Occasional cannabis use is associated with higher premorbid functioning and IQ in youth at clinical high-risk (CHR) for psychosis: Parallel findings to psychosis cohorts.

BACKGROUND: Neurocognitive deficits have been widely reported in clinical high-risk for psychosis (CHR) populations. Additionally, rates of cannabis use are high among CHR youth and are associated with greater symptom severity. Cannabis use has been sometimes shown to be associated with better neurocognition in more progressed psychosis cohorts, therefore in this study we aimed to determine whether a similar pattern was present in CHR. METHODS: CHR participants ages 12-30 from the North American Prodromal Longitudinal Study (NAPLS-3) (N = 698) were grouped according to: "minimal to no cannabis use" (n = 406), "occasional use" (n = 127), or "frequent use" (n = 165). At baseline, cannabis use groups were compared on neurocognitive tests, clinical, and functional measures. Follow-up analyses were used to model relationships between cannabis use frequency, neurocognition, premorbid, and social functioning. RESULTS: Occasional cannabis users performed significantly better than other use-groups on measures of IQ, with similar trend-level patterns observed across neurocognitive domains. Occasional cannabis users demonstrated better social, global, and premorbid functioning compared to the other use-groups and less severe symptoms compared to the frequent use group. Follow-up structural equation modeling/path analyses found significant positive associations between premorbid functioning, social functioning, and IQ, which in turn was associated with occasional cannabis use frequency. DISCUSSION: Better premorbid functioning positively predicts both better social functioning and higher IQ which in turn is associated with a moderate cannabis use pattern in CHR, similar to reports in first-episode and chronic psychosis samples. Better premorbid functioning likely represents a protective factor in the CHR population and predicts a better functional outcome.

Implementation and Effects of a Team-Based Quality Improvement Training Program Across a Health System: The Northwestern Medicine Academy for Quality and Safety Improvement.

BACKGROUND: Professional organizations emphasize the need to train health care professionals in quality improvement (QI). Many reports of QI education programs involve small numbers of participants. Little is known about QI education programs on a larger scale and whether participants subsequently engage in QI activities. METHODS: The Northwestern Medicine Academy for Quality and Safety Improvement (NM AQSI) was developed to prepare individuals across the Northwestern health system to lead QI. The 7-month program consists of classwork and team-based project work. Participant knowledge was assessed using a multiple-choice test and adapted Quality Improvement Knowledge Application Tool (QIKAT). The study team surveyed participants 18 months after AQSI completion to assess their activity in QI. Project status was assessed at AQSI completion and at 18 months. RESULTS: Over 8 years, 80 teams consisting of 441 individuals participated, representing a range of specialties, settings, and professions. Participants had higher multiple-choice test (70.7 ± 14.0 vs. 78.1 ± 13.0; p < 0.001) and adapted QIKAT scores (56.1 ± 15.9 vs. 60.8 ± 15.8; p < 0.001) after AQSI. The majority of participants at 18 months (180/243; 74.1%) had engaged in subsequent QI efforts; many (105/243; 43.2%) had led other QI projects, and (103/243; 42.4%) provided QI mentorship to others. The majority of teams (53/80; 66.3%) improved project measure performance. CONCLUSION: NM AQSI is a team-based QI training program that shows measurable improvements in care and a high degree of participants' subsequent involvement in QI. Other health systems may use a similar approach to successfully train health care professionals to lead QI.

Self-reported use of x-ray personal protective equipment by Saskatchewan veterinary workers.

OBJECTIVE To describe self-reported use of x-ray personal protective equipment (PPE) by veterinary workers in Saskatchewan, Canada, and to examine factors that affected their use of x-ray PPE. DESIGN Cross-sectional survey. SAMPLE 331 veterinary workers. PROCEDURES A questionnaire was distributed to Saskatchewan veterinary workers electronically and by conventional mail. Recipients were encouraged to share the questionnaire with colleagues. The questionnaire consisted of questions regarding radiation safety practices used during small animal radiographic procedures, including frequency of use of dosimeters and lead aprons, thyroid shields, eyeglasses, and gloves. Respondents were also requested to provide suggestions for increasing use of PPE. RESULTS 460 questionnaires were completed, of which 331 were returned by workers involved with performing radiographic procedures. Two hundred eighty-five of 331 (86%) respondents reported that at least 1 worker was always in the room during x-ray exposure, and 325 (98%), 291 (88%), and 9 (3%) respondents reported always wearing a lead apron, thyroid shield, and protective eyeglasses, respectively, during radiographic imaging. Two hundred seventeen of 327 (66%) respondents used lead gloves correctly less than half the time. Mean percentage of time that gloves were worn correctly was higher for workers who were required to do so by their employers than for those who were not. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested use of PPE during radiographic procedures can be increased by employers making PPE use mandatory. Other respondent-identified factors that would increase PPE use included the availability of properly fitting and functional PPE and education of workers about health risks associated with ionizing radiation exposure.

Updates on Multimodal Analgesia for Orthopedic Surgery.

Pain control after orthopedic surgery is challenging. A multimodal approach provides superior analgesia with fewer side effects compared with opioids alone. This approach is particularly useful in light of the current opioid epidemic in the United States. Several new nonopioid agents have emerged into the market in recent years. New agents included in this review are intravenous acetaminophen, intranasal ketorolac, and newer nonsteroidal anti-inflammatory drugs, and the established medications ketamine and gabapentinoids. This article evaluates the evidence supporting these drugs in a multimodal context, including a brief discussion of cost.

Ketamine for Refractory Headache: A Retrospective Analysis.

BACKGROUND AND OBJECTIVES: The burden of chronic headache disorders in the United States is substantial. Some patients are treatment refractory. Ketamine, an N-methyl-D-aspartate antagonist, provides potent analgesia in subanesthetic doses in chronic pain, and limited data suggest it may alleviate headache in some patients. METHODS: We performed a retrospective study of 61 patients admitted over 3 years for 5 days of intravenous therapy that included continuous ketamine to determine responder rate and patient and ketamine infusion characteristics. Pain ratings at 2 follow-up visits were recorded. An immediate responder was a patient with decrease of 2 points or greater in the numerical rating scale (0-10) from start to final pain in the hospital. Sustained response at office visits 1 and 2 was determined based on maintaining the 2-point improvement at those visits. Patients were assessed daily for pain and adverse events (AEs). RESULTS: Forty-eight (77%) of the 61 patients were immediate responders. There were no differences regarding demographics, opioid use, or fibromyalgia between immediate responders and nonresponders. Maximum improvement occurred 4.56 days (mean) into treatment. Sustained response occurred in 40% of patients at visit 1 (mean, 38.1 days) and 39% of patients at visit 2 (mean, 101.3 days). The mean maximum ketamine rate was 65.2 ± 2.8 mg/h (0.76 mg/kg per hour). Ketamine rates did not differ between groups. Adverse events occurred equally in responders and nonresponders and were mild. CONCLUSIONS: Ketamine was associated with short-term analgesia in many refractory headache patients with tolerable adverse events. A prospective study is warranted to confirm this and elucidate responder characteristics.

Structural Integrity of a Simple Method to Repair Disrupted Tracheal Tube Pilot Balloon Assemblies.

BACKGROUND: An intact pilot balloon assembly is crucial to the proper function of a cuffed tracheal tube. Disruption of the pilot balloon, transection of the inflation line, or valve incompetence results in cuff deflation, which may lead to inadequate ventilation and aspiration of secretions. Such failures typically result in tracheal tube replacement, but this may be a safety risk if a difficult reintubation is anticipated. We recently encountered such a patient who remained intubated postoperatively and in whom the inflation line was transected, causing a large leak. We describe a method to reconstitute the inflation line and report on the structural integrity of the repair. We hypothesized that the repaired assembly would maintain cuff pressure not statistically different from an intact device, but that the inflation line would be weaker. METHODS: The distal (tapered) portion of a 22-gauge intravenous (IV) catheter was partially inserted into the severed end of the inflation line. A new pilot balloon was cut from an intact tracheal tube with the tubing attached, the end of which had been dilated using a 22-gauge IV catheter. The new tubing was then guided over the protruding portion of the catheter, creating an internal stent. We measured the drop in cuff pressure after 8 hours in an artificial trachea for repaired and intact tracheal tubes. We tested the integrity of the repaired segments, underwater, to high-pressure inflation. We measured the static tensile strength of the inflation line from intact and repaired tracheal tubes. Data are presented as the mean ± standard error. Differences were assessed using the unpaired, 2-sided Student t test, with P < .05 required to claim statistical significance. RESULTS: Eight-hour interval measurements in 10 intact versus 10 repaired tracheal tubes demonstrated no significant difference in pressure drop (mean difference = 0.5 cm H2O; 95% confidence interval, -2.2 to 1.2 cm H2O; P = .54). There was no visible air leak from 10 repaired inflation line segments when the cuff was inflated to 120 mm Hg. The force needed to break the repaired inflation line was lower than for the intact tubing (n = 7 of each; mean difference = -21.9 N; 95% confidence interval, -25.7 to -18.1 N; P < 10). Repairs to tracheal tubes from various manufacturers with inner diameters ranging from 3.0 to 8.0 mm were successful. CONCLUSIONS: Repairing a disrupted pilot balloon assembly using an IV catheter as a stent inside the inflation line is an effective temporizing measure in situations where ventilation is impaired and where tracheal tube replacement may present an excessive patient risk.

Early initiation of postpartum contraception: does it decrease rapid repeat pregnancy in adolescents?

STUDY OBJECTIVE: Rapid repeat adolescent pregnancy is a significant public health concern. An effective and practical means of decreasing unintended second adolescent pregnancies needs to be identified. The objective of this study is to determine if early initiation of contraception, and in particular long acting reversible contraception (LARC), decreases rapid repeat pregnancy among first time adolescent mothers. DESIGN: Retrospective cohort study. SETTING: Urban teaching hospital. PARTICIPANTS: 340 first-time adolescent mothers age ≤ 19. INTERVENTIONS: None, study was retrospective. MAIN OUTCOME MEASURES: Repeat pregnancy within 2 years. RESULTS: 340 first time adolescent mothers with a documented follow-up time of 2 years had a repeat pregnancy rate of 35%. Average time from delivery to repeat pregnancy was 9.9 ± 6.4 months. Logistic regression analysis comparing adolescents with and without repeat pregnancy revealed that leaving the hospital postpartum without initiating any contraception was associated with significant increase risk of repeat pregnancy (OR = 2.447, 95% CI 1.326-4.515). Follow-up within 8 weeks postpartum was associated with lower chance of repeat pregnancy (OR = 0.322, 95% CI 0.172-0.603). Initiation of a LARC method (either an intrauterine device or etonogestrel subdermal implant) by 8 weeks postpartum was also associated with decreased chance of rapid repeat pregnancy (OR = 0.118, 95% CI 0.035-0.397). CONCLUSION: Adolescent mothers who initiate a LARC method within 8 weeks of delivery are less likely to have a repeat pregnancy within 2 years than those who choose other methods or no method. First time adolescent mothers should be counseled about this advantage of using LARC.

Radiological examination of the hip - clinical indications, methods, and interpretation: a clinical commentary.

UNLABELLED: There is a growing interest in musculoskeletal rehabilitation for young active individuals with non-arthritic hip pathology. History and physical examination can be useful to classify those with non-arthritic intra-articular hip pathology as having impingement or instability. However, the specific type of deformity leading to symptoms may not be apparent from this evaluation, which may compromise the clinical decision-making. Several radiological indexes have been described in the literature for individuals with non-arthritic hip pathology. These indexes identify and quantify acetabular and femoral deformities that may contribute to instability and impingement. The aim of this paper is to discuss clinical indications, methods, and the use of hip radiological images or radiology reports as they relate to physical examination findings for those with non-arthritic hip pathology. LEVEL OF EVIDENCE: 5.

Long-term local control and survival after concomitant boost accelerated radiotherapy for locally advanced cervix cancer.

Between 1989 and 1994, a prospective clinical trial tested the safety and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for patients with locally advanced cervix cancer. CBASF radiotherapy included 45 Gy/25 fractions to the pelvis and a 14.4 Gy/9 fraction concomitant boost to the primary tumor, followed by brachytherapy for a total point A dose of 85 Gy to 90 Gy. The 22 patients of International Federation of Gynecology and Obstetrics stages IIIA-IVA who received CBASF radiotherapy now have a median follow-up time of more than 8 years. The 7-year actuarial rates of local control and overall survival are 81% and 36%, respectively. Serious late toxicity included bowel injury requiring colostomy in eight patients within 2.5 years after treatment, but no other severe toxicity was observed after longer follow-up intervals. The local control and survival rates achieved with CBASF radiotherapy were higher than those observed within a matched contemporaneous cohort of patients treated with standard radiotherapy alone at the same institution (p = 0.1 for local control, 0.09 for survival). The encouraging trend toward improved tumor control, tempered by the complication rate, suggests an opportunity to apply more sophisticated radiotherapy techniques that might sustain the favorable effects of dose intensification while mitigating the normal tissue toxicity.

The relative role of ErbB1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells.

Activation of the epidermal growth receptor (ErbB1) occurs within minutes of a radiation exposure. Immediate downstream consequences of this activation are currently indistinguishable from those obtained with growth factors (GF), e.g. stimulation of the pro-proliferative mitogen-activated protein kinase (MAPK). To identify potential differences, the effects of GFs and radiation on other members of the ErbB family have been compared in mammary carcinoma cell lines differing in their ErbB expression profiles. Treatment of cells with EGF (ErbB1-specific) or heregulin (ErbB4-specific) resulted in a hierarchic transactivations of ErbB2 and ErbB3 dependent on GF binding specificity. In contrast, radiation indiscriminately activated all ErbB species with the activation profile reflecting that cell's ErbB expression profile. Downstream consequences of these ErbB interactions were examined with MAPK after specifically inhibiting ErbB1 (or 4) with tyrphostin AG1478 or ErbB2 with tyrphostin AG825. MAPK activation by GFs or radiation was completely inhibited by AG1478 indicating total dependance on ErbB1 (or 4) depending on which ErbB is expressed. Inhibiting ErbB2 caused an enhanced MAPK response simulating an amplified ErbB1 (or 4) response. Thus ErbB2 is a modulator of ErbB1 (or 4) function leading to different MAPK response profiles to GF or radiation exposure.

Substantially improved in vivo radiosensitization of rat glioma with mutant HSV-TK and acyclovir.

We recently demonstrated in vitro that a mutant HSV-TK (mutant 75) expressed from an adenovirus (AdCMV-TK75) radiosensitized rat RT2 glioma cells significantly better than wild type HSV-TK (AdCMV-TK) in combination with acyclovir (ACV). To examine whether a similar improvement could also be observed in vivo, we tested these viruses in a syngeneic rat glioma tumor model (RT2/Fischer 344). First, we demonstrate that treatment with AdCMV-TK and ACV significantly radiosensitizes implanted gliomas and roughly doubles the mean survival time to 37 days, compared to 20 days for control animals implanted with Adbetagal-transduced cells (P<.02). Second, it was important to first examine the effect of AdCMV-TK75 and ACV on survival without any irradiation. We found that AdCMV-TK75 appeared to sensitize gliomas more efficiently than AdCMV-TK, although this difference was not significant ( P= .19 ). Third, and most importantly, in combined HSV-TK, ACV and irradiation experiments, we demonstrate that AdCMV-TK75 is superior over AdCMV-TK and significantly (P<.005) prolonged the survival of treated animals. Our results suggest that AdCMV-TK75 is far more efficient than AdCMV-TK in radiosensitizing rat glioma when administered in combination with ACV.

Interstitial high-dose-rate brachytherapy boost: the feasibility and cosmetic outcome of a fractionated outpatient delivery scheme.

PURPOSE: To evaluate the feasibility, potential toxicity, and cosmetic outcome of fractionated interstitial high dose rate (HDR) brachytherapy boost for the management of patients with breast cancer at increased risk for local recurrence. METHODS AND MATERIALS: From 1994 to 1996, 18 women with early stage breast cancer underwent conventionally fractionated whole breast radiotherapy (50-50.4 Gy) followed by interstitial HDR brachytherapy boost. All were considered to be at high risk for local failure. Seventeen had pathologically confirmed final surgical margins of less than 2 mm or focally positive. Brachytherapy catheter placement and treatment delivery were conducted on an outpatient basis. Preplanning was used to determine optimal catheter positions to enhance dose homogeneity of dose delivery. The total HDR boost dose was 15 Gy delivered in 6 fractions of 2.5 Gy over 3 days. Local control, survival, late toxicities (LENT-SOMA), and cosmetic outcome were recorded in follow-up. In addition, factors potentially influencing cosmesis were analyzed by logistic regression analysis. RESULTS: The minimum follow-up is 40 months with a median 50 months. Sixteen patients were alive without disease at last follow-up. There have been no in-breast failures observed. One patient died with brain metastases, and another died of unrelated causes without evidence of disease. Grade 1-2 late toxicities included 39% with hyperpigmentation, 56% with detectable fibrosis, 28% with occasional discomfort, and 11% with visible telangiectasias. Grade 3 toxicity was reported in one patient as persistent discomfort. Sixty-seven percent of patients were considered to have experienced good/excellent cosmetic outcomes. Factors with a direct relationship to adverse cosmetic outcome were extent of surgical defect (p = 0.00001), primary excision volume (p = 0.017), and total excision volume (p = 0.015). CONCLUSIONS: For high risk patients who may benefit from increased doses, interstitial HDR brachytherapy provides a convenient outpatient method for boosting the lumpectomy cavity following conventional whole breast irradiation without overdosing normal tissues. The fractionation scheme of 15 Gy in 6 fractions over 3 days is well tolerated. The volume of tissue removed from the breast at lumpectomy appears to dominate cosmetic outcome in this group of patients.

Improved radiosensitization of rat glioma cells with adenovirus-expressed mutant herpes simplex virus-thymidine kinase in combination with acyclovir.

Adenovirus expressing herpes simplex virus-thymidine kinase (HSV-TK) sensitizes internal rat glioma cells to radiation in combination with acyclovir (ACV). However, relatively high concentrations of ACV (>10 microM) are required to obtain significant radiosensitization. Serum levels rarely reach more than the lower micromolar range, preventing the full use of this genetic approach to radiosensitize cells in vivo. To better use the lower concentrations of ACV available in sera, we constructed an adenovirus expressing a mutant HSV-TK (HSV-TK(75)) isolated for its approximately 20 times greater sensitivity to ACV than wild-type (wt) HSV-TK. We demonstrate that rat RT2 glioma cells infected with adenovirus AdCMV-TK(75) and exposed to either ACV or ganciclovir become more sensitive to lower concentrations (1-3 microM) of the drugs compared with cells infected with AdCMV-TK(wt), which expresses wt HSV-TK. Most importantly, the RT2 cells become more sensitive to low doses (2-4 Gy) of 60Co radiation than cells infected with an adenovirus expressing wt HSV-TK. This sensitization is accompanied by an increased rate of apoptosis. In summary, we show that infection of rat glioma cells with an adenovirus expressing a mutant HSV-TK sensitizes the cells to low doses of radiation after exposure to ACV at lower concentrations than those required for wt HSV-TK. This finding suggests that this mutant adenovirus may improve the in vivo efficacy of HSV-TK-based cancer gene therapy approaches.

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases.

PURPOSE: Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS: Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS: Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was $4119 less costly than SRS. CONCLUSION: HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.

Radiosensitization of rat glioma with bromodeoxycytidine and adenovirus expressing herpes simplex virus-thymidine kinase delivered by slow, rate-controlled positive pressure infusion.

Infection of rat RT2 glioma cells in vitro with an adenovirus (ADV-TK) expressing herpes simplex virus (HSV) thymidine kinase (TK) and subsequent exposure to 5-bromo-2'-deoxycytidine (BrdC), which is specifically incorporated into ADV-TK-infected cell DNA as 5-bromo-2'-deoxyuridine (BrdU), results in significant radiosensitization (sensitizer enhancement ratio: 1.4-2.3) compared with Ad beta gal-infected cells. Cell killing correlated well with increased BrdU DNA incorporation and with apoptosis. Whereas radiation (4 Gy) alone was relatively ineffective in inducing apoptosis, treatment with HSV-TK/BrdC resulted in BrdC dose- (10-100 microM) and time-dependent (24-48 hours) increases, and the combination of the two treatments produced a synergistic response (1.5- to 2-fold). To investigate the effects of the ADV-TK/BrdC treatment in vivo, RT2 cells were grown as soft tissue tumors in Fischer 344 rats and conditions for virus infusion were optimized by altering the volume and rate of infusion using a rate-controlled positive pressure device. We found that relatively large volumes (100-150 microL) of virus delivered at rates of < or = 1 microL/minute were optimal and gave uniform and reproducible results. Using these optimal infusion conditions, we were able to achieve 40% adenovirus infection in the tumor. Infection of RT2 tumors with ADV-TK and continuous administration of BrdC from an osmotic pump resulted in significant (.001 < P < .009) tumor regression 6 days after radiation (30 Gy delivered as 2 x 5 Gy over 3 days) compared with controls. In situ staining of sectioned tumors with anti-BrdU antibody or by high-performance liquid chromatography analysis of extracted and hydrolyzed tumor DNA confirmed that we obtained efficient and specific incorporation of BrdU into tumor cells. These results suggest that adenovirus-mediated delivery of HSV-TK in combination with BrdC and radiation can potentially be an efficient combination modality for the treatment of gliomas.

Use of comparison populations for evaluating the effectiveness of hearing loss prevention programs.

One approach for evaluating the effectiveness of Hearing loss prevention programs (HLPPs) is to compare the rate of hearing loss in a study population with that in a reference population. This approach was used to evaluate the HLPP of a population of 14,900 employees of an industrial company with branches across the United States. Three reference populations were selected from a database of 22 industrial companies compiled under the sponsorship of the National Institute for Occupational Safety and Health. The risk of hearing loss in the study population was estimated relative to each of the three reference populations using the Cox proportional hazards model after adjustment for race, age at baseline, and hearing threshold at time of enrollment in the HLPP. In comparison with the three reference populations, hearing loss was 2.1 to 3.9 times more likely to occur in study population males and 1.8 to 5.1 times more likely in study population females. The 95% confidence interval around each risk estimate precluded unity, indicating that each risk estimate was statistically significant. These results indicate that the performance of the subject HLPP needs improvement. This study demonstrated the use of comparison populations for evaluating the effectiveness of HLPPs.

Time trends analysis of hearing loss: an alternative approach to evaluating hearing loss prevention programs.

Two general approaches for evaluating the performance of hearing loss prevention programs (HLPPs) are described in the literature: (1) a comparison of the rate of hearing loss in an HLPP with a reference population and (2) a comparison of audiometric variability or annual incidence of hearing loss with an established set of criteria that rank HLPP performance on a graded scale. This article discusses a third method, time trends analysis, which assesses patterns in hearing loss over time. Patterns may reflect program improvement (decreased hearing loss incidence over time), deterioration (a pattern of increased incidence), or stasis (unchanged incidence). To demonstrate this method, a time trends analysis was conducted on a population of 44,547 industrial workers. Subjects were divided into 11 subgroups based on year of enrollment in the HLPP (1980-1990) and followed retrospectively for 3 years to determine the incidence of hearing loss. Hazard ratios (HRs) were estimated for each subgroup by gender using the Cox Proportional Hazards model and adjusting for age, race, and hearing threshold at enrollment in the HLPP. For women, plots of adjusted HRs against enrollment years produced a statistically significant (p < 0.05) quadratic trend of an initial increase in hearing loss, followed by decreasing incidence over time. For men, there was a statistically significant linear trend of decreasing hearing loss over time. The downward trend, particularly during the late 1980s, indicates improved HLPP performance during the latter portion of the decade. Time trends analysis can be a valuable tool for assessing HLPP performance for those with access to follow-up data and ability to work with statistical models.

Dominant negative EGFR-CD533 and inhibition of MAPK modify JNK1 activation and enhance radiation toxicity of human mammary carcinoma cells.

Exposure of MDA-MB-231 human mammary carcinoma cells to an ionizing radiation dose of 2 Gy results in immediate activation and Tyr phosphorylation of the epidermal growth factor receptor (EGFR). Doxycycline induced expression of a dominant negative EGFR-CD533 mutant, lacking the COOH-terminal 533 amino acids, in MDA-TR15-EGFR-CD533 cells was used to characterize intracellular signaling responses following irradiation. Within 10 min, radiation exposure caused an immediate, transient activation of mitogen activated protein kinase (MAPK) which was completely blocked by expression of EGFR-CD533. The same radiation treatment also induced an immediate activation of the c-Jun-NH2-terminal kinase 1 (JNK1) pathway that was followed by an extended rise in kinase activity after 30 min. Expression of EGFR-CD533 did not block the immediate JNK1 response but completely inhibited the later activation. Treatment of MDA-TR15-EGFR-CD533 cells with the MEK1/2 inhibitor, PD98059, resulted in approximately 70% inhibition of radiation-induced MAPK activity, and potentiated the radiation-induced increase of immediate JNK1 activation twofold. Inhibition of Ras farnesylation with a concomitant inhibition of Ras function completely blocked radiation-induced MAPK and JNK1 activation. Modulation of EGFR and MAPK functions also altered overall cellular responses of growth and apoptosis. Induction of EGFR-CD533 or treatment with PD98059 caused a 3-5-fold increase in radiation toxicity in a novel repeated radiation exposure growth assay by interfering with cell proliferation and potentiating apoptosis. In summary, this data demonstrates that both MAPK and JNK1 activation in response to radiation occur through EGFR-dependent and -independent mechanisms, and are mediated by signaling through Ras. Furthermore, we have demonstrated that radiation-induced activation of EGFR results in downstream activation of MAPK which may affect the radiosensitivity of carcinoma cells.

Accelerated superfractionated radiotherapy for inflammatory breast carcinoma: complete response predicts outcome and allows for breast conservation.

PURPOSE: Chemotherapy and accelerated superfractionated radiotherapy were prospectively applied for inflammatory breast carcinoma with the intent of breast conservation. The efficacy, failure patterns, and patient tolerance utilizing this approach were analyzed. METHODS AND MATERIALS: Between 1983 and 1996, 52 patients with inflammatory breast carcinoma presented to the Medical College of Virginia Hospitals of VCU and the New England Medical Center. Thirty-eight of these patients were jointly evaluated in multidisciplinary breast clinics and managed according to a defined prospectively applied treatment policy. Patients received induction chemotherapy, accelerated superfractionated radiotherapy, selected use of mastectomy, and concluded with additional chemotherapy. The majority were treated with 1.5 Gy twice daily to field arrangements covering the entire breast and regional lymphatics. An additional 18-21 Gy was then delivered to the breast and clinically involved nodal regions. Total dose to clinically involved areas was 63-66 Gy. Following chemoradiotherapy, patients were evaluated with physical examination, mammogram, and fine needle aspiration x 3. Mastectomy was reserved for those patients with evidence of persistent or progressive disease in the involved breast. All patients received additional chemotherapy. RESULTS: Median age was 51 years. Median follow-up was 23.9 months (6-86) months. The breast preservation rate at the time of last follow-up was 74%. The treated breast or chest wall as the first site of failure occurred in only 13%, and the ultimate local control rate with the selected use of mastectomy was 74%. Ten patients underwent mastectomy, 2 of which had pathologically negative specimens despite a clinically palpable residual mass. Response to chemotherapy was predictive of treatment outcome. Of the 15 patients achieving a complete response, 87% remain locoregionally controlled without the use of mastectomy. Five-year overall survival for complete responders was 68%. This is in contrast to the 14% 5-year overall survival observed with incomplete responders. The 5-year actuarial disease-free survival and overall survival for the entire patient cohort was 11% and 33%, respectively. All patients tolerated irradiation with limited acute effects, of which all were managed conservatively. CONCLUSION: Our experience demonstrates that induction chemotherapy, accelerated superfractionated radiotherapy, and the selected use of mastectomy results in excellent locoregional control rates, is well tolerated, and optimizes breast preservation. Based on our present results, we recommend that a patient's response to induction chemotherapy guide the treatment approach used for locoregional disease, such that mastectomy be reserved for incomplete responders and avoided in those achieving a complete response.

Evaluation of the precision of dimensional measurements of the mandible on panoramic radiographs.

The purpose of this study was to evaluate the precision of dimensional measurements of the mandible on orthopantomographic images and thus to evaluate their dimensional reliability. Different distances denoted by metal markers were measured on 25 dry mandibles. The same mandibles were then positioned in an orthopantomographic machine, and radiographic images of them were made. Measurements of the same distances were made on the panoramic images and then compared with the results of the measurements on the dry mandibles. All results were statistically analyzed. The results showed significant difference between the magnification factor listed by the manufacturer and calculated magnification factors, the latter being closer to 1.00. The study also showed that linear measurements made on only one side of the panoramic image of a mandible were very close to the actual dimensions of the dry mandible, whereas measurements that extended across the midline of the mandible were greatly enlarged because of large magnification factors; therefore, such measurements should not be made.