may contribute to functional deficits at diagnosis in patients who have resectable tumors.