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Overexposure to ultraviolet (UV) radiation is a threat to human health. It can cause skin cancer and cataracts. Human-made ozone-depleting substances (ODSs) reduce the ozone concentration in the Earth’s stratosphere, which acts as a protective shield from UV radiation. To protect and restore the ozone layer, the Montreal Protocol on Substances that Deplete the Ozone Layer was enacted in 1987 to phase out the production and consumption of certain ODSs and was later amended and adjusted to significantly strengthen its requirements. The United States Environmental Protection Agency (EPA) uses its Atmospheric and Health Effects Framework (AHEF) model to assess the adverse human health effects associated with stratospheric ozone depletion and the U.S. health benefits from the global implementation of the Montreal Protocol. Comparing the Montreal Protocol as amended and adjusted with a scenario of no controls on ODSs showed the prevention of an estimated 443 million cases of skin cancer and 63 million cataract cases for people born in the United States between 1890 and 2100. In addition, 2.3 million skin cancer deaths are avoided. Compared with the original 1987 Montreal Protocol, strengthening the Montreal Protocol, through its subsequent amendments and adjustments, resulted in an estimated 230 million fewer skin cancer cases, 1.3 million fewer skin cancer deaths, and 33 million fewer cataract cases.

Background Although literature exists regarding hip and knee arthroplasty outcomes in patients with skin allergy to metals, there is minimal information about skin allergy implications on shoulder arthroplasty outcomes. The purpose of this study was to determine the results, complications, and failure rate among patients with a self-reported metal allergy undergoing shoulder arthroplasty. Methods Fifty-two shoulder arthroplasties were performed at our Institution in 43 patients with self-reported metal allergies. Forty primary and 12 revision shoulder arthroplasties were performed using anatomic (30) and reverse (22) components. Retrospective chart review was performed to determine metal allergy history, implant composition, pain, motion, and complications. Radiographs were reviewed to determine mechanical failure rates. Average follow-up time was 65 months. Results Allergies reported included nickel (37), cobalt chrome (4), copper (2), zinc (1), titanium (1), gold (1), and nonspecific metal allergy (8); 8 patients reported multiple metal allergies. All components implanted in patients with nickel allergies contained nickel. At most recent follow-up, pain was rated as none or mild in 88% of shoulders. Active elevation improved from 80° to 141° and external rotation from 24° to 52°. Two revisions were performed for glenoid loosening (3.8%); both were revision cases with substantial glenoid bone loss. One patient with mild pain had a radiographically loose glenoid component 12 years after anatomic shoulder arthroplasty. Conclusion Results from this study suggest that shoulder arthroplasty in patients with self-reported metal allergy provides satisfactory pain relief and improved range of motion with low revision rates.

Introduction Upper extremity lymphedema can complicate mastectomy, lymph node dissection, and radiation. The purpose of this study is to present the outcomes of shoulder arthroplasty in patients with lymphedema. Methods The 19 shoulders with a shoulder arthroplasty and lymphedema on the surgical side (6 anatomic, 12 reverse, 1 hemiarthroplasty) were followed for four years (1–10 years). There were 2 males and 17 females; average age was 67.8 (48–86) years. Breast carcinoma was the most common reason for lymphedema (75%). A dedicated lymphedema questionnaire could be completed for 14 shoulders. Results Pain improved from moderate or severe preoperatively to no or mild in 18 shoulders. Motion improved in elevation (55° preoperatively, 107° at last follow-up), external rotation (14°, 43°), and internal rotation (sacrum, L5). Complications included an acromion stress fracture with a deep infection (1), deep infection (1), superficial infection (1), and glenoid loosening (1). Lymphedema worsened in nine cases, but worsening was permanent in only four. Currently, lymphedema treatment is being performed by 93% of survey respondents. No patients reported lymphangitis or lymphangiosarcoma. Conclusion Shoulder arthroplasty for an upper extremity with lymphedema provides substantial improvements in pain and motion; however, infection is a concerning complication. Fifty percent of the patients will experience worsening of their lymphedema and in 20% worsening may be permanent.

Background Preoperative planning software has been developed to measure glenoid version, glenoid inclination, and humeral head subluxation on computed tomography (CT) for shoulder arthroplasty. However, most studies analyzing the effect of glenoid positioning on outcome were done prior to the introduction of planning software. Thus, measurements obtained from the software can only be extrapolated to predict failure provided they are similar to classic measurements. The purpose of this study was to compare measurements obtained using classic manual measuring techniques and measurements generated from automated image analysis software. Methods Ninety-five two-dimensional computed tomography scans of shoulders with primary glenohumeral osteoarthritis were measured for version according to Friedman method, inclination according to Maurer method, and subluxation according to Walch method. DICOM files were loaded into an image analysis software (Blueprint, Wright Medical) and the output was compared with values obtained manually using a paired sample t-test. Results Average manual measurements included 13.8° version, 13.2° inclination, and 56.2% subluxation. Average image analysis software values included 17.4° version (3.5° difference, p Conclusions Glenoid version and inclination values from the software and manual measurement on two-dimensional computed tomography were relatively similar, within approximately 4°. However, subluxation measurements differed by approximately 20%.

In an effort to understand the difference between melanomas diagnosed in Australia (New South Wales) and Canada, where the incidence in New South Wales is almost three times greater than in Canada, and mortality is twice as high although survival is slightly more favorable, we had one pathologist review 1,271 melanomas from British Columbia and Ontario, Canada, to compare these to melanomas in New South Wales, Australia. We hypothesized that histopathologic characteristics might provide insight into divergent pathways to melanoma development. We found a number of differences in risk factors and tumor characteristics between the two geographic areas. There were higher mole counts and darker phenotypes in the Canadian patients, while the Australian patients had greater solar elastosis, more lentigo maligna melanomas, and more tumor infiltrating lymphocytes. We hypothesize that the differences observed may illustrate different etiologies – the cumulative exposure pathway among Australian patients and the nevus pathway among Canadian patients. This is one of the largest studies investigating the divergent pathway hypothesis and is particularly robust due to the evaluation of all lesions by one dermatopathologist.

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle genesilencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: this study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC., NHMRC Project Grant; Avner Innovation Grant; NHMRC CDF-I; NHMRC Ideas Grant ; Cancer-Institute NSW ECF/CDFs ; Cancer Institute NSW Innovation Grant; Cancer Institute NSW The Professor Rob Sutherland AO Make a Difference Award; Cancer Australia/Cancer Council; Cancer Australia/Kids Cancer Project; Cure Cancer Australia; Tour de Cure PhD Support Scholarship; Tour de Cure Established Research Grant; Tour de Cure Pioneering Research Grant; UNSW Interlude Grant Scheme; Cancer Research UK Core Funding and Grand Challenge Grants; NHMRC CDF-II; NHMRC Senior Research Fellowship; Suttons, Cancer Council NSW; Avner Grant from PanKind; Australian Pancreatic Cancer Foundation; Translational Cancer Research Network and Australian Postgraduate Award Scholarships; Australian Government Research Training Program Scholarship; UNSW Sydney Scientia PhD Scholarship; Pancreatic Cancer UK Future Leaders Academy; Len Ainsworth Pancreatic Cancer Fellowship

Cancer-Associated Fibroblasts (CAFs) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression, through pro-tumour cross-talk and the generation of fibrosis (physical barrier to drugs). CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumour stroma and its prognostic significance. Herein we show that high expression of SLC7A11 in PDAC tumour stroma (but not tumour cells) is independently prognostic of poorer overall survival. We demonstrate using orthogonal approaches that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis, and that SLC7A11 inhibition significantly decreases their proliferation, reduces their resistance to oxidative stress and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, our paradigm-shifting work demonstrates the need to inhibit SLC7A11 in the PDAC stroma, as genetic ablation of SLC7A11 in PDAC cells alone is not enough to reduce tumour growth. Finally, our work validates that a nano-based gene-silencing drug against SLC7A11, developed by our group, reduces PDAC tumour growth, CAF activation and fibrosis in a mouse model of PDAC.

OBJECTIVE To report the injury characteristics, radiographic findings, and long-term outcomes of nonoperative management for posterior shoulder instability (PSI). DESIGN A retrospective review of 143 patients with PSI using a large geographic database. SETTING Single county between January 1994 and July 2012. PATIENTS A clinical history and diagnosis of PSI, one confirmatory imaging study to support the diagnosis, and a minimum of 5 years follow-up were required for inclusion. Patients with seizure disorders, anterior-only instability, multidirectional instability, and superior labrum from anterior to posterior diagnosis were excluded. INTERVENTIONS Patients with PSI were managed nonoperatively or operatively. MAIN OUTCOME MEASURES Pain, recurrent instability, and progression into glenohumeral osteoarthritis at long-term follow-up. RESULTS One hundred fifteen patients were identified. Thirty-seven (32%) underwent nonoperative management. Twenty (54%) patients were diagnosed with posterior subluxation, 3 (8%) with a single dislocation, and 7 (19%) with multiple dislocations. Symptomatic progression of glenohumeral arthritis was observed in 8% (3) of patients. Pain improved in 46% (17) of patients and worsened in 19% (7). Recurrent instability and progression to osteoarthritis occurred in 15% (3/20) of patients with a traumatic instability event compared with 0% of atraumatic patients after nonoperative management (P = 0.234). Pain at follow-up was more common in nonoperative than operative patients (P = 0.017). CONCLUSIONS Nonoperative management is a viable option for many patients with posterior shoulder instability; however, many may continue to have posterior shoulder pain.

Over the last two decades, levels of childhood overweight and obesity have increased considerably in Malaysia, such that the country now has the highest prevalence of obesity in Asia. The preschool years are a key time for establishing healthy behaviours; hence, there is a need for effective interventions aimed at early childhood. The ToyBox Study is an intervention to prevent obesity in preschoolers that has previously been conducted successfully in six different countries but to date not outside Europe. Therefore, we conducted a feasibility study to determine whether the ToyBox Study methodology could be successfully adapted and applied in Malaysia.The ToyBox Study Malaysia was conducted in 15 kindergartens in Kuala Lumpur and suburbs in Selangor and 7 kindergartens in Sarawak (Borneo), Malaysia. All participating kindergartens were funded by Jabatan Kemajuan Masyarakat (KEMAS), the Community Development Department, Ministry of Rural and Regional Development.The existing ToyBox resources and questionnaires were translated into Bahasa Malaysia and the materials were adapted to suit local culture. Theory of change workshops and focus groups were conducted with parents, caregivers, teachers, cooks and government officers in order to help develop the implementation model. Train-the-trainer and teacher training sessions were organised before the study commenced.The study was a randomised controlled trial that compared the ToyBox Study with kindergarten usual practice, over a period of one year. The ToyBox Study specifically targeted four energy balance related behaviours, namely; eating healthy snacks and meals, making water the preferred drink, increasing physical activity and reducing sedentary behaviour. Food frequency questionnaires were used to assess food intake. Accelerometry was used to measure physical activity. Weight, height and waist circumference were also measured. All measurements were made at baseline and post-intervention. Equipment such as soft mats and drinking water stations were supplied where needed. Parents, caregivers and teachers were provided with relevant materials, newsletters and tip cards and encouraged to participate and act as role models. They also completed project evaluation surveys.If successful, it is envisaged that the ToyBox Study Malaysia will be adopted by other kindergartens in Malaysia, with the intention of helping Malaysian children and their families to achieve healthy energy balance related behaviours that will benefit their health and reduce obesity risk in the long-term.

BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.

Introduction While OA literature indicates greater pain is related to less time being physically active, it is not known if time curtailment occurs primarily for moderate intensity activities or for light activities or in both. We examine the cross-sectional association of knee pain with physical activity using data from 1874 Osteoarthritis Initiative participants. Methods Knee pain characteristics of constant and intermittent pain were each scored by the Intermittent and Constant Osteoarthritis Pain instrument and categorized into four pain levels (no pain, intermittent pain below and above median level, and constant pain). The relationships between knee pain levels and objectively measured physical activity (average weekly moderate or light intensity minutes) were assessed by quantile regression adjusted for socio-demographics and health factors. Results Knee pain levels had a strong negative relationship with moderate intensity physical activities (p-value for trend=0.029). Compared to the no pain group, persons with more severe knee pain, particularly those reporting higher intermittent or constant pain spent less time in moderate activity. In contrast, there was no notable trend related to pain with time spent in light intensity activity. These patterns remained when restricted to persons with clinical evidence (symptoms and/or radiographic) of knee OA and among persons not using medications for knee symptoms. Conclusion Greater knee pain levels were strongly related to less moderate intensity activity time, but not time spent in light intensity physical activity. This relationship suggests that light activity may be a more acceptable way to increase physical activity than moderate activity for people with symptomatic knee pain.

Background Management of shoulder arthritis associated with deltoid paralysis can be very challenging. The purpose of this study was to report the outcome of reverse shoulder arthroplasty with pedicled pectoralis transfer to reconstruct the anterior deltoid in patients with symptomatic shoulder arthritis and a paralyzed deltoid. Methods This study included 31 patients with an average age of 51 years (range, 27-73 years). All patients had chronic deltoid paralysis with significant loss of function due to progressive arthritis associated with rotator cuff deficiency. All patients underwent reverse shoulder arthroplasty with pedicled pectoralis muscle transfer. Additional transfers were performed in patients with no preoperative external rotation: 5 underwent latissimus transfer, and 3 underwent direct lower trapezius transfer to the infraspinatus. Results At an average follow-up of 37 months, 29 patients had significant improvements in pain; the shoulder subjective value; the Disabilities of the Arm, Shoulder and Hand score; and shoulder range of motion, mainly flexion of 83° and external rotation of 15°. Two patients sustained postoperative acromial fractures and had persistent pain after surgery with minimal improvement in shoulder flexion and external rotation. One of them had a failed attempt at open reduction–internal fixation of the acromion. Conclusion Reverse shoulder arthroplasty with pedicled pectoralis transfer is a promising procedure that may lead to improved pain and function in patients with shoulder arthritis associated with deltoid paralysis.

The physical demands of an athlete on the elbow joint can stress the native kinematics of the elbow joint leading to injury, aberrant mechanics, or osteoarthritis. Understanding the athletic demands and pathomechanics are paramount in diagnosing and treating this condition since painful motion and pathologic loss of function can be physically, as well as psychologically, devastating in this population. Accurate diagnosis can be achieved with physical exam and advanced imaging including computed tomography with three-dimensional reconstruction. After failure of conservative treatment, surgical intervention for elbow osteoarthritis in an athletic population includes open and arthroscopic debridement with total elbow arthroplasty as a salvage, activity-ending option. Arthroscopic treatment for arthritis is preferred as this limits soft tissue trauma, which may allow for quicker recovery and decreases associated morbidity. Preoperative planning and systematic arthroscopic technique facilitate understanding of elbow pathology and technical efficacy of elbow arthroscopy. Outcomes of debridement have shown improvements in range of motion, pain relief, and return to sport.

ObjectiveTo assess the risk of subsequent stroke among older patients discharged from an emergency department (ED) without a diagnosis of TIA or stroke.MethodsUsing electronic health record data from a large urban, university hospital and a community-based hospital, we analyzed patients aged 60–89 years discharged to home from the ED without an International Statistical Classification of Diseases and Related Health Problems, 9th or 10th Revision diagnosis of TIA or stroke. Based on the presence/absence of a head CT and the presence/absence of a chief complaint suggestive of TIA or stroke (“symptoms”) during the index ED visit, we created 4 mutually exclusive groups (group 1, reference: head CT no, symptoms no; group 2: head CT no, symptoms yes; group 3: head CT yes, symptoms no; and group 4: head CT yes, symptoms yes). We calculated rates of stroke in the 30, 90, and 365 days after the index visit and used multivariable logistic regression to estimate odds ratios (ORs) for subsequent stroke.ResultsAmong 35,622 patients (mean age 70 years, 59% women, and 16% African American), unadjusted rates of stroke in 365 days were as follows: group 4: 2.5%; group 3: 1.1%; group 2: 0.69%; and group 1: 0.54%. The adjusted OR for stroke was 3.30 (95% confidence interval [CI], 1.61–6.76) in group 4, 1.56 (95% CI, 1.16–2.09) in group 3, and 0.61 (95% CI, 0.22–1.67) in group 2.ConclusionsAmong patients discharged from the ED without a diagnosis of TIA or stroke, the occurrence of a head CT and/or specific neurologic symptoms established a clinically meaningful risk gradient for subsequent stroke.

Background The Walch classification was introduced to classify glenoid morphology in primary glenohumeral osteoarthritis. A modified Walch classification was recently proposed, with 2 additional categories, B3 (monoconcave glenoid with posterior bone loss leading to retroversion > 15° or subluxation > 70%) and D (excessive anterior subluxation), as well as a more precise definition of subtypes A2 and C. The purpose of this study was to evaluate the intraobserver and interobserver agreement of the modified Walch classification system using both plain radiographs and computed tomography (CT). Methods Three fellowship-trained shoulder surgeons blindly and independently evaluated radiographs and CT scans of 100 consecutive shoulders (98 patients) with primary glenohumeral osteoarthritis and classified all shoulders according to the modified Walch classification in 4 separate sessions, each 4 weeks apart. Statistical analysis with the κ coefficient was used to evaluate reliability. Results The first reading by the most senior observer on the basis of CT scans was used as the gold standard (distribution: A1, 18; A2, 12; B1, 20; B2, 25; B3, 22; C, 1; and D, 2). The average intraobserver agreement for radiographs and CT scans was 0.73 (substantial; 0.72, 0.74, and 0.72) and 0.73 (substantial; 0.77, 0.69, and 0.72), respectively. The average interobserver agreement was 0.55 (moderate; 0.61, 0.51, and 0.53) for radiographs and 0.52 (moderate; 0.63, 0.50, and 0.43) for CT scans. Conclusion Intraobserver agreement of the modified Walch classification was substantial both for axillary radiographs and for CT scans. Interobserver agreement was fair. Although the modified Walch classification represents an improvement over the original classification, automated computer-based analysis of CT scans may be needed to further improve the value of this classification.

Background: Standardized systematic approaches to asthma management result in increased adherence to asthma care guidelines and decreased medical service utilization. There is currently a gap between provided care and optimal care for asthma in resident clinics, and education tools such as practice improvement modules which can address this gap are not consistently utilized. Problem: There is significant variation in pediatric asthma management in the outpatient setting. Practice improvement modules aimed at improving resident physician adherence to asthma care guidelines have not yet been studied. Objective: Our objectives were that in a twelve month period, that …

Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+ with older age relative to the wild type (BRAF-/NRAS-) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction < 0.05) but inversely associated with BRAF V600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis.

© 2017 Elsevier Ltd Background Reoperation rates are high after surgery for hip fractures. We investigated the effect of a sliding hip screw versus cancellous screws on the risk of reoperation and other key outcomes. Methods For this international, multicentre, allocation concealed randomised controlled trial, we enrolled patients aged 50 years or older with a low-energy hip fracture requiring fracture fixation from 81 clinical centres in eight countries. Patients were assigned by minimisation with a centralised computer system to receive a single large-diameter screw with a side-plate (sliding hip screw) or the present standard of care, multiple small-diameter cancellous screws. Surgeons and patients were not blinded but the data analyst, while doing the analyses, remained blinded to treatment groups. The primary outcome was hip reoperation within 24 months after initial surgery to promote fracture healing, relieve pain, treat infection, or improve function. Analyses followed the intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT00761813. Findings Between March 3, 2008, and March 31, 2014, we randomly assigned 1108 patients to receive a sliding hip screw (n=557) or cancellous screws (n=551). Reoperations within 24 months did not differ by type of surgical fixation in those included in the primary analysis: 107 (20%) of 542 patients in the sliding hip screw group versus 117 (22%) of 537 patients in the cancellous screws group (hazard ratio [HR] 0·83, 95% CI 0·63–1·09; p=0·18). Avascular necrosis was more common in the sliding hip screw group than in the cancellous screws group (50 patients [9%] vs 28 patients [5%]; HR 1·91, 1·06–3·44; p=0·0319). However, no significant difference was found between the number of medically related adverse events between groups (p=0·82; appendix); these events included pulmonary embolism (two patients [

To the Editor: Intravenous artesunate is recommended by the World Health Organization as first-line treatment for severe malaria. While artemisinin-based therapies are well tolerated, recent studies have reported cases of severe delayed hemolysis after artesunate treatment for malaria (1–5). To date, all reported cases have been associated with the use of artesunate not produced under Good Manufacturing Practice (GMP) standards. The United States and Canada are the only countries that use GMP artesunate, and a recent review concluded that delayed hemolysis may be related to differences in GMP versus non-GMP artemisinins (5). We report a case of severe delayed hemolysis after administration of GMP artesunate to treat a patient with severe malaria. During October 2012, A previously healthy, 31-year-old Canadian-born man sought treatment at a hospital in Toronto, Ontario, Canada, after 3 days of fever and severe headaches. He had returned 10 days earlier from a 10-day work trip to South Sudan. He did not use malaria chemoprophylaxis while there but did sleep under an insecticide-treated net. During initial assessment, a blood smear showed Plasmodium falciparum malaria with parasitemia of 22% (1,100,000 parasites/μL) and the following levels: bilirubin, 88 (reference range 5–17) μmol/L; aminotransferase, 105 (reference range 10–38) U/L; creatinine, 130 (reference range 80–115) μmol/L; hemoglobin, 144 (reference range 140–160) g/L, and a platelet count of 17 × 109/L (reference range 150–450 × 109/L). In the emergency department, he was given 1 dose each of doxycycline, atovaquone/proguanil, and artemether/lumefantrine; within an hour of ingestion of these drugs, he vomited. He was transferred to a tertiary level hospital for admission to the intensive care unit and exchange transfusion. Intravenous artesunate was administered (2.4 mg/kg at 0, 12, 24, and 48 h), then a 3-day course of oral atovaquone/proguanil was ordered. On admission, his chest radiograph showed no abnormalities, and blood cultures were negative; his hemoglobin level was 125 g/L; no treatment was initiated for decreased hemoglobin. Parasitemia was undetectable within 36 hours of admission to the intensive care unit. The patient was discharged 5 days later. Four days after discharge, the patient returned to the tertiary level hospital seeking treatment. He reported that beginning 2 days after discharge, he had fever and “merlot-colored” urine. On admission, he was noted to be jaundiced. Laboratory values included levels of bilirubin of 89 μmol/L, lactate dehydrogenase (LDH) of 1,976 (reference 120–240) U/L, hemoglobin of 81 g/L and marked hemoglobinuria. Multiple thick and thin blood smears were negative for Plasmodium spp. During the course of his second admission, he required 8 blood transfusions to maintain his hemoglobin level above 75 g/L. He continued to have unexplained hemolysis and hemoglobinuria: laboratory results showed a nadir of hemoglobin at 68 g/L and an LDH peak of 3,429 U/L and a low haptoglobin level (

Objective Contradictory reported arthritic patterns of the metacarpal surface of the trapezium include preferential volar wear, radial wear, and dorsal-ulnar sparing. We investigated whether a predominant wear pattern exists in surgical trapeziectomy for advanced thumb carpometacarpal (CMC) arthritis. Methods We examined 36 intact trapezia from 34 thumb CMC arthroplasty patients over an 18-month period. The first metacarpal articular surface revealed three consistent morphology patterns: (1) saddle, (2) dish, and (3) cirque. The saddle represented cartilage loss with preservation of the normal trapezial morphology. The dish shape represented concave curvature, with loss of the normal saddle configuration. The cirque shape represented preferential volar concave wear, disrupting the convex volardorsal arc. Two surgeons classified the randomized specimens twice, blinded to patient identity and each other's categorization. Radiographic Eaton staging was correlated retrospectively for 35 of 36 of the trapezial specimens. Eight specimens were further quantified with micro-computed tomography (micro-CT). Results Thirty-six trapezia were classified as follows: 17 (47%) saddle, 12 (33%) dish, and 7 (19%) cirque. Intra-rater reliability was 0.97 and 0.95; inter-rater reliability in the second round was 0.95. The 36 trapezia represented 27 female (75%) and 9 male (25%) patients; 18 (50%) represented the dominant hand. Age at surgery averaged 64 (33-76). Complete cartilage loss of the entire metacarpal surface was seen in 15 (42%) of all specimens. Osteophyte presence was typically minimal in the saddle group; the dish group had characteristic extensive rimming osteophytes in a 91% female population (11/12), and the cirque group had volar osteophytes. Radiographic severity ranged from Eaton stage II to IV; less severe radiographic staging (Eaton II) predominated in the saddle configuration; advanced Eaton III-IV disease predominated in both cirque and dish shapes. Micro-CT verified the three discrete shapes with volardorsal and radioulnar orientation measurements. Conclusion The metacarpal surface of the trapezium demonstrates three distinct patterns of wear in arthritic surgical specimens. Sex, dominance, age distribution, and Eaton stage varied across the different shapes. Level of Evidence Level 3 Study Type Observational

Purpose In thumb carpometacarpal osteoarthritis, current evidence suggests that degenerative, bony remodeling primarily occurs within the trapezium. Nevertheless, the pathomechanics involved and the most common sites of wear remain controversial. Quantifying structural bone morphology characteristics with high-resolution computed tomography CT (micro-CT) infer regions of load transmission. Using micro-CT, we investigated whether predominant trabecular patterns exist in arthritic versus normal trapeziums. Methods We performed micro-CT analysis on 13 normal cadaveric trapeziums and 16 Eaton stage III to IV trapeziums. We computationally divided each specimen into 4 quadrants: volar-ulnar, volar-radial, dorsal-radial, and dorsal-ulnar. Measurements of trabecular bone morphologic parameters included bone volume ratio, connectivity, trabecular number, and trabecular thickness. Using analysis of variance with post hoc Bonferroni/Dunn correction, we compared osteoarthritic and normal specimen quadrant measurements. Results No significant difference existed in bone volume fraction between the osteoarthritic and normal specimens. Osteoarthritic trapeziums, however, demonstrated significantly higher trabecular number and connectivity than nonosteoarthritic trapeziums. Comparing the volar-ulnar quadrant of osteoarthritis and normal specimens collectively, this quadrant in both consistently possessed significantly higher bone volume fraction, trabecular number, and connectivity than the dorsal-radial and volar-radial quadrants. Conclusions The significantly greater trabecular bone volume, thickness, and connectivity in the volar-ulnar quadrant compared with the dorsal-radial and dorsal-ulnar quadrants provides evidence that the greatest compressive loads at the first carpometacarpal joint occur at the volar-ulnar quadrant of the trapezium, representing a consistently affected region of wear in both normal and arthritic states. Clinical relevance These findings suggest that trapezial trabecular morphology undergoes pathologic alteration. This provides indirect evidence that changes in load transmission occur with thumb carpometacarpal joint arthritis development.

There is variation in pediatric asthma management in the outpatient setting. Adherence to national asthma guidelines provides a systematic standardized approach to asthma management. There is a gap between usual and guideline-consistent asthma care in resident clinics. Practice improvement modules aimed at improving resident physician adherence to asthma care guidelines have not been consistently utilized and have not yet been studied. Our aim was to increase guideline consistent care in our pediatric resident clinic in a twelve-month period via increasing performance on the following measures to 75%: spirometry testing; influenza immunization recommendation; level of control assessed through the use of a standardized questionnaire; appropriate medications per national guideline; and use of written asthma action plans. A summarized pediatric-specific version of the National Heart Lung and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3 (NHLBI EPR-3) guidelines was made readily available to increase provider education. Electronic health record (EHR) enhancements included adding templates to create standardized asthma action plan, asthma control test and a pediatric asthma controller medication order-set. We also addressed the education of patients by simplifying patient instructions. We monitored our progress through the use of an online practice improvement module. We found statistically significant increases in use of a standardized instrument to determine level of control (20% to 81%); recommendation of influenza immunization (56% to 97%); use of national medication treatment guidelines (28% to 98%); distribution of asthma action plans (29% to 65%); and provision of asthma self-management education (35% to 74%). Standardizing the implementation of national guidelines for pediatric asthma through the use of a practice improvement module and electronic health records improved adherence to guidelines. The module allowed us to identify goals for improvement, collect and analyze our group performance data over time, assess the impact of each change, and redesign our process. Improving adherence to national pediatric asthma care guidelines is especially important in settings such as resident teaching clinics which provide care to underserved populations at higher risk for complications related to asthma.

Ligament innervation purportedly plays a critical role in stability, proprioception and pathology of joints with minimal bony constraints. The human thumb carpometacarpal (CMC) joint is such a joint: with a complex saddle configuration and wide circumduction, its constraint is primarily ligamentous and it is prone to osteoarthritis. CMC reconstruction is the most commonly performed arthritis surgery in the upper extremity. Little, however, is known about CMC ligament innervation. We describe a novel triple-staining immunofluorescence technique using the markers for low-affinity neurotrophin receptor p75, the pan-neuronal marker protein gene product (PGP) 9.5 and 4′,6′-diamidino-2-phenylindole (DAPI) to simultaneously detect and differentiate between specific sensory nerve endings: the Pacini corpuscles, the Ruffini endings and nerve fascicles. Five primary CMC ligaments (dorsal radial, dorsal central, posterior oblique, anterior oblique and ulnar collateral ligaments) were harvested from 10 fresh-frozen human cadaver hands. Following paraffin sectioning, each ligament was stained using a triple-stain technique and imaged with fluorescence microscopy. Multidimensional acquisition permitted simultaneous capture of images at different wavelengths. Pacini corpuscles were distinguished by their distinct p75 immunoreactive capsules, and Ruffini endings by their overlapping p75 and PGP9.5 immunoreactive dendritic nerve endings. Simultaneous use of PGP9.5, p75 and DAPI immunofluorescence to analyze innervation patterns in human ligaments provides descriptive analysis of staining patterns and receptor structure as well as clues as to the proprioceptive function of CMC ligaments and the joint as a whole. Our novel findings of CMC ligament innervation augment the study of normal and pathological joint mechanics in this joint so prone to osteoarthritis.

There is little information published comparing peripheral blood stem cells (PBSC) with bone marrow (BM) as the stem cell source in the long-term outcome in recipients of T-cell depleted (TCD) unrelated donor (UD) transplants. We present retrospective outcome data on 306 recipients of myeloablative, human leucocyte antigen-matched UD allografts using pre-transplant in-vivo Alemtuzumab. Transplants were performed between 2000 and 2007 for chronic myeloid leukaemia in first chronic phase and acute leukaemia in first or second complete remission; 184 patients received BM and 122 PBSC. The median age was 28·9 years (

Reduced-intensity allogeneic stem cell transplantation (RIC-AlloSCT) is being increasingly considered for patients with aggressive lymphoma, but limited evidence exists in mantle cell lymphoma (MCL). We report a retrospective study of transplant outcomes of RIC-AlloSCT for MCL in 70 patients (median age, 48 years, range: 30-67 years), with 57 patients receiving an Alemtuzumab-containing regimen. Thirty-four percent of patients had received a prior autologous stem cell transplant. The 1- and 5-year nonrelapse mortality (NRM) was 18% (95% confidence interval [CI] 10-27) and 21% (95% CI 12-31), respectively. The incidence of severe (grade III and IV) acute graft-versus-host disease (aGVHD) was 10%, and the 5-year incidence of chronic GVHD (cGVHD) was 61%. The cumulative relapse risk was 65% (95% CI 48-77) at 5 years, significantly affected by disease status at transplant (P = .0495), specifically the presence of chemosensitive disease (P = .0364). Fifteen of 18 relapsed patients received donor lymphocyte infustion (DLI) (n = 14) or a second RIC-AlloSCT (n = 1), with 11 of 15 currently in CR. The 5-year overall survival (OS) and progression-free survival (PFS) were 37% (95% CI 25%-56%) and 14% (95% CI 6%-34%), respectively. Age at transplantation and having

Objectives: Diagnosis of and treatment for posterior shoulder instability (PSI) has improved with advances in surgical technique and radiographic imaging. It is unknown if PSI, or surgical measures to correct PSI, affect the progression of osteoarthritis in the glenohumeral joint. The purpose of this study is to evaluate the effect of posterior capsulolabral reconstruction (PCLR) and demographic risk factors on the rate of radiographic progression of osteoarthritis in shoulders with PSI. Methods: The study population included 115 patients (14 females, 101 males) diagnosed with PSI between January 1994 and July 2012 with an average follow up of 12.5years (range 5-23). Medical records were reviewed to evaluate patient demographics, surgical intervention, and radiographic progression of osteoarthritis. Kaplan Meier survival was used to estimate survival and Cox models were used to examine associations with osteoarthritis progression. Results: Overall, 16/115 (14%) patients had radiographic progression of glenohumeral arthritis with 5-year survival at 88.3% (95% CI 79.7%-97.3%). Age ≥30 at the time of instability was associated with arthritis progression (p0.05). PCLR with at least one anchor along the posterior glenoid rim was performed in 56/115 (48%) of patients. There was no difference in the rate of radiographic arthritic progression in those who underwent PCLR and those who did not (7/56, 13% vs 10/59, 17%, p>0.05). One male patient who underwent PCLR progressed to end-stage arthritis, necessitating a shoulder arthroplasty at age 53. Conclusion: Radiographic progression of glenohumeral arthritis occurred 14% of patients with PSI. Age ≥30 at the time of initial instability was associated with radiographic progression of glenohumeral arthritis.

Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention. (Cancer Epidemiol Biomarkers Prev 2007;16(5):991–7)

Objective To examine the outcomes of home-based robot-guided therapy and compare it to laboratory-based robot-guided therapy for the treatment of impaired ankles in children with cerebral palsy. Design A randomized comparative trial design comparing a home-based training group and a laboratory-based training group. Setting Home versus laboratory within a research hospital. Participants Children (N=41) with cerebral palsy who were at Gross Motor Function Classification System level I, II, or III were randomly assigned to 2 groups. Children in home-based and laboratory-based groups were 8.7±2.8 (n=23) and 10.7±6.0 (n=18) years old, respectively. Interventions Six-week combined passive stretching and active movement intervention of impaired ankle in a laboratory or home environment using a portable rehabilitation robot. Main Outcome Measures Active dorsiflexion range of motion (as the primary outcome), mobility (6-minute walk test and timed Up and Go test), balance (Pediatric Balance Scale), Selective Motor Control Assessment of the Lower Extremity, Modified Ashworth Scale (MAS) for spasticity, passive range of motion (PROM), strength, and joint stiffness. Results Significant improvements were found for the home-based group in all biomechanical outcome measures except for PROM and all clinical outcome measures except the MAS. The laboratory-based group also showed significant improvements in all the biomechanical outcome measures and all clinical outcome measures except the MAS. There were no significant differences in the outcome measures between the 2 groups. Conclusions These findings suggest that the translation of repetitive, goal-directed, biofeedback training through motivating games from the laboratory to the home environment is feasible. The benefits of home-based robot-guided therapy were similar to those of laboratory-based robot-guided therapy.

Purpose Primary chemoradiotherapy in patients with advanced laryngeal cancer can achieve high rates of organ preservation without sacrificing survival compared with radiation alone or conventional laryngectomy. Appropriate selection of patients for organ preservation approaches could enhance overall treatment outcome and quality of life. We conducted a phase II organ preservation trial for patients with stage III and IV larynx cancer to determine whether late salvage surgery rates could be decreased and survival improved by selecting patients for organ preservation based on response to a single cycle of induction chemotherapy. Patients and Methods The chemotherapy was cisplatin 100 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d for 5 days. Patients who achieved less than 50% response had immediate laryngectomy. Patients who achieved more than 50% response went on to concurrent chemoradiotherapy. Histologic complete responders after chemoradiotherapy received two more cycles of chemotherapy. Patients with residual disease after chemoradiotherapy had planned salvage surgery. Results Of 97 eligible patients, 73 (75%) achieved more than 50% response and received chemoradiotherapy. A total of 29 patients (30%) had salvage surgery; 19 patients (20%) had early salvage surgery after the single cycle of induction chemotherapy, three patients (3%) had late salvage surgery after chemoradiotherapy, six patients (6%) eventually had salvage surgery for recurrence, and one patient had laryngectomy for chondroradionecrosis. The median follow-up time was 41.9 months. The overall survival rate at 3 years is 85%. The cause-specific survival rate was 87%. Larynx preservation was achieved in 69 patients (70%). Conclusion These results confirm excellent larynx preservation and improved overall survival rates compared with historical results.

Introduction: Organ-preservation treatment approaches for advanced laryngeal cancer patients that use combination chemoradiotherapy result in cure rates similar to primary laryngectomy with postoperative radiotherapy. In the national VA Larynx Cancer Trial, successful organ preservation was associated with an overall improvement in quality of life but not in subjective speech compared with long-term laryngectomy survivors. As part of a Phase II clinical trial, a prospective study of speech and swallowing results was conducted to determine if larynx preservation is associated with improved voice and swallowing compared with results in patients who require salvage laryngectomy. Subjects: A total of 97 patients with advanced laryngeal cancer (46 Stage III, 51 Stage IV) were given a single course of induction chemotherapy (cisplatin 100 mg/m 2 on Day 1 and 5-FU 1,000 mg/m 2 /day × 5 days), followed by assessment of response. Patients with less than 50% response underwent early salvage laryngectomy, and patients with 50% or better response underwent concurrent chemoradiation (72 Gy and cisplatin 100 mg/m 2 on Days 1, 22, and 43), followed by two cycles of adjuvant chemotherapy (DDP/5-FU). Direct laryngoscopy and biopsy were performed 8 weeks after radiation therapy to determine final tumor response. Late salvage surgery was performed on patients with persistent or recurrent disease. Methods: Completed survey data on voice and swallowing utilizing the Voice-Related Quality of Life Measure (V-RQOL) and the List Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) were obtained from 56 patients who were alive and free of disease at the time of survey, with a minimum follow-up of 8 months. Comparisons were made between patients with an intact larynx ( n = 37) vs. laryngectomy ( n = 19), as well as early ( n = 12) vs. late salvage laryngectomy ( n = 7). Multivariate analysis was performed to determine factors predictive of voice and swallowing outcomes. Overall 3-year determinant survival was 87%, with median follow-up of 40 months. Results: Patients with an intact larynx demonstrated significantly higher ( p = 0.02) mean V-RQOL scores (80.3) than did laryngectomy patients (65.4). This finding was consistent in the social-emotional ( p = 0.007) and physical functioning domains ( p = 0.03). No differences in V-RQOL scores were found in comparisons between early and late salvage laryngectomy. Multiple linear regression revealed that predictors of higher total V-RQOL scores include lower T stage ( p = 0.03), organ preservation ( p = 0.0007), and longer duration since treatment ( p = 0.01). Understandability of speech was better in patients with an intact larynx ( p = 0.001). Overall swallowing function was comparable between groups. Multiple logistic regression revealed that longer duration since treatment ( p = 0.03, odds ratio=1.1) and lower maximal mucositis grade ( p = 0.03, odds ratio=0.3) were predictive of higher likelihood of eating in public. Nutritional mode consisting of oral intake alone without nutritional supplements was achieved in 88.9% of patients with an intact larynx compared with 64.3% of laryngectomees ( p = 0.09). Conclusions: Voice-related quality of life is better in patients after chemoradiation therapy compared with salvage laryngectomy. Earlier salvage, although known to be associated with fewer surgical complications, did not result in improved voice; however, the number of patients analyzed is small. Overall swallowing function is good in all patients; however, patients with an intact larynx are more likely to obtain nutrition with oral intake alone without supplements. Such measures of function and quality of life are important endpoints to help judge overall effectiveness as newer, more aggressive treatment protocols with added toxicities are developed and evaluated.

BACKGROUND The survival of patients with head and neck squamous cell carcinoma (HNSCC) remains unaffected despite recent therapeutic advances. To reverse this trend, reliable and clinically applicable markers of tumor aggressiveness must be identified. One such marker may be the tumor-associated macrophage content. The authors hypothesized that tumor-associated macrophages contribute to HNSCC aggressiveness, and the objective of the current study was to prove this hypothesis using mRNA expression analysis and a large cohort of clinical specimens. METHODS Oligonucleotide microarray analysis was performed on a prospective cohort of 20 patients with previously untreated oral cavity or oropharynx squamous cell carcinoma (OC/OP SCCA) and on normal oropharyngeal mucosa from 4 patients. After determining whether macrophage chemoattractants were produced by tumors, conditioned media from three HNSCC cell lines were used to quantify macrophage migration in an in vitro assay. A high-density tissue microarray of 102 patients with previously untreated OC/OP SCCA was stained immunohistochemically for CD68 to identify tissue macrophages, and the results were correlated with clinicopathologic data and survival. RESULTS Monocyte chemoattractant protein 1 was up-regulated significantly in tumors compared with normal mucosa (P = 0.0025; fold change = 1.89). All University of Michigan SCC tumor cell line conditioned media caused a significant increase in macrophage migration (P < 0.05). Tissue microarray data revealed that macrophage content of the primary tumor was associated strongly with lymph node metastasis (P < 0.0001), extracapsular lymph node spread (P = 0.0001), and advanced clinical disease stage (P = 0.0002). When it was evaluated along with other clinicopathologic data, the macrophage content was found to be an independent predictor of lymph node metastasis (P < 0.0001). CONCLUSIONS Primary tumor macrophage content is a strong predictor of tumor aggressiveness in HNSCC. Cancer 2004. © 2004 American Cancer Society.

Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O(2) for 14 days, a model for human chronic neonatal lung injury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A(2) receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A(2) receptor contributed to O(2)-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A(2) receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O(2) or air exposure. L670596, but not DFU, prevented 60% O(2)-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O(2)-exposed animals. We conclude that TX A(2) receptor activation, though not by TX A(2), caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A(2) receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.

High-dose therapy and autologous stem cell transplantation (ASCT) have proven efficacy in patients with multiple myeloma responding well to induction therapy. For those who fail to achieve a stable partial response (PR), the effect of ASCT is unclear. We report on 126 patients identified from a national database, who underwent ASCT having achieved

Background: We previously reported a significant association between higher UV radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure before diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information. Methods: We conducted a multicenter, international population-based study in four countries—Australia, Italy, Canada, and the United States—with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient ultraviolet B (280–320 nm) dose, histologic solar elastosis, and season of diagnosis. Results: Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in 1 year within 10 years of diagnosis was inversely associated with survival; solar elastosis—a measure of lifetime cumulative exposure—was not. In addition, none of the intermittent exposure measures—water-related activities and sunny holidays—were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival. Conclusion: Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure before diagnosis is associated with greater melanoma-specific survival. Impact: This study adds to the evidence that sun exposure before melanoma diagnosis has little effect on survival with melanoma. Cancer Epidemiol Biomarkers Prev; 23(10); 2145–52. ©2014 AACR.

Summary: Purpose: The older antiepileptic drugs (AEDs) have a variety of effects on sleep, including marked reduction in REM, slow-wave sleep (SWS) and sleep latency, and increased percentage of light sleep. The effects of the newer AEDs on sleep are unknown. Our purpose was to study the effect of lamotrigine (LTG) on sleep. Methods: Ten adults with focal epilepsy, in whom the decision was made to add LTG to either phenytoin (PHT) or carbamazepine (CBZ) for control of seizures, were the subjects of this study. Patients underwent pre- and posttreatment polysomnography (PSG) and completed sleep questionnaires. Polygraphic variables and Epworth Sleepiness Scale (ESS) scores, a subjective measure of sleep propensity, were compared by using the Wilcoxon sign rank test. Results: Seven patients were taking CBZ, and three were treated with PHT. All subjects were titrated to an LTG dose of 400 mg/day. Treatment with LTG produced a significant decrease in SWS and an increase in stage 2 sleep percentage. No significant difference in ESS or any of the other polygraphic variables was observed. However, LTG treatment was associated with a reduction in arousals and stage shifts and an increase in REM periods. No subjects reported insomnia with treatment. Conclusions: LTG appears to be less disruptive to sleep than some of the older AEDs.

Measles remains a significant global health problem. Despite the decline in measles prevalence in Australia following the implementation of a national vaccination program, challenges surrounding this disease remain. This report describes a 22-year-old woman who presented with coordination loss, tremor, choreiform movements and marked visual blurring, and her condition rapidly deteriorated to coma and death. Antemortem investigations did not yield a unifying diagnosis. Postmortem examination provided a diagnosis of subacute sclerosing panencephalitis. This patient had a rare neurological complication of measles infection, and her condition is remarkable for the atypical clinical presentation.

Purpose The human thumb trapeziometacarpal (TM) joint is a unique articulation that allows stability during pinch and grip and great degrees of mobility. Because the saddle-shaped articulating surfaces of the TM joint are inherently unstable, joint congruity depends on the action of restraining ligaments and periarticular muscles. From other joints, it is known that proprioceptive and neuromuscular joint stability depend on afferent information from nerve endings within ligaments. We hypothesize that the TM joint ligaments may similarly be innervated, indicating a possible proprioceptive function of the joint. Methods We harvested 5 TM joint ligaments in entirety from 10 fresh-frozen cadaver hands with no or only minor signs of osteoarthritis and suture-marked them for proximal-distal orientation. The ligaments harvested were the dorsal radial, dorsal central, posterior oblique, ulnar collateral, and anterior oblique ligaments. After paraffin-sectioning, we stained the ligaments using a triple-antibody immunofluorescent technique and analyzed them using immunofluorescence microscopy. Results Using the triple-stain technique, mechanoreceptors could be classified as Pacinian corpuscles, Ruffini endings, or Golgi-like endings. The 3 dorsal ligaments had significantly more nerve endings than the 2 volar ligaments. Most of the nerve endings were close to the bony attachments and significantly closer ( P = .010) to the metacarpal insertion of each ligament. The anterior oblique ligament had little to no innervation in any of the specimens analyzed. Discussion The TM joint ligaments had an abundance of nerve endings in the dorsal ligaments but little to no innervation in the anterior oblique ligament. The Ruffini ending was the predominant mechanoreceptor type, with a greater density in the mobile metacarpal portion of each ligament. Clinical relevance Presence of mechanoreceptors in the dorsal TM joint ligaments infers a proprioceptive function of these ligaments in addition to their biomechanical importance in TM joint stability.

Autologous stem cell transplant as primary (first ASCT) therapy in multiple myeloma (MM) is standard practice. The role of a second ASCT as management of relapsed disease remains uncertain. We conducted a retrospective case-matched control analysis on patients (n = 106) who underwent a second ASCT compared with conventional chemotherapy (CCT) as for relapsed MM. The median age was 53 years (range: 26-75) and median follow-up 48 months (range: 8, 136). The cumulative incidence of 1 and 5 years nonrelapse mortality (NRM) was 7% (95% confidence interval [CI] 3%-13%) and 12% (95% CI 7%-19%), with a second ASCT inducing a greater partial remission (PR) rate of 63%. The 4-year overall survival (OS) rate was 33% (95% CI 24%-45%). Factors associated with improved OS and progression-free survival (PFS) included younger age (9 months from first ASCT, and a greater PR in response to their first ASCT. In a matched-cohort analysis with patients receiving conventional chemotherapy (CCT), the same factors were associated with improved OS, with the exception of a longer remission duration (>18 months) from first ASCT. Second ASCT in relapsed MM is associated with superior OS and PFS compared with CCT, offering a potential consolidative option for selected patients.

Auto-SCT is the standard first-line consolidative therapy in patients with multiple myeloma (MM). We performed a national benchmarking outcome analysis for patients with MM who underwent a single auto-SCT in 1999 and 2005. They were identified from the British Society of Blood and Marrow Transplantation (BSBMT) (n=211 and n=453) and EBMT (n=1311 and n=1978) registries. An improvement in Day+100 and D+365 non-relapsed mortality (NRM) was shown between years 1999 and 2005 (P=0.0495). The 4-year relapse rate (RR) was significantly higher in 2005 (P=0.0003) and was associated with a shorter time to next treatment (TTNT) (P=0.025). The 4-year PFS was significantly lower in 2005 (P=0.0012), with the year of auto-SCT (P=0.001) and status at auto-SCT (P=0.02) being independently significant. The 4-year OS was similar between the year cohorts (P=0.266). In the 'benchmarking' comparison, the European Group for Blood and Marrow Transplantation (EBMT) 1999 cohort demonstrated the best PFS, although no year-of-transplant effect could be demonstrated on the 4-year OS rates (P=0.760). An improvement in supportive care resulting in reduced NRM is evident between the decades. The main cause of treatment failure remains disease progression. The similarity in OS between the years may reflect the introduction of novel agents in salvage therapy. The reduced PFS in 2005 is as yet not fully explained, but may represent recent disease response criterion standardization.

Background: Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one. Methods: We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed. Results: Only the BsmI variant was associated with multiple primary melanoma (OR = 1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high. Conclusion: These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR. © 2011 Elsevier Ltd. Fil: Mandelcorn Monson, Rochelle. University of Toronto; Canadá Fil: Marrett, Loraine. Cancer Care Ontario; Canadá Fil: Kricker, Anne. The University Of Sydney; Australia Fil: Armstrong, Bruce K.. The University Of Sydney; Australia Fil: Orlow, Irene. Memorial Sloan-kettering Cancer Center; Estados Unidos Fil: Goumas, Chris. The University Of Sydney; Australia Fil: Paine, Susan. University Of New Mexico Cancer Center; Estados Unidos Fil: Rosso, Stefano. Piedmont Tumor Registry; Italia Fil: Thomas, Nancy. Unc Health Care; Estados Unidos Fil: Millikan, Robert C.. Unc Health Care; Estados Unidos Fil: Pole, Jason D.. University of Toronto; Canadá Fil: Cotignola, Javier Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Memorial Sloan-kettering Cancer Center; Estados Unidos Fil: Rosen, Cheryl. University of Toronto; Canadá Fil: Kanetsky, Peter A.. The Pennsylvania State University; Estados Unidos Fil: Lee Taylor, Julia. The Earth And Sun Systems Laboratory; Estados Unidos Fil: Begg, Colin B.. Memorial Sloan-kettering Cancer Center; Estados Unidos Fil: Berwick, Marianne. University Of New Mexico Cancer Center; Estados Unidos

Background: Solar elastosis adjacent to melanomas in histologic sections is regarded as an indicator of sun exposure, although the associations of UV exposure and phenotype with solar elastosis are yet to be fully explored. Methods: The study included 2,589 incident primary melanoma patients with assessment of histologic solar elastosis in the population-based Genes, Environment, and Melanoma study. Ambient erythemal UV (UVE) at places of residence and sun exposure hours, including body site-specific exposure, were collected. We examined the association of cumulative site-specific and non-site-specific sun exposure hours and ambient UVE with solar elastosis in multivariable models adjusted for age, sex, center, pigmentary characteristics, nevi, and, where relevant, body site. Results: Solar elastosis was associated most strongly with site-specific UVE [odds ratio (OR) for top exposure quartile, 5.20; 95% confidence interval (95% CI), 3.40-7.96; P for trend 70 years, 7.69; 95% CI, 5.14-11.52; P for trend < 0.001) and having more than 10 back nevi (OR, 0.77; 95% CI, 0.61-0.97; P = 0.03) were independently associated with solar elastosis. Conclusion: Solar elastosis had a strong association with higher site-specific UVE dose, older age, and fewer nevi. Impact: Solar elastosis could be a useful biomarker of lifetime site-specific UV. Future research is needed to explore whether age represents more than simple accumulation of sun exposure and to determine why people with more nevi may be less prone to solar elastosis. Fil: Thomas, Nancy E.. Fil: Kricker, Anne. Fil: From, Lynn. Fil: Busam, Klaus. Fil: Millikan, Robert C.. Fil: Ritchey, Mary E.. Fil: Armstrong, Bruce K.. Fil: Lee-Taylor, Julia. Fil: Marrett, Loraine D.. Fil: Anton-Culver, Hoda. Fil: Zanetti, Roberto. Fil: Rosso, Stefano. Fil: Gallagher, Richard P.. Fil: Dwyer, Terence. Fil: Goumas, Chris. Fil: Kanetsky, Peter A.. Fil: Begg, Colin B.. Fil: Orlow, Irene. Fil: Wilcox, Homer. Fil: Paine, Susan. Fil: Berwick, Marianne. Fil: Mujumdar, Urvi. Fil: Hummer, Amanda J.. Fil: Mitra, Nandita. Fil: Roy, Pampa. Fil: Canchola, Rebecca. Fil: Clas, Brian. Fil: Cotignola, Javier Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Monroe, Yvette. Fil: Litchfield, Melisa. Fil: Tucker, Paul. Fil: Stephens, Nicola. Fil: Switzer, Teresa. Fil: Theis, Elizabeth. Fil: Chowdhury, Noori. Fil: Vanasse, Louise. Fil: Purdue, Mark. Fil: Northrup, David. Fil: Sacerdote, Carlotta. Fil: Leighton, Nancy. Fil: Gildea, Maureen. Fil: Gruber, Stephen B.. Fil: Bonner, Joe. Fil: Jeter, Joanne. Fil: Klotz, Judith. Fil: Weiss, Helen. Fil: Mattingly, Dianne. Fil: Player, Jon. Fil: Tse, Chiu-Kit. Fil: Rebbeck, Timothy R.. Fil: Kanetsky, Peter. Fil: Walker, Amy. Fil: Panossian, Saarene. Fil: Mohrenweiser, Harvey. Fil: Setlow, Richard. Fil: Taylor, Julia Lee. Fil: Madronich, Sasha.

The biology of the normal colonic mucosa suggests that colon cancer originates from normal colon stem cells. CD44 cancer stem cells have been identified in breast and prostate cancer, and we therefore examined whether CD44 similarly identified colon cancer stem cells. Initial assays found CD44(hi) colon tumor cells to have enhanced soft agar colony-forming ability. Subsequently, CD44(hi) cells isolated from 4 primary colon adenocarcinoma xenografts were found to be highly tumorigenic in immune deficient mice. CD44(hi) cells consistently formed tumors with 1,000 cells, and in multiple experiments, as few as 10 and 100 CD44(hi) cells formed tumors in 7/10 and 21/28 mice, respectively. In contrast, CD44(-) colon tumor cells were either nontumorigenic or 10-50-fold less tumorigenic. CD44(hi) cells could be serially passaged up to 4 times in vivo, suggesting self-renewal capacity, and formed tumors that recapitulated the heterogeneity of the original patient tumor. CD44(hi) cells were significantly enriched for nuclear activated beta-catenin, a key element in normal stem/progenitor cells and in early colon tumor progression. Bromodeoxyuridine (BrdU) labeling studies indicated that CD44(hi) cells divide slowly relative to the CD44(-) cells, suggesting their tumorigenicity is not simply due to faster proliferation. Aldehyde dehydrogenase (ALDH) sort further increased the tumorigenicity of CD44(hi) cells from 2/2 patient tumors, but CD133 tumor cells in our hands did not have increased tumorigenicity. Our observations indicate that CD44 is a marker of stem-like cells in colon cancer, and support the use of additional markers to further purify colon cancer stem cells.

Purpose: Cisplatin resistance remains a barrier to organ-sparing and survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). Targeted therapies to overcome cisplatin-resistant HNSCC are being developed. Methods and Materials: Cisplatin-sensitive parental HNSCC cell lines and cisplatin-resistant progeny were studied. Pretreatment HNSCC biopsies were used to construct tissue microarrays which were stained for p53 and Bcl-xL. Results: HNSCC cell lines selected for cisplatin resistance had wild-type p53 and high levels of Bcl-xL. Expression of wild-type p53 in cell lines with low Bcl-xL enhanced cisplatin sensitivity. Expression of both Bcl-xL and wild-type p53 caused tumor cells to become cisplatin resistant. Patients whose tumors expressed low levels of p53 and Bcl-xL enjoyed the best organ preservation and disease-free survival whereas patients whose tumors expressed low levels of p53 and high levels of Bcl-xL had the worst outcome. Novel agents that inhibit Bcl-xL or activate p53 function may target cisplatin-resistant HNSCC. Conclusion: Cisplatin resistance in HNSCC is mediated, at least in part, by high Bcl-xL and functional p53.

[1] We present new modeled estimates of global methyl halide emissions from rice cultivation. We extrapolate existing data on rice behavior, including temperature, seasonality and soil moisture effects, to the global scale and on a monthly basis. Our best estimates are 2.4 to 4.9 Gg yr−1 for methyl chloride, 0.5 to 0.9 Gg yr−1 for methyl bromide, and 16 to 29 Gg yr−1 for methyl iodide, with additional uncertainty ranges of ±73%, ±87% and ±75%, respectively. Our central range of estimates reflects the greatest remaining model uncertainty, emission response to soil halide concentrations. We find that peak emissions of methyl halides, especially methyl iodide, are sharply defined in regional and temporal extent. Ambient temperature strongly influences rice emissions of methyl bromide and methyl iodide, which rise by ∼10% for an increase of 1°C.

Summary: Purpose: Catamenial epilepsy is a condition characterized by an increase in seizures during particular phases of the menstrual cycle. The incidence of catamenial epilepsy varies widely, partly because of a lack of a universally adopted definition. Specific treatment options for these patients are limited. The use of acetazolamide (AZ) has been based largely on anecdotal reports demonstrating efficacy in small or poorly characterized populations. The purpose of this study was to analyze retrospectively the efficacy, safety profile, and tolerability of AZ in women with catamenial epilepsy. Methods: Women with catamenial epilepsy identified from 1990 through 1999 were invited to participate in a retrospective telephone questionnaire addressing the relationship of seizures and the menstrual cycle and the use, efficacy, and adverse effects of AZ. Seizure outcome was classified as: seizure free (SF), significantly improved (SI), or not significantly improved (NSI). Responses to AZ were compared in women with different types of epilepsy and comparing continuous versus intermittent dosing using Fisher’s exact tests. Results: Twenty women were identified who had received or were currently taking AZ. The drug was given continuously in 55% and intermittently in 45% of patients. A $50% decrease in the seizure frequency was reported by 40% of subjects. Response rates were similar in generalized and focal epilepsy and in temporal and extratemporal epilepsy. There was no significant difference in effectiveness comparing continuous with intermittent dosing. A loss of efficacy over 6‐24 months was reported by 15% of women. Conclusions: Despite our small sample and retrospective design, AZ appears to demonstrate efficacy for catamenial epilepsy. Key Words: Catamenial epilepsy—Acetazolamide— Diamox—Focal epilepsy.

The p53 tumor suppressor gene is mutated in up to 70% of pancreatic adenocarcinomas. We determined the effect of reintroduction of the wild-type p53 gene on proliferation and apoptosis in human pancreatic cancer cells using an adenoviral vector containing the wild-type p53 tumor suppressor gene.Transduction efficiencies of six p53-mutant pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, CFPAC-1, MIA PaCa-2, and PANC-1) were determined using the reporter gene construct Ad5/CMV/beta-gal. Cell proliferation was monitored using a 3H-thymidine incorporation assay, Western blot analysis for p53 expression was performed, and DNA laddering and fluorescence-activated cell sorter analysis were used to assess apoptosis. p53 gene therapy was tested in vivo in a subcutaneous tumor model.The cell lines varied in transduction efficiency. The MIA PaCa-2 cells had the highest transduction efficiency, with 65% of pancreatic tumor cells staining positive for beta-galactosidase (beta-gal) at a multiplicity of infection (MOI) of 50. At the same MOI, only 15% of the CFPAC-1 cells expressed the beta-gal gene. Adenovirus-mediated p53 gene transfer suppressed growth of all human pancreatic cancer cell lines in a dose-dependent manner. Western blot analysis confirmed the presence of the p53 protein product at 48 hours after infection. DNA ladders demonstrated increased chromatin degradation, and fluorescence-activated cell sorter analysis demonstrated a four-fold increase in apoptotic cells at 48 and 72 hours following infection with Ad5/CMV/p53 in the MIA PaCa-2 and PANC-1 cells. Suppression of tumor growth mediated by induction of apoptosis was observed in vivo in an established nude mouse subcutaneous tumor model following intratumoral injections of Ad5/CMV/p53.Introduction of the wild-type p53 gene using an adenoviral vector in pancreatic cancer with p53 mutations induces apoptosis and inhibits cell growth. These data provide preliminary support for adenoviral mediated p53 tumor suppressor gene therapy of human pancreatic cancer.