ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer.

BACKGROUND: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. MATERIALS AND METHODS: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC. RESULTS: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype. CONCLUSIONS: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.

The Analgesic Effectiveness of Ipsilateral Transversus Abdominis Plane Block in Adult Patients Undergoing Appendectomy: A Prospective Randomized Controlled Trial.

Transversus abdominis plane block (TAP) has been shown to produce effective pain relief following lower abdominal surgeries but is yet to be routinized in different type of surgeries including appendectomy. The main risk of visceral injury can be logically avoided when the block is performed with the abdomen open using landmark technique in the absence of ultrasound guidance. Objective To assess the effectiveness of TAP block with bupivacaine for postoperative analgesia using landmark technique (performed with the abdomen open) in adult patients undergoing appendectomy. Method Forty patients undergoing appendectomy were randomized to undergo ipsilateral TAP block with bupivacaine (n=20) versus control (n=20) in addition to standard postoperative analgesia. All patients received standard general anaesthesia. The block was performed using the landmark technique with 20 ml of 0.5% bupivacaine or isotonic saline on ipsilateral side just before abdominal closure. Pain severity was measured using Visual Analogue Scale (VAS). Tramadol 50 mg was administered as rescue analgesic intravenously when VAS was four or more postoperatively. The duration of analgesia and the requirement of tramadol in 24 hours postoperatively were recorded. Result Mean duration of analgesia in the TAP block with bupivacaine was longer as compared with placebo (724.00±299.07 min vs 168.25±55.18 min; p< 0.01). The TAP block with bupivacaine compared with saline significantly reduced postoperative VAS pain scores. Mean tramadol requirement in the first 24 hours was also reduced (42.50±37.25 mg vs 120.00±55.18 mg; p<0.01). There were no significant complications attributable to the TAP block. Conclusion Ipsilateral TAP block with bupivacaine using landmark technique with the abdomen open in appendectomy provides effective postoperative analgesia and opioids sparing effect.

Managing glaucoma in Lagos State, Nigeria - availability of Human resources and equipment.

AIMS AND OBJECTIVES: There is a paucity of data onthe human resourcesand ophthalmic equipmentavailable for the diagnosis and management of glaucoma in Nigeria. This study is aimed at describing the ophthalmic human resources, as well as available and functioning equipment used in diagnosing and managing glaucoma in Lagos State, Nigeria. MATERIALS AND METHODS: This was a prospective multicentre cross sectional study.Data on human resources and equipmentavailable were collected from all government tertiaryand secondary health institutions in the state. One large-practice private eye hospital in the state was included for comparative purposes. RESULTS: The average number of ophthalmologists per hospital was 1.3 and 4.5 in the secondary and tertiary centres respectively, with overall ophthalmologists to population ratio of 1:400,000, and ophthalmic nurses to population ratio of 1:150,000. There were only 2 full time low vision therapists and 3 equipment technicians. Only the private hospital had a dedicated patient counsellor and an eye unit manager. 64% of ophthalmic equipment in the government sector were functioning compared with 100% in the private centre. Overall, equipment to population ratios were; slit lamp=1:517,000, 78/90D lens=1:1,487,000, tonometer=1:660,000, visual field analyser=1:2,380,000, and pachymeter=1:5,950,000. CONCLUSIONS: Current population ratios for ophthalmologists and ophthalmic nurses in the state meets vision 2020 recommendations, but there are shortages of other key human resources such as equipment technicians, low vision therapists and patient counsellors. In addition, equipment required for the management of glaucoma wereinadequate, not available or not functioning. Findings from this study suggest that there is an urgent need for increased government funding to glaucoma services in Lagos State.

Computational methods for identification of recurrent copy number alteration patterns by array CGH.

Recurrent DNA copy number alterations (CNA) are widely studied in diagnostic and cytogenetic cancer research. CNAs reveal locations that may alter gene dosage and thus expression of the genes contained within. Array comparative genomic hybridization has emerged as a popular high-throughput, genome-wide technique to interrogate tumor genomes for copy number alterations. When studying a group of tumors derived from a patient cohort, it is of great interest to detect the copy number alterations that are common across the population and thus assumed to be potential diagnostic markers and/or predictors of clinical outcome. In this paper, we review extant and available computational approaches for detecting such recurrent copy number alterations from array comparative genomic hybridization (aCGH) data. This is a challenging computational problem due to various sources of noise in the data that can obscure the recurrent copy number signals or induce false positives in their prediction. In this paper, we qualitatively evaluate methods designed to detect recurrent copy number alterations for aCGH data based on their analytical strengths and limitations, and discuss expected future directions in this important area of cancer research.

Causes of severe visual impairment and blindness in Bangladesh: a study of 1935 children.

OBJECTIVE: To identify the anatomical site and underlying aetiology of severe visual impairment and blindness (SVI/BL) in children in Bangladesh. DESIGN: A national case series. METHODS: Children were recruited from all 64 districts in Bangladesh through multiple sources. Causes were determined and categorised using standard World Health Organization methods. RESULTS: 1935 SVI/BL children were recruited. The median age was 132 months, and boys accounted for 63.1% of the sample. The main site of abnormality was lens (32.5%), mainly unoperated cataract, followed by corneal pathology (26.6%) and disorders of the whole eye (13.1%). Lens-related blindness was the leading cause in boys (37.0%) compared with corneal blindness in girls (29.8%). In 593 children, visual loss was due to childhood factors, over 75% being attributed to vitamin A deficiency. Overall 1338 children (69.2%) had avoidable causes. Only 2% of the country's estimated SVI/BL children have access to education and rehabilitation services. CONCLUSIONS: This is the first large-scale study of SVI/BL children in Bangladesh over two-thirds of whom had avoidable causes. Strategies for control are discussed.

Causes of blindness and visual impairment in Pakistan. The Pakistan national blindness and visual impairment survey.

OBJECTIVE: To determine the causes of blindness and visual impairment in adults (> or =30 years old) in Pakistan, and to explore socio-demographic variations in cause. METHODS: A multi-stage, stratified, cluster random sampling survey was used to select a nationally representative sample of adults. Each subject was interviewed, had their visual acuity measured and underwent autorefraction and fundus/optic disc examination. Those with a visual acuity of <6/12 in either eye underwent a more detailed ophthalmic examination. Causes of visual impairment were classified according to the accepted World Health Organization (WHO) methodology. An exploration of demographic variables was conducted using regression modeling. RESULTS: A sample of 16 507 adults (95.5% of those enumerated) was examined. Cataract was the most common cause of blindness (51.5%; defined as <3/60 in the better eye on presentation) followed by corneal opacity (11.8%), uncorrected aphakia (8.6%) and glaucoma (7.1%). Posterior capsular opacification accounted for 3.6% of blindness. Among the moderately visually impaired (<6/18 to > or =6/60), refractive error was the most common cause (43%), followed by cataract (42%). Refractive error as a cause of severe visual impairment/blindness was significantly higher in rural dwellers than in urban dwellers (odds ratio (OR) 3.5, 95% CI 1.1 to 11.7). Significant provincial differences were also identified. Overall we estimate that 85.5% of causes were avoidable and that 904 000 adults in Pakistan have cataract (<6/60) requiring surgical intervention. CONCLUSIONS: This comprehensive survey provides reliable estimates of the causes of blindness and visual impairment in Pakistan. Despite expanded surgical services, cataract still accounts for over half of the cases of blindness in Pakistan. One in eight blind adults has visual loss from sequelae of cataract surgery. Services for refractive errors need to be further expanded and integrated into eye care services, particularly those serving rural populations.

Cataract prevalence, cataract surgical coverage and barriers to uptake of cataract surgical services in Pakistan: the Pakistan National Blindness and Visual Impairment Survey.

AIM: To estimate the prevalence of visual impairment and blindness caused by cataract, the prevalence of aphakia/pseudophakia, cataract surgical coverage (CSC) and to identify barriers to the uptake of cataract services among adults aged >or=30 years in Pakistan. METHODS: Probability proportional-to-size procedures were used to select a nationally representative sample of adults. Each subject underwent interview, visual acuity measurement, autorefraction, biometry and ophthalmic examination. Those that saw <6/12 in either eye underwent a more intensive examination procedure including corrected visual acuity, slit lamp and dilated fundus examination. CSC was calculated for different levels of visual loss by person and by eye. Individuals with <6/60 in the better eye as a result of cataract were interviewed regarding barriers. RESULTS: 16 507 Adults were examined (95.5% response rate). The crude prevalence of blindness (presenting <3/60 in the better eye) caused by bilateral cataract was 1.75% (95% CI 1.55%, 1.96%). 1317 Participants (633 men; 684 women) had undergone cataract surgery in one or both eyes, giving a crude prevalence of 8.0% (95% CI 7.6%, 8.4%). The CSC (persons) at <3/60, <6/60 and <6/18 were 77.1%, 69.3% and 43.7%, respectively. The CSC (eyes) at <3/60, <6/60 and <6/18 were 61.4%, 52.2% and 40.7%, respectively. Cost of surgery (76.1%) was the main barrier to surgery. CONCLUSION: Approximately 570 000 adults are estimated to be blind (<3/60) as a result of cataract in Pakistan, and 3,560000 eyes have a visual acuity of <6/60 because of cataract. Overall, the national surgical coverage is good but underserved populations have been identified.

One-year results of photodynamic therapy for small predominantly classic choroidal neovascular membranes secondary to age-related macular degeneration.

PURPOSE: To determine the visual and angiographic outcomes of patients with small predominantly classic choroidal neovascular membranes (CNV) undergoing photodynamic therapy (PDT). METHODS: The subjects were a cohort of patients with age-related predominantly classic CNV with lesion size of greatest linear diameter of 2000 microm or less treated with PDT. Lesion size and visual acuity were recorded at baseline and at 3-month intervals. Visual treatment failure was defined as either loss of at least 15 letters or visual acuity less than 35 letters on a modified Early Treatment Diabetic Retinopathy Study chart. Lesion treatment failure was defined as increase in greatest linear diameter (GLD) of at least 500 microm. RESULTS: Twenty-five eyes of 25 patients were included. Visual treatment failure occurred in 16 and mean visual acuity dropped from 58 letters to 34 letters (p<0.0001). In 11 of these patients this occurred within the first 3 months. Lesion treatment failure occurred in 18 patients. Mean GLD increased from 1331 to 2935 microm (p<0.0001). Early growth of the lesion was associated with poor visual outcome with growth in GLD in the first 3 months of 310 microm in patients without eventual visual treatment failure and 1131 microm in patients with eventual visual failure (p=0.027). CONCLUSIONS: Small predominantly classic lesions commonly cause visual deterioration if treated with PDT alone. In the first year over 50% may lose at least 15 letters or drop below 35 letters, with most visual loss occurring in the first 3 months. Visual loss is associated with early lesion growth.

Factors predicting outcome of vitrectomy for diabetic macular oedema: results of a prospective study.

AIM: To determine preoperative demographic, clinical, and optical coherence tomography (OCT) factors which might predict the visual and anatomical outcome at 1 year in patients undergoing vitrectomy and inner limiting membrane peel for diabetic macular oedema (DMO). METHODS: A prospective, interventional case series of 33 patients who completed 1 year follow up. Measurements were taken preoperatively and at 1 year. Outcome measures were logMAR visual acuity (VA) and OCT macular thickness. A priori explanatory variables included baseline presence of clinical and/or OCT signs suggesting macular traction, grade of diabetic maculopathy, posterior vitreous detachment, fluorescein leakage and ischaemia on angiography, presence of subretinal fluid, and peroperative indocyanine green (ICG) use. RESULTS: 33 patients completed 1 year follow up. On average VA deteriorated by 0.035 logMAR (p = 0.40). Macular thickness significantly improved by a mean of 139 microm (95% CI; 211 to 67, p<0.001). Patients with evidence of clinical and/or OCT macular traction significantly improved logMAR acuity (logMAR improvement = 0.08) compared with patients without traction (logMAR deterioration 0.11, p = 0.01). Presence of subretinal fluid significantly predicted worse postoperative result (p = 0.01) CONCLUSION: On average, patients showed a statistically significant improvement in central macular thickness following treatment but a marginal acuity worsening. Presence of subretinal fluid on OCT is hypothesised to be exudative rather than tractional in nature. The visual benefit of vitrectomy for DMO in this study was limited to patients who exhibit signs of macular traction either clinically and/or on OCT.

Acute retinal necrosis presenting as central retinal artery occlusion with cilioretinal sparing.

PURPOSE: To report a case of acute retinal necrosis presenting as central retinal artery occlusion with cilioretinal sparing. METHODS: Single interventional case report. The findings of the ophthalmic examination, MRI, blood parameters, biopsy results and clinical course are reported. RESULTS: A forty two year old gentleman reporting sudden loss of sight, ophthalmic examination revealing uveitis, central retinal artery occlusion with cilioretinal sparing and peripheral necrotizing retinitis. CONCLUSIONS: Central retinal artery occlusion can be an early feature of acute retinal necrosis (ARN).

DoEpi. Computer-assisted instruction in epidemiology and computing and a framework for creating new exercises.

DoEpi is a series of computer exercises and a framework for making new exercises based on the Epi Info programs for epidemiologic computing. The system contains three outbreak investigations, a research survey, four exercises in advanced Epi Info programming, and four exercises in public health surveillance. The exercises are available via the Internet (www.cdc.gov, under "Publications, Products, and Software") with provision for CME and CEU credit from the Centers for Disease Control and Prevention. They can serve as a useful adjunct to lectures and textbooks in teaching epidemiology or epidemiologic computing. A new DoEpi exercise with hypertext, low-resolution photographs, questions, answers, and an examination can be constructed in hours rather than weeks or months using an Exercise Development "wizard" provided as part of the instructor's module. Epi Info exercises with data files and customized programs require more work to construct but can be added by those with the necessary skills. DoEpi exercises can be used in a variety of ways for different curricula and students of different background levels, including those with English as a second language. Translation of DoEpi exercises into other languages is facilitated by the instructor's module, and construction of new exercises with locally suitable materials is encouraged. DoEpi is based on DOS programs to allow the widest use. The format lends itself to conversion to hypertext programs in the Microsoft Windows and Internet formats at a future date.

Solubilization of salicylamide and acetaminophen by antihistamines in aqueous solution.

The effect of self-association of the antihistaminic drugs pheniramine, chlorpheniramine, and brompheniramine as their maleate salts on the solubilization of salicylamide and acetaminophen in aqueous solution has been investigated. The total solubility of salicylamide increased nonlinearly at lower antihistamine concentrations (less than 0.4 M), but reached limiting linearity (slope = 0.34 mol/mol of antihistamine) at higher concentrations (up to 0.8 M). Salicylamide solubility increases are approximately 10-fold at high concentrations (0.6-0.8 M) of antihistamine, while acetaminophen solubility increases are about fivefold at similar antihistamine concentrations. The solubilization data were analyzed with a stepwise self-association model. Based on a dimer model, the experimental and theoretical log excess salicylamide solubility profiles were in good agreement (r2 = 0.982) except at the lowest chlorpheniramine maleate concentrations. Such deviation at the lowest concentrations increased when trimer and 11-mer models were utilized. To account for this deviation, a monomer-dimer model based on interaction with both the chlorpheniramine maleate monomer and dimer was proposed. This model was in excellent agreement (r2 = 0.996) with the solubility data.

Development of liposomal amphotericin B dry powder inhaler formulation.

The purpose of our study was to prepare and optimize liposomal Amphotericin B (AMB) dry powder inhaler (DPI) formulation for treatment of invasive lung fungal infection. Liposomes were prepared by reverse phase evaporation technique using ethyl acetate and ethanol (1:1) as organic solvents to avoid a possible risk for human health and to impart adequate stability of the vesicles. Drug lipid ratio was 1:10 with membrane composition of hydrogenated soyaphosphatidylcholine; cholesterol and either saturated soyaphosphatidylglycerol (7:3:0.5) or stearylamine (1:1:0.1) was used to prepare negatively (AMB1) and positively (AMB2) charged liposomes, respectively. Liposomes were extruded through 2 microm polycarbonate membrane, separated from unentrapped drug and subjected to lyophilization using Tris buffer containing cryoprotectants in various mass ratios. Sucrose was found to be the best cryoprotectant for liposomal AMB in a mass ratio of lipid: sucrose at 1:5 for AMB1 and AMB2, respectively. Sorbolac 400 and sieved Pharmatose 325 M (500#) in varying mass ratios were used as carriers to prepare the liposomal DPI formulations and subjected to determination of angle of repose, compressibility index, dispersiblity index, water content, scanning electron microscopy, and fine particle fraction (FPF). Carrier blend of Sorbolac 400 and 10% sieved Pharmatose 325 M (liposome: carrier ratio to be 1:6) resulted in 22.6 +/- 2.2% and 16.8 +/- 2.2% FPF for AMB1 and AMB2, respectively with significantly different (p >.05) device fraction. Percent dug retention studies were conducted at different storage conditions and demonstrated a shelf life over 1 year at refrigerated storage condition (2-8 degrees C).

Comparative efficacy of oral sustained released bronchodilator in stable asthmatics.

Double blind randomized trial of oral conventional and sustained release bronchodilators was undertaken to observe comparative efficacy in 30 patients older than 15 years. All cases selected were stable asthmatics at least for last 2 years having FEV1 improvement > or = 20%. Basal Pulmonary functions like FEV1, FVC and PEFR were recorded before and after drug administration at 1/2, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours. Four drug regimens were given as a single dose in the morning on randomized crossover manner on 1st, 4th, 7th and 10th days, sustained release theophylline 300 mg+salbutamol 4 mg (Drug I), salbutamol 4 mg + theophylline 300 mg (Drug II), salbutamol sustained released (asthalin SA) 8 mg (Drug III), salbutamol sustained released (ventorlin CR) 8 mg (Drug IV). Mean FEV1 changes observed at 0, 6 and 12 hours for all the drugs were compared which showed no statistical significance (t = 2.3876). Therefore, we conclude that using single dose fixed combination of oral salbutamol and aminophylline either in a plain or slow released form have no additive bronchodilator effect as compared to salbutamol alone in stable asthmatics.

Liposomal amphotericin B dry powder inhaler: effect of fines on in vitro performance.

The aim of the present investigation was to improve in vitro pulmonary deposition of amphotericin B (AMB) liposomal dry powder inhaler (LDPI) formulations. Liposomes with negative (AMB1) and positive (AMB2) charge were prepared by the reverse phase evaporation (REV) technique, extruded to reduce size, separated from unentrapped drug and lyophilized using an optimized cryoprotectant to achieve maximum drug retention. Lactose carrier (Sorbolac 400) in varying mass ratio with or without addition of fines (500# sieved Pharmatose 325M) in different mixing sequence were used to formulate AMB LDPI formulations. In vitro evaluation was done with twin stage impinger (TSI) for fine particle fraction. The lactose carrier containing 10% fines was found to be optimum blend at 1:6 mass ratio of liposome: lactose. The addition of fines and order of mixing fines were found to influence the fine particle fraction (FPF) significantly. FPF of LDPI formulations using a Rotahaler (Cipla, India) as delivery device at 30, 60 and 90 L/min were found to be 23.1 +/- 1.5 percent and 17.3 +/- 2.2 percent; 25.3 +/- 1.8 percent and 19.6 +/- 1.5 percent and 28.4 +/- 2.1 percent and 22.9 +/- 1.9 percent for AMB1 and AMB2 respectively.

Study of ipratropium bromide inhalation in stable asthma.

An open two weeks short term trial of Ipratropium Bromide (IB) inhalation (0.02 mg per dose) was carried out in 20 stable asthamatics to study its efficacy and safety. Early significant rise in PEFR (P < 0.001) and FEV1 (P < 0.05) was observed after 15 min of IB inhalation and reached significant peak (P < 0.01) after 1 hour which was persistent beyond three hours after IB inhalation. No side effects were observed. It was concluded that Ipratropium Bromide Imhalation is safe and has efficient bronchodilatory effect on short term basis in stable asthmatics.

Ehlers-Danlos syndrome.

A case of Ehlers-Danlos Syndrome in a 19 years old male involving cutaneous and skeletal systems is reported. A clinical scoring system to diagnose such cases is highlighted.

Peripheral myxoma of maxilla. A case report.

The intra-oral soft tissue myxoma or peripheral myxoma is a rare, slowly growing, benign mesenchymal tumor. Pathologically, it may be difficult to differentiate from other tumors with myoxid stroma and is occasionally misinterpreted as malignant. Though its counterpart, central odontogenic myxoma shows aggressive local behaviour and high recurrence rate following conservative excision, no much detail is available regarding peripheral myxoma of the oral cavity in the published English literature. In this paper, a rare case of peripheral myxoma of maxilla in a 35 years old female is presented with emphasis on review of relevant literature, histological aspects in differential diagnosis and 'semi-radical approach' in its management.