Neurologic Outcomes After Radiation Therapy for Severe Spinal Cord Compression in Multiple Myeloma: A Study of 162 Patients.

BACKGROUND: Bone destruction is the most frequent disease-defining clinical feature of multiple myeloma (MM), resulting in skeletal-related events such as back pain, pathological fractures, or neurologic compromise including epidural spinal cord compression (ESCC). Up to 24% of patients with MM will be affected by ESCC. Radiation therapy has been proven to be highly effective in pain relief in patients with MM. However, a critical knowledge gap remains with regard to neurologic outcomes in patients with high-grade ESCC treated with radiation. METHODS: We retrospectively included 162 patients with MM and high-grade ESCC (grade 2 or 3) who underwent radiation therapy of the spine between January 2010 and July 2021. The primary outcome was the American Spinal Injury Association (ASIA) score after 12 to 24 months, or the last known ASIA score if the patient had had a repeat treatment or died. Multivariable logistic regression was used to assess factors associated with poor neurologic outcomes after radiation, defined as neurologic deterioration or lack of improvement. RESULTS: After radiation therapy, 34 patients (21%) had no improvement in their impaired neurologic function and 27 (17%) deteriorated neurologically. Thirty-six patients (22%) underwent either surgery or repeat irradiation after the initial radiation therapy. There were 100 patients who were neurologically intact at baseline (ASIA score of E), of whom 16 (16%) had neurologic deterioration. Four variables were independently associated with poor neurologic outcomes: baseline ASIA (odds ratio [OR] = 6.50; 95% confidence interval [CI] = 2.70 to 17.38; p < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (OR = 6.19; 95% CI = 1.49 to 29.49; p = 0.015), number of levels affected by ESCC (OR = 4.02; 95% CI = 1.19 to 14.18; p = 0.026), and receiving steroids prior to radiation (OR = 4.42; 95% CI = 1.41 to 16.10; p = 0.015). CONCLUSIONS: Our study showed that 38% of patients deteriorated or did not improve neurologically after radiation therapy for high-grade ESCC. The results highlight the need for multidisciplinary input and efforts in the treatment of high-grade ESCC in patients with MM. Future studies will help to improve patient selection for specific and standardized treatments and to clearly delineate which patients are likely to benefit from radiation therapy. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Accumulation of resveratrol, ferulic acid and iron in seeds confer iron deficiency chlorosis tolerance to a novel genetic stock of peanut (Arachis hypogaea L.) grown in calcareous soils.

Peanut is mostly grown in calcareous soils with high pH which are deficient in available iron (Fe2+) for plant uptake causing iron deficiency chlorosis (IDC). The most pertinent solution is to identify efficient genotypes showing tolerance to limited Fe availability in the soil. A field screening of 40 advanced breeding lines of peanut using NRCG 7472 and ICGV 86031 as IDC susceptible and tolerant checks, respectively, was envisaged for four years. PBS 22040 and 29,192 exhibited maximum tolerance while PBS 12215 and 12,185 were most susceptible. PBS 22040 accumulated maximum seed resveratrol (5.8 ± 0.08 ppm), ferulic acid (378.6 ± 0.31 ppm) and Fe (45.59 ± 0.41 ppm) content. Enhanced chlorophyll retention (8.72-9.50 µg ml-1), carotenoid accumulation (1.96-2.08 µg ml-1), and antioxidant enzyme activity (APX: 35.9-103.9%; POX: 51- 145%) reduced the MDA accumulation (5.61-9.11 µM cm-1) in tolerant lines. The overexpression of Fe transporters IRT1, ZIP5, YSL3 was recorded to the tune of 2.3-9.54; 1.45-3.7; 2.20-2.32- folds respectively in PBS 22040 and 29,192, over NRCG 7472. PBS 22040 recorded the maximum pod yield (282 ± 4.6 g/row), hundred kernel weight (55 ± 0.7 g) and number of pods per three plants (54 ± 1.7). The study thus reports new insights into the roles of resveratrol, ferulic acid and differential antioxidant enzyme activities in imparting IDC tolerance. PBS 22040, being the best performing line, can be the potent source of IDC tolerance for introgression in high yielding but susceptible genotypes under similar edaphic conditions. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01321-9.

Variability of retinopathy consequent upon novel mutations in LAMA1.

PURPOSE: Bi-allelic mutations in LAMA1 (laminin 1) (OMIM # 150320) cause Poretti-Boltshauser Syndrome (PTBHS), a rare non-progressive cerebellar dysplasia disorder with ophthalmic manifestations including oculomotor apraxia, high myopia, and retinal dystrophy. Only 38 variants, nearly all loss of function have been reported. Here, we describe novel LAMA1 variants and detailed retinal manifestations in two unrelated families. METHODS: Whole-genome sequencing was conducted on three siblings of a consanguineous family with myopia and retinal dystrophy and on a child from an unrelated non-consanguineous couple. Clinical evaluation included full ophthalmic examination, detailed colour, autofluorescence retinal imaging, retinal optical coherence tomography (OCT), fluorescein angiography under anesthesia, and pattern and full-field electroretinography. RESULTS: Genetic analysis revealed a novel homozygous LAMA1 frameshift variant, c.1492del p.(Arg498Glyfs *25), in the affected siblings in family 1 and a novel frameshift c.3065del p.(Gly1022Valfs *2) and a deletion spanning exons 17-23 in an unrelated individual in family 2. Two of the three siblings and the unrelated child had oculomotor apraxia in childhood; none of the siblings had symptoms of other neurological dysfunction as adults. All four had myopia. The affected siblings had a qualitatively similar retinopathy of wide-ranging severity. The unrelated patient had a severe abnormality of retinal vascular development, which resulted in vitreous haemorrhage and neovascular glaucoma in the left eye and a rhegmatogenous retinal detachment in the right eye. CONCLUSIONS: This report describes the detailed retinal structural and functional consequences of LAMA1 deficiency in four patients from two families, and these exhibit significant variability with evidence of both retinal dystrophy and abnormal and incomplete retinal vascularisation.

Multimodality imaging in primary hyperparathyroidism.

Institutional variations in parathyroid adenoma localisation are largely dictated by local experience and availability of imaging investigations, with no consensus on the optimal approach. This review evaluates the role of multiple imaging techniques in primary hyperparathyroidism and highlights their advantages and limitations in different clinical contexts. A clinico-radiological review of parathyroid imaging techniques is illustrated with example cases and data from the literature. These include high-resolution ultrasound, 99mTc-sestamibi planar scintigraphy with and without thyroid subtraction techniques, integrated 99mTc-sestamibi single-photon-emission computed tomography (SPECT)/computed tomography (CT), four-dimensional (4D) CT, and other techniques, such as magnetic resonance imaging, integrated 18F-choline/11C-methionine positron-emission tomography (PET)/CT and angiographic selective venous sampling. The crucial role of parathyroid embryological and gross anatomy in informing the surgical approach to parathyroidectomy is discussed. Finally, a systematic approach to imaging is proposed to maximise the accuracy of imaging localisation of parathyroid lesions, which is crucial for optimal patient management.

Baseline PET/CT imaging parameters for prediction of treatment outcome in Hodgkin and diffuse large B cell lymphoma: a systematic review.

PURPOSE: To systematically review the literature evaluating clinical utility of imaging metrics derived from baseline fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for prediction of progression-free (PFS) and overall survival (OS) in patients with classical Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). METHODS: A search of MEDLINE/PubMed, Web of Science, Cochrane, Scopus and clinicaltrials.gov databases was undertaken for articles evaluating PET/CT imaging metrics as outcome predictors in HL and DLBCL. PRISMA guidelines were followed. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: Forty-one articles were included (31 DLBCL, 10 HL). Significant predictive ability was reported in 5/20 DLBCL studies assessing SUVmax (PFS: HR 0.13-7.35, OS: HR 0.83-11.23), 17/19 assessing metabolic tumour volume (MTV) (PFS: HR 2.09-11.20, OS: HR 2.40-10.32) and 10/13 assessing total lesion glycolysis (TLG) (PFS: HR 1.078-11.21, OS: HR 2.40-4.82). Significant predictive ability was reported in 1/4 HL studies assessing SUVmax (HR not reported), 6/8 assessing MTV (PFS: HR 1.2-10.71, OS: HR 1.00-13.20) and 2/3 assessing TLG (HR not reported). There are 7/41 studies assessing the use of radiomics (4 DLBCL, 2 HL); 5/41 studies had internal validation and 2/41 included external validation. All studies had overall moderate or high risk of bias. CONCLUSION: Most studies are retrospective, underpowered, heterogenous in their methodology and lack external validation of described models. Further work in protocol harmonisation, automated segmentation techniques and optimum performance cut-off is required to develop robust methodologies amenable for clinical utility.

The efficacy of endoscopic third ventriculostomy in children 1 year of age or younger: A systematic review and meta-analysis.

PURPOSE: Hydrocephalus is a major cause of morbidity in the pediatric population, with potentially severe consequences if left untreated. Two viable strategies for management of non-communicating hydrocephalus are endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunting. However, there is uncertainty over the safety and efficacy of ETV in younger infants aged 1 year or below. In this systematic review, we aim to elucidate the success rate and procedural risks of ETV in this age group. METHODS: A multi-database (PubMed, Embase, Web of Science) literature search between January 1990 and April 2018 was performed in accordance with PRISMA guidelines. Eligible studies were included if they (i) examined non-communicating hydrocephalus; (ii) quantified the success/failure rates of ETV; and (iii) assessed outcomes in children 1 year of age or younger. RESULTS: A total of 19 articles with 399 patients were eligible for inclusion. Mean age at procedure was 4.2 months (range 34 weeks gestation to 12 months), with 116 females and 143 males. Commonest underlying aetiology was congenital aqueductal stenosis (AS) (60.4%). Remaining causes included post-haemorrhagic, post-infection, Chiari malformations, malignancies and others. Overall and AS mean success rates were 51.6% and 56.5% respectively. Overall complication rate was 10.0%, consisting mainly of CSF leak, infection, and haemorrhage. Younger age was significantly associated with poorer ETV success rate when divided into <6 months and 6-12 months of age (44.4 vs 66.7%; p = 0.0007). Underlying pathology had no significant association with ETV outcome when divided into AS and other pathologies (p = 0.53). CONCLUSIONS: Age is significantly associated with ETV success rates. Pathology-dependent effects were not found in this age group. Despite a lower ETV success rate at younger ages (44.4 vs 66.7%), it offers a comparable safety profile that is independent of age. ETV remains a viable treatment option for non-communicating hydrocephalus for infants aged 1 year or younger.

Initial clinical experience with a powered circular stapler for colorectal anastomosis.

BACKGROUND: The Echelon circular™ powered stapler (ECP stapler) obviates the need for manual firing of conventional circular staplers during the construction of a colorectal anastomosis, but has not been evaluated clinically. The aim of this study was to perform a clinical evaluation of this stapler. METHODS: A retrospective review of the initial clinical experience of a single surgeon using the ECP stapler for left-sided colorectal anastomosis construction during elective colorectal resections for benign and malignant disease was conducted by analyzing results from a prospectively maintained study database. Additionally, four attending colorectal and/or general surgeons who had performed ≥ 5 colorectal operations with the ECP stapler were invited to complete an anonymous online survey to subjectively assess the user experience with the device. Statistical analysis was conducted using Microsoft Excel Version 15.33. RESULTS: Seventeen patients underwent left-sided anastomotic reconstruction using the ECP stapler. All donuts (proximal and distal) were intact. Anastomotic integrity was evaluated using the air-leak test utilizing flexible video sigmoidoscopy. No leaks were observed, although one patient (5.9%) developed a postoperative pelvic abscess. The anonymous survey was completed by all four surgeons. Subjective evaluation of the ECP stapler suggests that the overall stapling quality, overall device ease-of-use, and the overall perception of anastomotic quality as above average when compared to manual 'end-to-end anastomosis' (EEA) stapling devices. CONCLUSIONS: In an initial clinical evaluation of the ECP stapler, the safety and ease-of-use of the device appears to be satisfactory. Powered stapling and the design of '3D stapling' may provide advantages over manual systems, and may improve the construction quality of left-sided colorectal anastomosis.

Patient advice regarding participation in sport in children with disorders of cerebrospinal fluid (CSF) circulation: a national survey of British paediatric neurosurgeons.

BACKGROUND: Management of children with disorders of cerebrospinal fluid (CSF) circulation is a common aspect of paediatric neurosurgical practice. Sport and physical activity play an integral role in the lives of patients in this age group. However, there is little evidence to support the dissemination of appropriate advice to children regarding such activities. The aim of this study was to evaluate the perspectives of clinicians across the UK regarding the participation of children with disorders of CSF circulation in sports. METHODS: Questionnaires were distributed to Consultant Paediatric Neurosurgeons practising across the UK via the Society of British Neurological Surgeons (SBNS). Five different patient scenarios were supplied, and participants were asked to choose whether they would advise participation in the following sports: Taekwondo, rugby, skiing, and football. RESULTS: An overall response rate of 66.7% (36 out of 54 paediatric neurosurgeons) was achieved. The following percentages of clinicians advocated football, rugby, Taekwondo, and skiing across all scenarios: 96%, 75%, 77%, and 97%, respectively. The majority of responders (91.2%) relied on personal experience when providing advice, whilst 50% used available literature and 19.4% used available guidelines. CONCLUSIONS: There is a paucity of evidence in the literature to support the dissemination of appropriate advice to children with disorders of CSF circulation regarding participation in sports. Our findings demonstrate that the majority of clinicians rely on personal experience to make such decisions, emphasizing the necessity of larger scale studies to inform evidence-based guidelines.

A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

Protocol-driven multidetector SPECT/CT: integration of hybrid imaging into the routine workflow of whole-body bone scintigraphy in oncology patients.

AIM: To analyse the additional clinical value of protocol-driven and selective use of multidetector single-photon-emission tomography/computed tomography (SPECT/CT) in oncology patients undergoing whole-body bone scintigraphy (BS) and to analyse reporter confidence in diagnosis with and without SPECT/CT. MATERIALS AND METHODS: During a 2-year period, 2,954 whole-body BS examinations were performed in oncology patients, with 444 (15%) undergoing additional protocol-driven SPECT/CT. Retrospective evaluation of planar BS and SPECT/CT images was performed by two experienced dual-trained nuclear medicine radiologists. The BS and SPECT/CT images were graded blindly using a five-point scale designed to evaluate the likelihood of a lesion being benign or malignant. Interpretation was applied on a per-patient basis. RESULTS: There was a 74.5% increase in definitive diagnostic classification and a 26.6% reduction in equivocal findings with SPECT/CT when compared to BS alone (p<0001). Of cases initially classified as "probably benign" on BS, 5.1% (10/193) were reclassified to "probably malignant" (1%) or "malignant" (4.1%) using the SPECT/CT data. The highest impact in reporter confidence was seen with SPECT/CT in the interpretation of lesions within the pelvis (34%), ribs (23%), lumbar spine (22%), and thoracic spine (21%). CONCLUSION: Protocol-driven, selective use of SPECT/CT imaging to augment planar BS reduces equivocal findings and improves reporter confidence whilst minimising the impact on patient and reporting workflows.

Accuracy of scleral transillumination techniques to identify infant ciliary body for sclerostomy and intravitreal injections.

IMPORTANCE: There is variation in the literature for sclerotomy and intravitreal injection placement in young children, ranging from 0.5 to 3.0 mm from the limbus. We assess the accuracy of scleral transillumination to identify the ciliary body in infants for safe sclerotomy and intravitreal injections in young children. BACKGROUND: The study compares the perilimbal "dark band" seen on scleral transillumination (STI) with the ultrasound biomicroscopy (UBM), and compares these measurements with the current guidelines for sclerotomy in infants. DESIGN: Prospective case series in a tertiary paediatric hospital. PARTICIPANTS: Children aged ≤36 months undergoing general anaesthesia for eye procedures. METHODS: Scleral transillumination was performed to measure the perilimbal dark band. UBM of the ciliary body region was then performed, and correlated with transillumination findings. MAIN OUTCOME MEASURES: The midpoints of STI and UBM were compared to current cadaver-based guidelines to assess the safe point for sclerotomy. RESULTS: Twenty children were recruited, 36 STI and 35 UBM measurements were obtained. The posterior edge of the dark band had good correlation with the posterior border of the ciliary body. Transillumination and UBM correlated well for midpoint measurements. The midpoint of the dark band on transillumination was confirmed to be in the ciliary body by UBM in all cases. CONCLUSIONS AND RELEVANCE: The STI technique is a useful and fast technique to demonstrate the ciliary body. The midpoint of the dark band on STI correlates well with the UBM, and has a potential use for confirming safe-entry into the posterior segment if using current guidelines. The current cadaver-based paediatric guidelines safely avoid retinal injury.

Diagnostic performance of a streamlined 18F-choline PET-CT protocol for the detection of prostate carcinoma recurrence in combination with appropriate-use criteria.

AIM: To evaluate the efficacy of single time-point half-body (skull base to thighs) fluorine-18 choline positron emission tomography-computed tomography (PET-CT) compared to a triple-phase acquisition protocol in the detection of prostate carcinoma recurrence. MATERIALS AND METHODS: Consecutive choline PET-CT studies performed at a single tertiary referral centre in patients with biochemical recurrence of prostate carcinoma between September 2012 and March 2017 were reviewed retrospectively. The indication for the study, imaging protocol used, imaging findings, whether management was influenced by the PET-CT, and subsequent patient outcome were recorded. RESULTS: Ninety-one examinations were performed during the study period; 42 were carried out using a triple-phase protocol (dynamic pelvic imaging for 20 minutes after tracer injection, half-body acquisition at 60 minutes and delayed pelvic scan at 90 minutes) between 2012 and August 2015. Subsequently following interim review of diagnostic performance, a streamlined protocol and appropriate-use criteria were introduced. Forty-nine examinations were carried out using the single-phase protocol between 2015 and 2017. Twenty-nine (69%) of the triple-phase studies were positive for recurrence compared to 38 (78%) of the single-phase studies. Only one patient who had a single-phase study would have benefited from a dynamic acquisition, they have required no further treatment or imaging and are currently under prostate-specific antigen (PSA) surveillance. CONCLUSION: Choline PET-CT remains a useful tool for the detection of prostate recurrence when used in combination with appropriate-use criteria. Removal of dynamic and delayed acquisition phases reduces study time without adversely affecting accuracy. Benefits include shorter imaging time which improves patient comfort, reduced cost, and improved scanner efficiency.

A case report of caecal herniation through the foramen of Winslow.

Caecal herniation through the foramen of Winslow is a rare entity of which radiologist should be aware. We present a case of this entity in a patient presenting with diabetic ketoacidosis and ongoing epigastric pain. Abdominal computed tomography demonstrated herniation of the caecum into the lesser sac via the foramen of Winslow. Despite the caecum appearing viable at the time of surgery, the surgeons performed a right hemicolectomy via laparotomy to prevent future recurrence.

Feasibility of a streamlined imaging protocol in technetium-99m-Tektrotyd somatostatin receptor SPECT/CT.

AIM: To assess the feasibility and efficacy of a streamlined single time-point 99mTc-HYNIC-Tyr3-octreotide (Tektrotyd) somatostatin receptor scintigraphy (SRS) protocol to differentiate pathological uptake by neuroendocrine tumours (NETs) from physiological activity. METHODS AND MATERIALS: Tektrotyd imaging in 50 consecutive patients with NETs was reviewed retrospectively. Imaging was independently assessed by two experienced reporters with dual-certification in radiology and nuclear medicine and agreed in consensus. The presence of physiological bowel activity and/or further sites of equivocal uptake on 4-hour planar imaging and whether combined single-photon-emission computed tomography (SPECT)/computed tomography (CT) assessment allowed accurate diagnosis was tabulated. A judgement was also made in each case on whether 2-hour planar imaging was necessary for accurate diagnostic interpretation. RESULTS: Thirty-six patients (72%) had positive findings on Tektrotyd SPECT/CT. Eight patients (16%) had bowel activity on 4-hour planar imaging, which could be considered to have hampered interpretation without access to SPECT/CT. Eleven studies in 10 patients (20%) demonstrated areas of indeterminate uptake on planar imaging; five in the uncinate process of the pancreas, three in the nasal cavity or paranasal sinuses, one in the adrenal glands, one in a focus of inflammation on the posterior abdominal wall, and one at the tip of a central venous line. In all cases, accurate interpretation of findings was possible with SPECT/CT, without the 2-hour planar image. CONCLUSION: Two-hour planar imaging could be safely omitted from Tektrotyd SRS incorporating SPECT/CT imaging without reducing the accuracy of diagnostic interpretation. Streamlined imaging has the potential to reduce patient inconvenience and improve scanner and staff efficiency.

RETINAL DETACHMENT AND RETROBULBAR CYSTS IN A LARGE COHORT OF OPTIC NERVE COLOBOMA.

PURPOSE: To examine the relationship between retinal detachment and retrobulbar cysts in patients with optic nerve coloboma (ONC) and Morning Glory syndrome (MGS). METHODS: Patients diagnosed with either ONC or MGS were identified through a search of the Sick Kids database. Seventy-one patients either agreed to come in for a B-scan or had an incidental orbital B-scan or magnetic resonance imaging or both. Eyes with orbital B-scan ultrasound and/or magnetic resonance imaging images were assessed independently by two ophthalmologists and a radiologist for the presence of retrobulbar cysts. Retinal detachment was identified clinically with either indirect ophthalmoscopy or from fundus photographs. RESULTS: Forty-five of 71 (63%) and 26/71 (37%) patients had ONC and MGS, respectively. Retinal detachment occurred significantly more often in eyes with MGS than with ONC (9/17 [53%] vs. 5/45 [11%], P = 0.03, respectively). Retrobulbar cysts were not detected more often in MGS than in ONC (11/45 [24%] vs. 7/26 [27%]; P = 1.0). Eyes with retrobulbar cysts were significantly more likely to be associated with retinal detachment than those without (7/18 [39%] vs. 7/53 [13%]; P = 0.04). CONCLUSION: Retinal detachment occurs more frequently in MGS than in ONC in a cohort of patients referred to a specialist children's retinal service. Eyes with retrobulbar cysts are more likely to be associated with retinal detachment.

Effect of Kollidon VA®64 particle size and morphology as directly compressible excipient on tablet compression properties.

The study evaluates use of Kollidon VA®64 and a combination of Kollidon VA®64 with Kollidon VA®64 Fine as excipient in direct compression process of tablets. The combination of the two grades of material is evaluated for capping, lamination and excessive friability. Inter particulate void space is higher for such excipient due to the hollow structure of the Kollidon VA®64 particles. During tablet compression air remains trapped in the blend exhibiting poor compression with compromised physical properties of the tablets. Composition of Kollidon VA®64 and Kollidon VA®64 Fine is evaluated by design of experiment (DoE). A scanning electron microscopy (SEM) of two grades of Kollidon VA®64 exhibits morphological differences between coarse and fine grade. The tablet compression process is evaluated with a mix consisting of entirely Kollidon VA®64 and two mixes containing Kollidon VA®64 and Kollidon VA®64 Fine in ratio of 77:23 and 65:35. A statistical modeling on the results from the DoE trials resulted in the optimum composition for direct tablet compression as combination of Kollidon VA®64 and Kollidon VA®64 Fine in ratio of 77:23. This combination compressed with the predicted parameters based on the statistical modeling and applying main compression force between 5 and 15 kN, pre-compression force between 2 and 3 kN, feeder speed fixed at 25 rpm and compression range of 45-49 rpm produced tablets with hardness ranging between 19 and 21 kp, with no friability, capping, or lamination issue.

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.

The resonance® metallic ureteric stent in the treatment of chronic ureteric obstruction: a safety and efficacy analysis from a contemporary clinical series.

BACKGROUND: We evaluate the efficacy and safety of metallic ureteric stenting using the Cook Resonance® stent in the treatment of chronic ureteric obstruction of benign and malignant aetiology. Published experience of using this stent in this context is limited. We add to the body of literature on this topic. METHODS: All patients who had a Resonance® metallic stent inserted between April 2009 and November 2014 in our institution were identified from a prospectively maintained stent-database. Primary outcome was relief of ureteric obstruction, defined by successful clinical and radiological treatment of hydronephrosis/hydroureter. Secondary outcome measures included operative time, radiological exposure, total stent dwell time (defined as the cumulative time in months for which a Resonance® metallic stent was in situ), and early and late complications. RESULTS: Twenty-one patients underwent 52 stent insertion episodes (SIE). Median age was 58 years (range 39-90). Stent insertion resulted in successful treatment of hydronephrosis/hydroureter in 96% (2 SIE resulted in failure to relieve ureteric obstruction). Median operative time was 21 min (range 12-90) Median radiation exposure was 815.3 cGy/cm2 (range 192.9-5366.3). Median stent dwell time was 19.5 months (range 6-52) in non-malignant and 12 months (range 2-48) in malignant ureteric obstruction. One stent migrated proximally during insertion and had to be retrieved using an antegrade approach. 5 patients re-admitted with haematuria: all resolved without intervention or blood transfusion. 3 episodes of post-operative urinary infection were recorded; all were successfully treated with oral antibiotics. CONCLUSION: Metallic ureteric stenting using the Resonance® stent is safe and effective for treating ureteric obstruction from both malignant and benign causes. The success rate in our series is 96%.

Investigating nutrition and lifestyle factors as determinants of abdominal obesity: an environment-wide study.

BACKGROUND: The increasing global trends in obesity and its associated burden of disease indicate a need to identify modifiable determinants of obesity. METHODS: A total of 182 nutrition and lifestyles factors were investigated in relation to abdominal obesity among 7,403 male and 8,328 female participants of the Third U.S. National Health and Examination Survey (NHANES III). We used the first phase (1988-1991) of the NHANES III to identify factors with a false discovery rate (FDR) of <5%. Of these, we tentatively replicated our findings in the second phase (1992-1994) of the survey. Principal component analysis was performed to identify unobserved factors underlying the association between validated factors and abdominal obesity, defined as waist circumference >88 cm for women and >102 cm for men. RESULTS: We found five tentatively replicated factors showing significant associations with abdominal obesity in men: serum α-carotene, ß-carotene, serum ß-cryptoxanthin, serum vitamin D and vigorous physical activity. In women, 7 factors were identified: serum α-carotene, ß-carotene, serum ß-cryptoxanthin, serum vitamin C, serum vitamin D, vigorous physical activity and aspartame intake. In contrast to the other factors which showed inverse associations with abdominal obesity, aspartame intake displayed a positive relationship with this outcome (OR: 1.18, 95% CI: 1.10-1.26 for each log increase in aspartame intake in women). Principal component analysis suggested three principal components underlying such associations, each comprising: (1) serum antioxidants; (2) serum vitamin D and vigorous physical activity; and (3) aspartame intake. All three principal components also displayed significant associations with abdominal obesity. CONCLUSION: Our observational investigation that systematically investigates multiple modifiable factors simultaneously has enabled the creation of data-driven hypotheses regarding the possible role of determinants of abdominal obesity and has identified potential avenues for mechanistic investigations to clarify suitable targets of intervention.

Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery: An International Multicenter Study.

PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.