Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Association between changes in knee load and effusion-synovitis: evidence of mechano-inflammation in knee osteoarthritis using high tibial osteotomy as a model.

OBJECTIVE: Although mechanically-induced inflammation is an appealing explanation linking different etiologic factors in osteoarthritis (OA), clinical research investigating changes in both biomechanics and joint inflammation is limited. The purpose of this study was to evaluate the association between change in surrogate measures of knee load and knee effusion-synovitis in patients with medial compartment knee OA undergoing high tibial osteotomy (HTO). METHODS: Thirty-six patients with medial compartment knee OA and varus alignment underwent 3D gait analysis and 3T magnetic resonance imaging (MRI) preoperatively and 1 year after medial opening wedge HTO. Primary outcome measures were the change in the external knee adduction moment impulse during walking and change in knee suprapatellar effusion-synovitis volume manually segmented on MRI by one blinded assessor. RESULTS: Mean (SD) knee adduction moment impulse [24.0 (6.5) Nm•s] and knee effusion-synovitis volume [8976.7 (8016.9) mm3] suggested substantial preoperative medial knee load and inflammation. 1-year postoperative changes in knee adduction moment impulse [-10.1 Nm•s (95%CI: -12.7, -7.4)], and knee effusion-synovitis volume [-1856 mm3 (95%CI: -3830, 117)] were positively correlated [r = 0.60 (95% CI 0.34, 0.78)]. Simple linear regression suggested a 448 mm3 (95%CI: 241, 656) reduction in knee effusion-synovitis volume per 1 Nm•s reduction in knee adduction moment impulse. Change in knee adduction moment impulse explained 36% (R2 = 0.36) of the variance of change in knee effusion-synovitis volume. CONCLUSIONS: Reduction in medial knee load is positively associated with reduction in knee inflammation after HTO, suggesting the phenomenon of mechano-inflammation in patients with knee OA.

Early or delayed anterior cruciate ligament reconstruction: Is one superior? A systematic review and meta-analysis.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is a rapidly developing orthopaedic field and an area of notable clinical equipoise. The optimal timing of surgery in an acute (< 3 weeks) or delayed (≥ 3 weeks) time frame remains unresolved with a 2010 meta-analysis concluding no difference between these two groups across multiple outcomes. In an era of evidence-based medicine, surgeons are still basing their decisions on when to operate on little more than anecdotal evidence and personal preference. Clear guidance is required to determine whether the timing of surgery can optimise outcomes in this largely young and active patient cohort. METHODS: A systematic literature search was performed in January 2018 of Embase, Medline and OpenGrey in accordance with (PRISMA) guidelines. A total of 658 articles were retrieved, with 6 suitable for inclusion, covering 576 ACL reconstructions. Four meta-analyses were performed assessing subjective measures of Tegner activity scale and Lysholm score, and objective measures of arthroscopically identified meniscal and chondral injury. Additional relevant outcome measures underwent narrative review. Study bias was assessed and reported using the Downs and Black checklist. RESULTS: A statistically significant difference of 0.39 points was found on the Tegner activity scale in favour of early surgery within 3 weeks (RR 0.39, CI 0.10, 0.67, p = 0.008). No statistically difference was found between groups for the patient-reported Lysholm score (RR - 0.18, CI - 2.40, 2.05, p = 0.17). There was no statistically significant difference between groups for intra-operative findings of meniscal lesions (RR 0.84, CI 0.66, 1.08, p = 0.17). A trend towards significance was observed for the incidence of chondral lesions in the early surgery group (RR 0.56, CI 0.31, 1.02, p = 0.06). All the studies were rated either fair or good on the Downs and Black checklist with no study excluded due to bias. CONCLUSIONS: Although there was a statistically significant result for the Tegner activity scale in favour of early surgery, the magnitude of the effect is unlikely to translate into any clinically meaningful difference. At present, there remains no clear evidence to determine superiority of acute/early or delayed reconstruction of a ruptured anterior cruciate ligament. Further research through methodologically robust randomised controlled trials or through the UK National Ligament Registry  may help to provide clearer guidance.

Constant Isothiocyanate-Release Potentials across Biofumigant Seeding Rates.

Biofumigation is an integrated pest-management method involving the mulching of a glucosinolate-containing cover crop into a field in order to generate toxic isothiocyanates (ITCs), which are effective soil-borne-pest-control compounds. Variation in biofumigation efficacy demonstrates a need to better understand the factors affecting pest-control outcomes and develop best practices for choosing biofumigants, growth conditions, and mulching methods that allow the greatest potential isothiocyanate release. We measured the glucosinolate concentrations of six different commercial varieties of three biofumigant plant species: Brassica juncea (ISCI99, Vitasso, and Scala) Raphanus sativus (Diablo and Bento), and Sinapis alba (Ida Gold). The plants were grown in the range of commercially appropriate seeding rates and sampled at three growth stages (early development, mature, and 50% flowering). Within biofumigant species, the highest ITC-release potentials were achieved with B. juncea cv. ISCI99 and R. sativus cv. Bento. The highest ITC-release potential occurred at the 50% flowering growth stage across the species. The seeding rate had a minor impact on the ITC-release potential of R. sativus but had no significant effects on the ITC-release potentials of the B. juncea or S. alba cultivars.

Parental pre-pregnancy BMI is a dominant early-life risk factor influencing BMI of offspring in adulthood.

OBJECTIVE: We examined parental and early-life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22. METHODS: Data were analysed on 1355 participants from the Western Australian Pregnancy Cohort (Raine) Study, with anthropometry collected during pregnancy, at birth, one year and at three yearly intervals thereafter. Multivariate analyses and cross-sectional logistic regression quantified the timing and contribution of early-life risk factors for overweight and obesity in young-adulthood. RESULTS: At five years of age 12.6% of children were overweight and 5.2% were obese. By early adulthood, the prevalence of obesity had increased to 12.8%, whilst overweight remained relatively stable at 14.2% (range from early childhood to adulthood 11-16%). Parental pre-pregnancy body mass index (BMI) was the strongest determinant of adult offspring BMI. Although rapid first year weight gain was associated with increased offspring BMI, the impact of first year weight-gain diminished over childhood, whilst the impact of parental BMI increased over time. CONCLUSIONS: Parental pre-pregnancy BMI and rapid early-life weight gain predispose offspring to obesity in adulthood.

Posterior orbital cellulitis: case report and literature review.

INTRODUCTION: It is rare for isolated sphenoid sinusitis to cause orbital cellulitis. We present a rare case of posterior orbital cellulitis, so caused, together with a review of the relevant literature. CASE REPORT: A 29-year-old woman presented with a 6-week history of progressive, unilateral, retro-orbital and periorbital right eye pain. On examination, the only finding was reduced visual acuity in the right eye. A computed tomography scan demonstrated right frontal and sphenoid sinus opacification. Sphenoidotomy and frontal sinus trephination were subsequently performed, following failure to respond to intravenous antibiotics. After surgery, the patient's vision returned to normal. CONCLUSION: Isolated sphenoid sinusitis is rare but can cause significant visual disturbance and permanent loss of vision. Vague symptoms unsupported by clinical signs at presentation are a feature of posterior orbital cellulitis. The presented case highlights the problem, and the need for a high index of clinical suspicion even in the absence of firm clinical signs, in order to prevent permanent visual loss.

Management of globus pharyngeus.

Globus pharyngeus is a common ENT condition. This paper reviews the current evidence on globus and gives a rational guide to the management of patients with globus. The aetiology of globus is still unclear though most ENT surgeons believe that reflux whether acidic or not plays a significant role. Though proton pump inhibitors are used extensively in practice, there is little evidence to support their efficacy. Most patients with globus can be discharged after simple office investigations. The role of pepsin-induced laryngeal injury is an exciting concept that needs further study. Given the benign nature of globus pharyngeus, in most cases, reassurance rather than treatment or extensive investigation with rigid oesophagoscopy or contrast swallows is all that is needed. We need more research into the aetiology of globus.

Nematode 18S rRNA gene is a reliable tool for environmental biosafety assessment of transgenic banana in confined field trials.

Information on relatedness in nematodes is commonly obtained by DNA sequencing of the ribosomal internal transcribed spacer region. However, the level of diversity at this locus is often insufficient for reliable species differentiation. Recent findings suggest that the sequences of a fragment of the small subunit nuclear ribosomal DNA (18S rRNA or SSU), identify genera of soil nematodes and can also distinguish between species in some cases. A database of soil nematode genera in a Ugandan soil was developed using 18S rRNA sequences of individual nematodes from a GM banana confined field trial site at the National Agricultural Research Laboratories, Kawanda in Uganda. The trial was planted to evaluate transgenic bananas for resistance to black Sigatoka disease. Search for relatedness of the sequences gained with entries in a public genomic database identified a range of 20 different genera and sometimes distinguished species. Molecular markers were designed from the sequence information to underpin nematode faunal analysis. This approach provides bio-indicators for disturbance of the soil environment and the condition of the soil food web. It is being developed to support environmental biosafety analysis by detecting any perturbance by transgenic banana or other GM crops on the soil environment.

Presentation of laryngeal papilloma in childhood: the Leeds experience.

INTRODUCTION: The human papilloma virus (HPV) can cause laryngeal papillomatosis in childhood. The aetiology is thought to be vertical transmission. Clinically these children are usually asymptomatic for the first 6 months of life. As the papillomas develop locally, symptoms begin to develop. The symptoms range from voice change to frank hoarseness, and 'noisy' breathing, most commonly inspiratory stridor. METHOD: Clinical images from microlaryngoscopy and bronchoscopy over a 12-year period were assessed for laryngeal papilloma. RESULTS: In Leeds seven cases presented to the specialist centre over the past 12 years, the average age at presentation was 6.8 years and duration of onset of symptoms to specialist review was 21 months. Five of the children had been treated for asthma and two presented in extremis. CONCLUSION: The take home message for clinicians is hoarse voice associated with shortness of breath needs specialist referral.

Paediatric day-case tonsillectomy: a three-year prospective audit spiral in a district hospital.

BACKGROUND: Paediatric tonsillectomy is a common ENT operation. The use of day-case surgery is increasing, in order to improve efficiency in healthcare. METHODS: A prospective audit spiral was carried out from January 2006 to December 2008 for all children undergoing day-case tonsillectomy at Huddersfield Royal Infirmary. RESULTS: There was a haemorrhage rate of 2.6 per cent over three years. The most common complication was nausea and vomiting, seen in 5.3 per cent of patients. CONCLUSIONS: For a well selected group of children, day-case tonsillectomy in a district hospital setting is a safe and efficient alternative to an in-patient stay. A dedicated day-case team, good anaesthetic technique, adequate post-operative analgesia and on-site paediatric in-patient facilities are essential.

Central nervous system relapse in CD56+, FLT3/ITD+ promyelocytic leukemia.

Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare and tends to be seen mostly following treatment with all-trans retinoic acid (ATRA), due to prolonged patient survival and poor penetration of the drug in the CNS. At least 10% of extramedullary relapses in APL involve the CNS, and associated factors include an increased age, the BCR isoform, the development of differentiation syndrome, a high white cell count at presentation and hemorrhage into the CNS during induction therapy. We present the case of a patient with high-risk APL, CD56+, CD2+ in whom a CNS relapse was diagnosed through the presence of a PML/RARα rearrangement on PCR of the cerebrospinal fluid (CSF).

Clinical, ultrasound and biochemical features of polycystic ovary syndrome in adolescents: implications for diagnosis.

BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) in adolescence is clinically challenging. The prevalence of clinical, ultrasound and biochemical features of PCOS in a community-based adolescent population using current diagnostic criteria has not previously been described. METHODS: This was a prospective cohort study with 244 unselected post-menarchal girls, mean age 15.2 years, of whom 91% were Caucasian. Subjects were recruited from a large population-based birth cohort (the Raine cohort). Clinical hyperandrogenism (HA) was quantified using Ferriman-Gallwey scores. In the early follicular phase (Day 2-6), we measured circulating androgens and sex hormone-binding globulin by immunoassay, and ovarian morphology was assessed by transabdominal ultrasound examination. BMI and waist-hip ratio were measured. RESULTS: Normal ranges for early follicular phase androgens in adolescence were derived for this population. The top 5 and 10% of circulating free testosterone levels were 45.6 and 34.5 pmol/l, respectively. Fifty-one percent of girls reported menstrual irregularity. Clinical HA was uncommon, being observed in only 3.5% of girls. Mean ovarian volume was greater than that reported by others in adult women and 35% of girls had polycystic ovary morphology on transabdominal ultrasound. Taking the upper 5% of free testosterone as HA, 42 girls (18.5%) would have met the Rotterdam criteria for PCOS, 11 girls (5%) the Androgen Excess Society criteria and 7 girls (3.1%) the National Institutes of Health criteria. CONCLUSIONS: Menstrual irregularity is common in adolescence and does not relate to clinical or biochemical HA. Diagnostic criteria for PCOS which include ovarian volume and morphology may be of limited use in adolescence.

Thalassemia major. A report of two cases with severe skeletal involvement.

Beta thalassemia major is rare in Serbia. Previously incurable, affected patients now live to adulthood with regular blood transfusions. The improvement in supportive treatment over recent decades has given rise to many more patients suffering from the associated metabolic complications of anaemia and iron overload, such as osteopenia and other skeletal changes. We present two patients with severe beta thalassemia major from early childhood, who encountered pathological long-bone fractures during the clinical course of their disease. One suffered a distal femoral diaphyseal fracture, and the second a distal tibia fracture. Both fractures occurred in osteopenic bone and were managed non-operatively due to the patients' general medical condition. Despite intense medical intervention, both patients died from disease progression within one year of their fractures, aged 23 and 24 years. As life expectancy rises it is anticipated that an increased number of beta thalassemia major patients will suffer pathological long-bone and other osteoporotic fractures. These fractures appear to both herald and contribute to a general clinical deterioration of this disease. Advances in stem-cell technology may hold the key for a definitive cure.

The challenge of osteo-articular tuberculosis in the twenty-first century: a 15-year population-based study.

SETTING: Serbia, an intermediate tuberculosis (TB) incidence country in socio-economic transition. OBJECTIVE: To examine the epidemiological and clinical pattern of osteo-articular TB (OATB) in Serbia over 15 years. DESIGN: This retrospective observational study included OATB cases diagnosed between 1 January 1993 and 31 December 2007, according to the National Referral Institute of Lung Diseases and TB in Belgrade and the Central TB Register. Population estimates with extrapolations were based on 1991 and 2002 census data. RESULTS: The 295 OATB cases represented 10.9% (range 5.3-20.2) of all extra-pulmonary TB cases notified in Serbia over the period. One tenth of these were relapses. The incidence rate showed a significant increasing trend (y = 0.1167 + 0.0175x, R(2) = 0.3196), with an average age-specific incidence rate of 0.26 per 100 000 population. The peak number of cases was in the 45-64 year age group for both men and women. The average male:female ratio was 0.85. The outcome was favourable for 279 of the 295 patients (94.6%). In addition to a standardised chemotherapy regimen, 25.4% patients underwent surgery. CONCLUSION: The increasing time trend of OATB is caused by increased morbidity, a higher TB detection rate and better notification. Although rare in children, OATB remains a challenge in clinical practice.

Executive function, memory, and gait speed decline in well-functioning older adults.

BACKGROUND: In community-dwelling older adults, global cognitive function predicts longitudinal gait speed decline. Few prospective studies have evaluated whether specific executive cognitive deficits in aging may account for gait slowing over time. METHODS: Multiple cognitive tasks were administered at baseline in 909 participants in the Health, Aging, and Body Composition Study Cognitive Vitality Substudy (mean age 75.2 ± 2.8 years, 50.6% women, 48.4% black). Usual gait speed (m/s) over 20 minutes was assessed at baseline and over a 5-year follow-up. RESULTS: Poorer performance in each cognitive task was cross-sectionally associated with slower gait independent of demographic and health characteristics. In longitudinal analyses, each 1 SD poorer performance in global function, verbal memory, and executive function was associated with 0.003-0.004 m/s greater gait speed decline per year (p =.03-.05) after adjustment for baseline gait speed, demographic, and health characteristics. CONCLUSIONS: In this well-functioning cohort, several cognitive tasks were associated with gait speed cross-sectionally and predicted longitudinal gait speed decline. These data are consistent with a shared pathology underlying cognitive and motor declines but do not suggest that specific executive cognitive deficits account for slowing of usual gait in aging.

Maternal and umbilical cord androgen concentrations do not predict digit ratio (2D:4D) in girls: a prospective cohort study.

Digit ratio (2D:4D) is widely used as a marker of prenatal androgen exposure. However, there are no published prospective studies where prenatal androgen exposure has been measured and correlated with digit ratio in adult life. We aimed to establish the prospective relationship between prenatal androgen exposure in the second and third trimesters of pregnancy (as measured by maternal circulating androgen concentrations and umbilical cord androgen concentrations) and digit ratio in adolescent girls. Androgen concentrations (testosterone, free androgen index, androstenedione, DHEAS) and sex hormone binding globulin (SHBG) were measured in stored plasma samples from pregnant mothers at 18 (n=118) and 34/36 (n=114) weeks of gestation and in cord blood (n=82) from the Western Australian Pregnancy (Raine) Cohort Study (www.rainestudy.org.au). Digit ratio was measured in 244 female offspring from this cohort at age 14-16 years. Only one borderline statistically significant correlation between maternal circulating androstenedione levels at 18 weeks of gestation and left hand digit ratio was seen. No other statistically significant relationship between maternal androgen concentrations or umbilical cord androgen concentrations and digit ratio in adolescence were observed. These findings suggest that variation in 2D:4D in girls is not established as a result of testosterone concentrations in the second and third trimesters. We conclude that prenatal androgen exposure as measured by maternal circulating androgen concentrations at 18 and 34/36 weeks of gestation or in the umbilical cord at birth may not predict digit ratio in girls.

The relationship between maternal and umbilical cord androgen levels and polycystic ovary syndrome in adolescence: a prospective cohort study.

CONTEXT: The prenatal antecedents of polycystic ovary syndrome (PCOS) are not known, but prenatal androgen exposure is thought to contribute. This has not previously been investigated in large prospective studies of normal human pregnancy. OBJECTIVE: The aim of the study was to establish the prospective relationship between early life androgen exposure and PCOS in adolescence. DESIGN AND SETTING: A prospective cohort study was conducted in the general community. PATIENTS OR OTHER PARTICIPANTS: A total of 2900 pregnant women were recruited at 18 wk gestation. Prenatal androgen exposure was measured from maternal blood samples (at 18 and 34-36 wk) and umbilical cord blood. Timed (d 2-5 menstrual cycle) blood samples were collected, clinical hyperandrogenism was assessed, and transabdominal ultrasound examination of ovarian morphology was performed in 244 unselected girls from the Raine cohort aged 14-17 yr. MAIN OUTCOME MEASURE(S): We examined the relationship between early life androgen exposure and PCOS in adolescence. RESULTS: We did not observe a statistically significant relationship between early life androgen exposure and PCOS in adolescence. CONCLUSIONS: This is the first prospective study to evaluate the relationship between prenatal androgen exposure and PCOS in adolescence in normal pregnancy. Our findings do not support the hypothesis that maternal androgens, within the normal range for pregnancy, directly program PCOS in the offspring.

Organizational role for pubertal androgens on adult hypothalamic-pituitary-adrenal sensitivity to testosterone in the male rat.

The inhibitory effect of androgens on the hypothalamic-pituitary-adrenal (HPA) axis in basal and stress conditions in adult male rats is well documented. Major sex-related neuroendocrine changes take place during puberty. There is a robust rise in production and secretion of gonadal steroids, which is thought to underlie numerous neural and behavioural changes brought on after puberty. The present study investigated the effect of the pubertal rise in gonadal steroid levels on the subsequent adult corticosterone profile, particularly the sensitivity of the adult HPA axis to testosterone. Animals were castrated either prepubertally (28 days) or in adulthood (11 weeks) and adult animals were subsequently treated with subcutaneous implants containing either testosterone or cholesterol. Using an automated blood sampling system, blood was collected from each freely moving, conscious rat every 10 min (i) over a 24 h period; (ii) in response to 10 min of noise stress, and (iii) following an immunological challenge with lipopolysaccharide (LPS). Analysis revealed that testosterone treatment did not significantly affect overall corticosterone release over the 24 h period in adult animals castrated before puberty in contrast to animals castrated in adulthood in which testosterone significantly suppressed corticosterone secretion. Following either a noise stress or LPS injection, testosterone treatment did not affect the hypothalamic or adrenal stress response in animals castrated prepubertally. Testosterone significantly suppressed the corticotrophin-releasing hormone and arginine vasopressin mRNA as well as the corticosterone response to LPS in castrated animals that had had their testes intact over puberty. These data provide evidence that puberty is a critical organizational period during which rising levels of gonadal steroids programme the sensitivity of the adult HPA axis to gonadal steroids in adulthood.

Verrucous carcinoma of the foot: a case report.

We present a case of verrucous carcinoma of the foot in a 34-year-old man. This is a rare, locally invasive, well-differentiated, low-grade squamous cell carcinoma, with human papilloma virus as a possible causative agent. It follows a chronic course and mimics a variety of skin lesions, delaying diagnosis by up to 15 years. The definitive diagnosis is made histologically, and treatment by wide local excision is recommended. Our patient underwent wide local excision and partial 5th metatarsal amputation because of invasive disease, local infection, and peripheral vascular disease. There were no postoperative complications. At the 10-year follow-up, there were no signs of tumour recurrence.