Straub Medical Center

PURPOSE Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4–blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. PATIENTS AND METHODS In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. RESULTS A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A ( P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B ( P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. CONCLUSION Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

OBJECTIVE: To compare clinical features, visual characteristics, and treatment of idiopathic intracranial hypertension patients with and without papilledema. BACKGROUND: Idiopathic intracranial hypertension does not often occur without papilledema. This study estimates the prevalence and compares the clinical characteristics of idiopathic intracranial hypertension patients with and without papilledema. METHODS: We performed a cross-sectional analysis of all idiopathic intracranial hypertension patients diagnosed at the University of Utah Neuro-Ophthalmology Unit between 1990 and 2003. Patient records were reviewed for presence of papilledema and other signs, symptoms, and treatment characteristics. Each patient without papilledema was matched to the patient with papilledema who was closest to his/her age and sex. McNemar's and Wilcoxon-signed rank sum tests were used to compare characteristics between matched pairs. RESULTS: Among all patients (n = 353), the prevalence of those without papilledema was 5.7% (n = 20). Patients without papilledema reported photopsias (20%), and were found to have spontaneous venous pulsations (75%) and non-physiologic visual field constriction (20%) more often than did those with papilledema. Mean opening pressure, although above normal, was lower in patients without papilledema (mean = 309 mm cerebrospinal fluid) compared with those with papilledema (mean = 373 mm cerebrospinal fluid, P = .031). Idiopathic intracranial hypertension patients without papilledema had more frequent diagnostic lumbar punctures than did patients with papilledema. Visual acuities and treatment were similar between groups. CONCLUSIONS: The clinical presentation of idiopathic intracranial hypertension without papilledema is only somewhat different from that of idiopathic intracranial hypertension with papilledema. The lower opening pressure in patients without papilledema may explain variations in symptoms and signs between the 2 groups. When there are visual field changes in idiopathic intracranial hypertension without papilledema, non-physiologic visual loss should be considered.

A series of nine cases of tarsometatarsal dislocation due to indirect trauma with a follow-up from two and a half to fifteen years is presented. Distinction is made between dislocations due to direct and those due to indirect trauma. It is our opinion that, despite the superficial similarity between the two, the lesions are quite different in mechanism of production, direction of displacement, and extent of soft-tissue damage. Their treatment and prognosis also differ. In this series, all the dislocations were due to indirect violence; seven cases were fresh and two were old injuries of months' or years' duration. Reduction was accomplished by closed and open methods. Partial redislocation occurred after both methods in some instances. Two patients had persistent marked dislocation. In all patients followed for two and a half years or more the functional end results were excellent even when severe widespread dislocation persisted. Despite these facts, we believe when dislocation recurs or when closed methods of reduction fail, open reduction and internal fixation with Kirschner wires are advisable. Open reduction provides a better looking foot and appreciably hastens convalescence. In this series none of the dislocations, not even the persistent widespread ones, caused symptoms that suggested the need for surgical fusion. Although disastrous circulatory disturbances have been described in the literature, none were experienced in this series.

BACKGROUND: Telavancin, a novel lipoglycopeptide, exerts concentration-dependent, rapid bactericidal activity on account of its multiple mechanisms of action. Telavancin is highly active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate, and vancomycin-resistant strains. METHODS: We conducted a randomized, double-blind, controlled, phase-2 clinical trial. Patients > or = 18 years of age with a diagnosis of complicated skin and soft-tissue infection caused by suspected or confirmed gram-positive organisms were randomized to receive either intravenously administered telavancin once daily or standard therapy (antistaphylococcal penicillin 4 times daily or vancomycin twice daily). RESULTS: For the study, 167 patients were randomized and received at least 1 dose of study medication. Success rates were similar in all analysis populations at the test-of-cure evaluation. Of patients with S. aureus infection at baseline (n = 102), 80% of the telavancin group were cured and 77% of the standard therapy group were cured. For patients with MRSA infection at baseline (n = 48), cure rates were 82% for the telavancin group and 69% for the standard therapy group. Microbiologic eradication in patients with MRSA infection was 84% for the telavancin group versus 74% for the standard therapy group. MIC90 values were lower for telavancin in all tested strains of S. aureus (< or = 0.25 ug/mL) compared with the MIC90 values for vancomycin and oxacillin. Similar proportions of patients discontinued therapy for adverse events in both treatment groups (approximately 5%). Fewer serious adverse events were reported in the telavancin group (4 events) than were for the standard therapy group (9). CONCLUSION: Clinical and microbiological results of this study support the further development of telavancin, especially for treatment of infection due to MRSA.

To determine the influence of age on the signs and symptoms of hyperthyroidism we prospectively examined 880 patients and matched them by age, sex, race, and visit date with similarly examined euthyroid control subjects. Many signs and symptoms showed little change with age until after the fifth decade of life when they began to decrease gradually. Findings that increased with age were weight loss and atrial fibrillation, while those that decreased most markedly with age were increased appetite and weight gain. The diagnosis is more difficult as age progresses because there are fewer findings and because the significance of those present may not be appreciated. Identification of the most sensitive and specific signs and symptoms in each age decade should improve the early detection of hyperthyroidism.

The authors investigate the impact of overweight in patients with chronic venous disease and determine if the eventual effect can be explained by increased venous reflux alone. Patients with chronic venous disease who underwent duplex-ultrasound scanning at the Vascular Center, Straub Clinic and Hospital during 1999 were classified according to the clinical, etiologic, anatomic, and pathophysiologic (CEAP) system and body mass index (kg/m(2)) was calculated. Reflux duration was measured in seconds and peak reverse flow velocity in cm/second. Multi-segment reflux score (total score) was calculated for both reflux duration and peak reverse flow velocity. The reflux pattern and body mass index were correlated to the clinical presentation. Four hundred and one lower extremities (204 right, 197 left) in 272 patients (173 female) with a mean age of 60 years (range 14-90) were investigated. The mean body mass index was 28.9 (+/-7.76). One hundred sixty-seven patients (61%) were overweight (body mass index 25 kg/m(2) or more). There was a significant association between body mass index and the clinical severity (p<0.001). This association persisted after adjustments for total peak reverse flow velocity and total reflux score were made (p<0.001). Overweight patients were more likely to have skin changes and ulceration (p<0.001) than patients with a body mass index less than 25 kg/m(2), despite similar values for total reflux time (p=0.92) and total peak reverse flow velocity (p=0.98). There was an ethnic difference, with Pacific Islanders being significantly heavier and younger compared to patients of white, Asian and Filipino ancestries. The variations in the frequency of skin changes were consistent with ethnic differences in body mass index. The correlation of body mass index with clinical severity independent of reflux measurements indicates that the effect of overweight may involve a mechanism separate from local effects on venous flow. Overweight appears to be a separate risk factor for increased severity of skin changes in patients with chronic venous disease.

To determine the effect of a 72 Hz pulsating electromagnetic field (PEMF) on bone density of the radii of osteoporosis-prone women, the nondominant forearms of 20 subjects were exposed to PEMF 10 h daily for a period of 12 weeks. Bone density before, during, and after the exposure period was determined by use of a Norland-Cameron bone mineral analyzer. Bone mineral densities of the treated radii measured by single-photon densitometry increased significantly in the immediate area of the field during the exposure period and decreased during the following 36 weeks. A similar but weaker response occurred in the opposite arm, suggesting a "cross-talk" effect on the nontreated radii, from either possible arm proximity during sleep or very weak general field effects. The data suggest that properly applied PEMFs, if scaled for whole-body use, may have clinical application in the prevention and treatment of osteoporosis.

An apnea score (AS) was developed as a potential screening tool for sleep apnea. This was based on self-report questionnaire responses of 76 sleep disorder center patients and 20 sleep survey volunteers. Twenty volunteers and 23 patients (group I) comprised the initial AS development group. Their questionnaire responses were compared to polysomnographic apnea indexes (AI) and apnea plus hypopnea indexes (AHI). Stepwise multivariate discriminant analysis was used to test whether or not selected group I questionnaire responses could be used to correctly classify respondents into apnea (AI or AHI greater than 5) or nonapnea (AI, AHI less than or equal to 5) groups. Self-reports of "stops breathing during sleep," "loud snoring," and history of adenoidectomy best discriminated normal (AI less than or equal to 5) from apnea (AI greater than 5) cases. The AS derived from group I responses to these three variables was then computed for group II (n = 53). After examination of the AS results, the AS was modified to include just "stops breathing" and "loud snoring" and the AI criterion was raised to 10 per hour. This revised AS correctly identified 100% of the cases with moderate-severe sleep apnea (AI or AHI greater than 40) and 70-76% of all sleep apnea cases with AI or AHI greater than 5. Predictive accuracy was 88% for AI greater than 10. The two questions that comprise the AS should be incorporated into risk appraisal instruments or interviews to screen for sleep apnea.

OBJECTIVES: The objective of this study was to evaluate whether patients with surgically refractory medial temporal lobe epilepsy (MTLE) exhibit a distinct pattern of structural network organization involving the temporal lobes and extratemporal regions. METHODS: We retrospectively studied 18 healthy controls and 20 patients with medication refractory unilateral MTLE who underwent anterior temporal lobectomy for treatment of seizures. Patients were classified as seizure-free or not seizure-free at least 1 year after surgery. The presurgical brain connectome was calculated through probabilistic connectivity from MRI-diffusion tensor imaging from 83 anatomically defined regions of interest encompassing the whole brain. The connectivity patterns were analyzed regarding group differences in regional connectivity and network graph properties. RESULTS: Compared with controls, patients exhibited a decrease in connectivity involving ipsilateral thalamocortical regions, with a pathologic increase in ipsilateral medial temporal lobe, insular, and frontal connectivity. Among patients, those not seizure-free exhibited a higher connectivity between structures in 1) the ipsilateral medial and lateral temporal lobe, 2) the ipsilateral medial temporal and parietal lobe, and 3) the contralateral temporal pole and parietal lobe. Patients not seizure-free also exhibited lower small-worldness in the subnetwork within the ipsilateral temporal lobe, with higher subnetwork integration at the expense of segregation. CONCLUSIONS: MTLE is associated with network rearrangement within, but not restricted to, the temporal lobe ipsilateral to the onset of seizures. Networks involving key components of the medial temporal lobe and structures traditionally not removed during surgery may be associated with seizure control after surgical treatment of MTLE.

Since hypothyroidism is commonplace after treatment of Graves' disease with radioiodine, the goal should be cure of hyperthyroidism rather than avoidance of hypothyroidism. To find the optimal dose to accomplish cure, we treated 605 patients with stepwise increasing doses of 3, 4, 5, 6, 8, and 10 mCi, analyzing the relationship of dose, age, sex, gland weight, and thyroidal uptake to cure. Estimates of cure at doses above 10 mCi were made from the literature. Cure was directly related to dose between 5 and 10 mCi. There was no significant relationship between cure and age (chi-square, p = 0.74), sex (chi-square, p = 0.12), and 24-hr uptake if over 30% (chi-square for slope, p greater than 0.10). Cure and gland weight had an inverse relationship (chi-square for slope, 0.01 less than p less than 0.02). We concluded that the optimal 131I dose for curing hyperthyroidism is approximated by starting with 10 mCi and increasing it for unusually large glands or for special patient circumstances.

OBJECTIVE: To study risk factors for the development of air travel-related acute venous thromboembolism. METHODS: A retrospective study of 254 patients admitted from 1988 to 1993 under the diagnosis of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) identified 44 patients who developed symptoms during or after air flight. RESULTS: There were 24 males and 20 females with a mean age of 63 years. Flight times were 5-17 hours. Twenty-eight patients (63.6%) had DVT only, five patients (11.4%) PE only, and 11 patients (25%) DVT and PE. Ninety-five percent had extension of the thrombus above the calf: popliteal vein, 10 patients; superficial femoral vein, 13 patients; common femoral vein, six patients; and iliac vein, eight patients. Five patient-related risk factors were identified: history of previous DVT (34%), presence of chronic disease or malignancy (25%), hormone therapy (16%), recent lower limb injury (11%), and recent surgery or femoral catheterization (9%). CONCLUSIONS: We can speculate about the role of seven cabin-related risk factors: low humidity, hypoxia, diuretic effect of alcohol, insufficient fluid intake, smoking, "coach" position, and immobilization. In travelers with patient-related risk factors, the cabin-related risk factors are superimposed and may increase the risks for air travel-related acute venous thromboembolism. Active prophylaxis is recommended.

BACKGROUND: Data on 349,154 prostate cancer cases diagnosed since 1986 have been entered to the American College of Surgeons National Cancer Data Base (NCDB). Previous annual reports have examined subsets of these data. The present report highlights major trends in the presentation and treatment of prostate cancer in the United States evident from longitudinal analyses of the entire data. METHODS: NCDB data are collected following a computerized, standard format. Hospital participation is voluntary. RESULTS: Since the first year of data collection, the number of participating hospitals has increased from 496 to 996 and the number of prostate cancer patients reported to the NCDB increased from 19,531 to 84,408. The proportion of men diagnosed at ages younger than 70 years increased from 37.8% in 1986 to 46.9% in 1993. Completeness of reporting stage of disease and tumor grade has improved. The proportions of both the earliest (American joint Committee an Cancer [AJCC] Stage Groups 0 and I) and the most advanced (AJCC++ Stage Group IV) stages declined. The proportion of Grade 2 (moderately differentiated) tumors increased from 38.6% in 1986 to 57.5% in 1993. The proportion of AJCC Stage II prostate cancer increased from 19% in 1986 to 48.4% in 1993. The proportion of patients treated by prostatectomy increased from 9.9% in 1986 to 29.2% in 1993. The proportion of patients receiving no cancer directed treatment declined from 41.8% in 1986 to 21.6% in 1993. Less change was observed in the use of radiation and hormonal treatments. CONCLUSIONS: These data show that the clinical patterns of prostate cancer have changed markedly in recent years.

A new type of fixation device for the treatment of pertrochanteric fractures of the hip is described. The device has an axial-compression screw to allow compression along an axis parallel to the femoral shaft. As the fracture settles postoperatively, dynamic axial compression continues. This axial-compression device was used in twenty-five patients who had an unstable intertrochanteric or proximal subtrochanteric fracture of the proximal part of the femur. The average extent of axial impaction or settling was five millimeters (standard deviation, 1.3 millimeters) at the most recent follow-up examination, and the relationship between the femoral head and shaft was altered less than with the use of a conventional compression screw-plate device. A larger proportion of the patients who had the new device were able to walk fifteen meters (fifty feet) independently by the time of discharge from the hospital, even though they left the hospital earlier. No technical failures were seen in the patients who were treated with the axial-compression screw device. We believe that the axial-compression screw-plate device is appropriate for the treatment of unstable pertrochanteric fractures of the hip.

OBJECTIVE: This study was designed to determine concussion incidence, risk, and relative risk among middle and high school athletes participating in various sports. METHOD: Data were retrospectively obtained from 10,334 athletes of 12 different sports in Hawaii. In addition to determining the overall concussion incidence, comparisons of incidence, risk, and relative risk were made according to age, sex, concussion history, sport, and football position. RESULTS: The overall incidence of concussion among youth athletes was 1,250 (12.1%). The relative risk for a concussion was almost two times greater in 18-year olds than in 13-year-old athletes. In comparable sports, girls had a 1.5 times higher concussion risk than boys. Athletes with a prior concussion had 3-5 times greater risk to sustain a concussion than those with no history of a concussion. Among varied sports, wrestling and martial arts had the highest relative risk of a concussion, followed by cheerleading, football, and track and field. No differences in concussion risks were found among the football players in different positions. CONCLUSIONS: Older youths, females, those with a history of concussion, and those participating in high contact sports were found to have higher risks of sustaining a concussion. The findings increase awareness of concussion patterns in young athletes and raise concerns regarding protective strategies and concussion management in youth sports.

In Brief Study Design. The authors reviewed a series of nontraumatic spinal cord injuries associated with surfing lessons. Objectives. To characterize a unique syndrome of paraplegia/paraparesis to improve clinical recognition, treatment, and prevention. Summary of Background Data. Surfer’s myelopathy is a previously unreported nontraumatic spinal cord injury that affects inexperienced surfers. Nine patients with paraparesis/paraplegia were evaluated and treated after nontraumatic surfing events. Methods. An office-based registry tracked patients with surfer’s myelopathy between July 2001 and December 2002. A retrospective review of hospital records searched for additional patients. Nine cases of surfer’s myelopathy are retrospectively analyzed to characterize the incidence, risk factors, and outcome. The literature related to surfing injuries is reviewed. Results. Nine patients were detected with surfer’s myelopathy between June 1998 and January 2003. The average age was 25 years. Most patients presented with back pain, paraparesis, and urinary retention. Other presenting symptoms included paraplegia, hypesthesia/hypalgesia, and hyperesthesia. At the time of discharge, three patients had a complete recovery and four patients had mild weakness without sensory deficits. Three in this group had residual urinary retention. One patient remained paraplegic. All patients had abnormal signal change in the lower thoracic spinal cord by magnetic resonance imaging. Conclusion. Surfer’s myelopathy is a nontraumatic paraparesis/paraplegia that affects first-time surfers. Although most patients have a complete or near-complete recovery, complete paraplegia has occurred. Surfer’s myelopathy is a previously unreported nontraumatic paraparesis/paraplegia that affects first-time surfers. Patients typically present with back pain, paraparesis, urinary retention, and abnormal magnetic resonance image signal change in the lower thoracic spinal cord. Although the typical course yields near-complete or complete recovery, paraplegia has occurred.

BACKGROUND: Antimicrosomal (anti-M) and antithyroglobulin (anti-Tg) antibodies are commonly measured together to detect Hashimoto's thyroiditis. Since this nearly doubles the cost of testing for one antibody, we wished to determine whether significant diagnostic loss would occur if the two tests were replaced by anti-M alone. METHODS: Both tests were performed in 2030 consecutive patients referred by general internists and endocrinologists. RESULTS: With a positive result defined as either test being positive at a 1:100 dilution, anti-M was much more sensitive than anti-Tg. Anti-M was positive in 99% (823/831) of all patients with positive tests, while anti-Tg was positive in 36% (302/831). Anti-M was the only positive test in 64% of all patients with positive tests, while anti-Tg was the only positive test in 1%. With a cutoff point of 1:400 dilution, the results were similar. CONCLUSIONS: Anti-M alone appears sufficient to detect autoimmune thyroid disease at about one half the cost of routinely performing both anti-M and anti-Tg studies. The widespread practice of performing both tests increases the cost without an offsetting diagnostic gain.

Increased understanding of bone biology has led to the discovery of several unique signaling pathways that regulate bone formation and resorption. The Wnt signaling pathway plays a significant role in skeletal development, adult skeletal homeostasis, and bone remodeling. Sclerostin is an inhibitor of the Wnt signaling pathway. Romosozumab, a humanized monoclonal antibody that binds to sclerostin, prevents sclerostin from exerting this inhibitory effect. Therefore, in the presence of romosozumab, the Wnt signaling pathway is activated leading to bone formation and bone mineral density gain. Clinical studies of romosozumab have shown that this agent is one of the most potent bone anabolic agents in development to date. Romosozumab does not act solely as an anabolic agent, but rather, it has effects on increasing bone formation as well as reducing bone resorption. In the clinical studies, patients tolerated romosozumab well with no major safety signals reported. In a Phase III study, romosozumab as compared to placebo has been shown to reduce vertebral fractures by 73% after 1 year of treatment. Sequential therapy with romosozumab for 1 year followed by denosumab in the second year reduced vertebral fractures by 75% as compared to the group that received placebo for 1 year and denosumab in the second year. Romosozumab holds significant potential, by a novel mechanism of action, to expand our ability to treat osteoporosis. More studies are needed to determine the ideal setting in which romosozumab may be used to optimize osteoporosis treatment.

BACKGROUND: Brazilian jiu-jitsu (BJJ) is a unique style of martial arts with rapid growth in the United States and internationally. Although studies have examined injuries in other martial arts and combat sports, to date, no published medical study has examined injuries in BJJ competitions. PURPOSE: (1) To estimate the incidence of injuries in BJJ competitions and (2) to identify and describe the types and mechanisms of injuries associated with competitive BJJ. STUDY DESIGN: Descriptive epidemiology study. METHODS: Injury data were obtained from records of on-site medical coverage at 8 statewide BJJ tournaments in Hawaii, USA, between 2005 and 2011. RESULTS: The identified injury incidence on the day of matches was 9.2 per 1000 exposures (46 injuries out of 5022 exposures, ie, match participations). Orthopaedic injuries were the most common and accounted for 78% of all injuries (n = 36), followed by costochondral or rib injuries (n = 7) and lacerations requiring medical care (n = 3). The elbow was found to be the joint most commonly injured during BJJ competitions, with the arm bar being the most common mechanism. We propose that this BJJ-specific injury mechanism, the "arm bar," be recognized as another mechanism of hyperextension injury to the elbow in sports. CONCLUSION: Comparison of the BJJ injury data with injury data reported for judo, taekwondo, wrestling, and mixed martial arts showed that BJJ competitors were at substantially lower risk of injury compared with these other sports. With orthopaedic injuries being most common and the elbow being the area most vulnerable to injury in BJJ, it is important that participants, referees, and physicians be properly educated about the unique mechanisms of injury that can occur, particularly to the elbow.

Wolfe's criteria were assigned to mammograms of 202 women without breast cancer. Parity decreased the frequency of P2 patterns but not DY. P1 and N1 patterns apparently increased at the expense of P2 patterns. For every birth, the probability that a P2 pattern changed to P1 or N1 was roughly 7 or 8%. This effect was not limited to the first pregnancy, but also held for additional pregnancies. Low body weight was associated with dysplasia and prominent duct patterns. Reported declines of radiographic density with increasing age and/or menopause were confirmed. Ethnic group was unrelated to parenchymal pattern.

Fibrinopeptide A (FpA) concentrations in plasma and in 24 hr urine specimens as well as beta-thromboglobulin (BTG) in plasma were measured in 17 patients with severe angina pectoris, including both stable and unstable angina, and in 19 patients with acute myocardial infarction. Patients with unstable angina had plasma FpA and BTG levels of 5.2 +/- 1.7 ng/ml and 91 +/- 23 ng/ml, respectively. The corresponding concentrations of FpA in the 24 hr urine specimens were 8.2 +/- 1.4 micrograms/24 hr. These values were similar to those measured in patients with acute myocardial infarction and higher than the corresponding levels in patients with stable angina (p less than .05) and in normal control subjects (p less than .01). The similarity of the platelet and coagulation findings in patients with unstable angina and in those with myocardial infarction favors the hypothesis that coronary thrombosis may play a major role in the pathogenesis of acute myocardial infarction.