Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS).

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses several rare conditions resulting from activating variants in PIK3CA. Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies. This study evaluated the safety and efficacy of alpelisib in pediatric and adult patients with PROS. METHODS: EPIK-P1 (NCT04285723) was a non-interventional, retrospective chart review of 57 patients with PROS (≥2 years) treated with alpelisib through compassionate use. Patients had severe/life-threatening PROS-related conditions and confirmed PIK3CA pathogenic variant. The primary end point assessed patient response to treatment at Week 24 (6 months). RESULTS: Twenty-four weeks (6 months) after treatment initiation, 12 of 32 (37.5%) patients with complete case records included in the analysis of the primary end point experienced a ≥20% reduction in target lesion(s) volume. Additional clinical benefit independent from lesion volume reduction was observed across the full study population. Adverse events (AEs) and treatment-related AEs were experienced by 82.5% (47/57) and 38.6% (22/57) of patients, respectively; the most common treatment-related AEs were hyperglycemia (12.3%) and aphthous ulcer (10.5%). No deaths occurred. CONCLUSION: EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS symptom management.

Stereotactic Radiosurgery in the Management of Brain Metastases: A Case-Based Radiosurgery Society Practice Guideline.

Purpose: Brain metastases are common among adult patients with solid malignancies and are increasingly being treated with stereotactic radiosurgery (SRS). As more patients with brain metastases are becoming eligible for SRS, there is a need for practical review of patient selection and treatment considerations. Methods and Materials: Two patient cases were identified to use as the foundation for a discussion of a wide and representative range of management principles: (A) SRS alone for 5 to 15 lesions and (B) a large single metastasis to be treated with pre- or postoperative SRS. Patient selection, fractionation, prescription dose, treatment technique, and dose constraints are discussed. Literature relevant to these cases is summarized to provide a framework for treatment of similar patients. Results: Treatment of brain metastases with SRS requires many considerations including optimal patient selection, fractionation selection, and plan optimization. Conclusions: Case-based practice guidelines developed by the Radiosurgery Society provide a practical guide to the common scenarios noted above affecting patients with metastatic brain tumors.

Reduction in the urinary aflatoxin M1 biomarker as an early indicator of the efficacy of dietary interventions to reduce exposure to aflatoxins.

Aflatoxin B1 is a persistent public health issue in Ghana. Assessment of AFB1 intervention efficacy is currently dependent on long-term biomarkers. This study was designed to determine whether daily AFM1 biomarker levels could be utilized as an early detection method for intervention efficacy. Participants were treated with a refined calcium montmorillonite clay (UPSN) or a placebo (calcium carbonate) in a crossover study. Urine samples were assessed for AFM1 levels daily. UPSN treatment reduced AFM1 biomarkers by 55% compared to the placebo. This is the first study to show that daily urinary AFM1 levels can be used as a biomarker of internal aflatoxin B1 exposure in short-term intervention trials to determine efficacy.

Endoscopic Reconstruction of the Anterior Skull Base Following Tumor Resection: Application of a Novel Bioabsorbable Plate.

OBJECTIVE: Endoscopic repair of skull base defects is required following resection of intracranial pathology via the endoscopic endonasal approach (EEA). Many closure techniques have been described, but choosing between techniques remains controversial. We report outcomes of 560 EEA procedures of skull base reconstruction performed on 508 patients over a 15-year-period. Halfway through this period, we adopted the use of a rigid, bioabsorbable extrasellar plate for reconstruction, enabling a comparison between this technique and those used previously. METHODS: All patients undergoing EEA from 2005 to 2019 at our institution were retrospectively reviewed. Demographic information, surgical pathology, tumor dimensions and radiographic features, reconstructive technique, and patient-related outcomes were collected and analyzed with univariate and multivariate statistical modeling. RESULTS: Five-hundred sixty procedures were performed on 508 patients. The series complication rate was 8.2%. Overall, cerebrospinal fluid (CSF) leak rate was 5.0% but varied significantly across closure techniques (p < 0.001). Critically, the CSF leak rate in the 272 cases prior to our 2013 adoption of the Resorb-X Plate (RXP) was 8.5%, whereas leak rate in the subsequent 288 cases was 1.7%. RXP was protective against CSF leak (p = 0.001), whereas gross total resection (GTR) correlated with increased leak rate (p = 0.001). Patient BMI was significantly associated with risk of leak (p = 0.047). Other variables did not impact leak risk. CONCLUSION: Reconstructive technique, extent of resection, and patient BMI significantly contributed to CSF leak rate. GTR was associated with increased leak risk while the RXP was protective. The bioabsorbable RXP is an effective option for rigid skull base repair with comparatively few complications. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1092-1098, 2023.

Age, body mass index, and osteoporosis are more predictive than imaging for adjacent-segment reoperation after lumbar fusion.

BACKGROUND: Adjacent-segment disease (ASD) is a well-described long-term complication after lumbar fusion. There is a lack of consensus about the risk factors for development of ASD, but identifying them could improve surgical outcomes. Our goal was to analyze the effect of patient characteristics and radiographic parameters on the development of symptomatic ASD requiring revision surgery after posterior lumbar fusion. METHODS: In this retrospective cohort study, we identified patients who underwent lumbar fusion surgery and revision surgery from May 2012 to November 2018 using an institutional lumbar fusion registry. Patients having both pre- and post-operative upright radiographs were included in the study. Revision surgeries for which the index operation was performed at an outside hospital were excluded from analysis. Univariate analysis was conducted on candidate variables, and variables with P< 0.2 were selected for multivariate logistic regression. RESULTS: Of the 106 patients identified, 21 required reoperation (29 months average follow-up). Age >65 years (OR 4.14, 95% CI 1.46-11.76, P= 0.008), body mass index (BMI) >34 (OR 1.13, 95% CI 1.04-1.23, P = 0.004), and osteoporosis (OR 14, 95% CI 1.38-142.42, P = 0.03) were independent predictors of reoperation in the multivariate analysis. Increased facet diastasis at fusion levels (OR 0.60, 95% CI 0.42-0.85, P = 0.004) was associated with reduced reoperation rates. Change in segmental LL at the index operation level, rostral and caudal facet diastasis, vacuum discs, and T2 hyperintensity in the facets were not predictors of reoperation. CONCLUSION: Age >65, BMI >34, and osteoporosis were independent predictors of adjacent-segment reoperation after lumbar spinal fusion.

Case series of sphenoid wing meningioma - What is a maximal safe resection?

BACKGROUND: Sphenoid wing meningiomas are a challenging surgical disease with relatively high perioperative morbidity. Most studies to date have focused on resection strategies as it relates to disease recurrence. Few have examined the optimal strategy as it relates to overall patient survival. We retrospectively reviewed our case series and evaluated extent of resection and perioperative stroke as it relates to all cause and disease-specific survival. PATIENTS/METHODS: Ninety-four patients were included in the study. Demographics, clinical features, operative features and clinical course, and time to mortality evaluation were collected. Extent of resection (EOR) was defined as gross total (GTR, 100%), near total (NTR, ≥ 95%), and subtotal (STR,<95%). RESULTS: The overall mean EOR was 94.5% with 70.2% of cases achieving GTR, 12.8% achieved NTR, and 17% achieved STR. Postoperative stroke only occurred with GTR or NTR (p=0.041). Age alone was significant on Cox regression analysis for all cause mortality (p=0.042, HR 1.054 [95% CI 1.002 - 1.109]). Postoperative stroke was associated with worse disease-specific mortality (p=0.046, HR 23.337 [95% CI 1.052 - 517.782) with no impact from extent of resection (p=0.258). CONCLUSIONS: Although maximizing resection and minimizing recurrence is ideal, GTR or NTR confer a significantly higher stroke risk. Most patients do not die from their meningioma, as all cause mortality was associated only with age. However, perioperative stroke conferred decreased survival throughout follow up. This series demonstrates that an overly aggressive surgical philosophy negatively impacted disease specific survival.

Effect of Chronic Alcoholism on Traumatic Intracranial Hemorrhage.

BACKGROUND: Traumatic intracranial hemorrhage (TICH) is one of the commonest indications for neurosurgical consultation after trauma. Worsening neurologic examination results, size of initial TICH, presence of displaced skull fracture, and concomitant anticoagulant use at the time of injury drive the recommendations for repeat computed tomography of head (RCTH), to assess for stability of intracranial hemorrhage. Chronic alcohol use is not generally considered an indication for repeat head computed tomography (CT). METHODS: A retrospective study of 423 patients with TICH with normal admission platelet (PLT) counts was reviewed for this study, taken as a subset of 1330 patients with TICH admitted to Lahey Hospital and Medical Center over a 3-year period. Of these 423 patients, 330 were classified as nonalcoholics and 93 were classified as alcoholics, based on whether alcohol use disorder was documented in the patient's medical record, present before injury. The normal PLT level was defined as ≥100,000 µ/L. Patients were excluded from review if they had comorbid conditions that could cause PLT dysfunction or coagulopathy. Continuous and categorical variables were compared using independent t test and χ2, respectively. Binary logistic regression was used to predict outcome: stable versus worsening of TICH on RCTH. Statistical analysis was conducted using SPSS version 25. RESULTS: The mean age of the nonalcoholic and alcoholic cohorts were 71.9 years and 54.8 years, respectively. A significantly higher percentage of alcoholics were male. There was a statistically significant difference (χ2 = 8.14; P < 0.004) in radiologic progression of TICH between the 2 groups, with the alcoholics having a worsening RCTH 16.1% of the time compared with only 6.7% in nonalcoholics. Chronic alcohol use was an independent predictor of radiologic progression in patients with normal PLT level (odds ratio, 2.69; confidence interval, 1.34-5.43; P < 0.006). CONCLUSIONS: Chronic alcohol use was an independent predictor of radiologic progression of TICH in the setting of normal PLT level. Modification of this risk of progression with transfusion of fresh PLTs in chronic alcoholic patients with TICH needs to be investigated in a prospective trial.

Use of Microspore-Derived Calli as Explants for Biolistic Transformation of Common Wheat.

There are specific advantages of using microspores as explants: (1) A small number of explant donors are required to obtain the desired number of pollen embryoids for genetic transformation and (2) microspores constitute a synchronous mass of haploid cells, which are transformable by various means and convertible to doubled haploids therefore allow production of homozygous genotypes in a single generation. Additionally, it has been demonstrated in wheat and other crops that microspores can be easily induced to produce embryoids and biolistic approach to produce a large number of transformants. In view of these listed advantages, we optimized the use of microspore-derived calli for biolistic transformation of wheat. The procedure takes about 6 months to obtain the viable transformants in the spring wheat background. In the present communication, we demonstrated the use of this method to produce the reduced immunogenicity wheat genotypes.

PAH exposure in a Ghanaian population at high risk for aflatoxicosis.

It was postulated that a population in sub-Saharan Africa, known to be at high risk for aflatoxicosis due to frequent ingestion of aflatoxin (AF)-contaminated foods could also be exposed to polycyclic aromatic hydrocarbons (PAHs) from a variety of environmental sources. Previously, participants in this population were shown to be highly exposed to AFs, and this exposure was significantly reduced by intervention with NovaSil clay (NS). Objectives of this study were 1) to assess PAH exposure in participants from the AF study using urinary biomarker 1-hydroxypyrene (1-OHP); 2) examine the effect of NS clay and placebo (cellulose) treatment on 1-OHP levels; and 3) determine potential association(s) between AF and PAH exposures. A clinical trial was conducted in 177 Ghanaians who received either NS capsules as high dose or low dose, or placebo (cellulose) for a period of 3 months. At the start and end of the study, urine samples were analyzed for 1-OHP. Of the 279 total samples, 98.9% had detectable levels of 1-OHP. Median 1-OHP excretion in nonsmokers was 0.64 micromol/mol creatinine at baseline and 0.69 micromol/mol creatinine after 3 months. Samples collected at both time points did not show significant differences between placebo and NS-treated groups. There was no linear correlation between 1-OHP and AF-albumin adduct levels. Results show that this population is highly exposed to PAHs (and AFs), that NS and cellulose treatment had no statistically significant effect on 1-OHP levels, and that this urinary biomarker was not linearly related with AF exposure.

Doubled Haploid Transgenic Wheat Lines by Microspore Transformation.

Microspores are preferred explant choice for genetic transformation, as their use shortens the duration of obtaining homozygous transformants. All established gene-delivery methods of particle bombardment, electroporation, and cocultivation with Agrobacterium tumefaciens were optimized on androgenic microspores or derived tissues. In the biolistic gene delivery method 35-40 days old haploid microspore embryoids were used for genetic transformation, whereas freshly isolated androgenic microspores were used for genetic transformation in the electroporation and Agrobacterium cocultivation-based methods. The genetic transformation methods of biolistic gene-delivery and electroporation gave rise to the chimeric plants, whereas the method involving cocultivation with Agrobacterium yielded homozygous transformants. These methods were tested on a large number of cultivars belonging to different market classes of wheat, and found to be fairly independent of the explant genotype. Other benefits of using microspores or derived tissues for transformation are: (1) a few explant donors are required to obtain desired transformants and (2) the time required for obtaining homozygous transformants is about 8 months in case of spring wheat genotypes and about a year in case of winter wheat genotypes.

Short-term safety and efficacy of calcium montmorillonite clay (UPSN) in children.

Recently, an association between childhood growth stunting and aflatoxin (AF) exposure has been identified. In Ghana, homemade nutritional supplements often consist of AF-prone commodities. In this study, children were enrolled in a clinical intervention trial to determine the safety and efficacy of Uniform Particle Size NovaSil (UPSN), a refined calcium montmorillonite known to be safe in adults. Participants ingested 0.75 or 1.5 g UPSN or 1.5 g calcium carbonate placebo per day for 14 days. Hematological and serum biochemistry parameters in the UPSN groups were not significantly different from the placebo-controlled group. Importantly, there were no adverse events attributable to UPSN treatment. A significant reduction in urinary metabolite (AFM1) was observed in the high-dose group compared with placebo. Results indicate that UPSN is safe for children at doses up to 1.5 g/day for a period of 2 weeks and can reduce exposure to AFs, resulting in increased quality and efficacy of contaminated foods.

Assessment of genetic diversity among barley cultivars and breeding lines adapted to the US Pacific Northwest, and its implications in breeding barley for imidazolinone-resistance.

Extensive application of imidazolinone (IMI) herbicides had a significant impact on barley productivity contributing to a continuous decline in its acreage over the last two decades. A possible solution to this problem is to transfer IMI-resistance from a recently characterized mutation in the 'Bob' barley AHAS (acetohydroxy acid synthase) gene to other food, feed and malting barley cultivars. We focused our efforts on transferring IMI-resistance to barley varieties adapted to the US Pacific Northwest (PNW), since it comprises ∼23% (335,000 ha) of the US agricultural land under barley production. To effectively breed for IMI-resistance, we studied the genetic diversity among 13 two-rowed spring barley cultivars/breeding-lines from the PNW using 61 microsatellite markers, and selected six barley genotypes that showed medium to high genetic dissimilarity with the 'Bob' AHAS mutant. The six selected genotypes were used to make 29-53 crosses with the AHAS mutant and a range of 358-471 F1 seeds were obtained. To make informed selection for the recovery of the recipient parent genome, the genetic location of the AHAS gene was determined and its genetic nature assessed. Large F2 populations ranging in size from 2158-2846 individuals were evaluated for herbicide resistance and seedling vigor. Based on the results, F3 lines from the six most vigorous F2 genotypes per cross combination were evaluated for their genetic background. A range of 20%-90% recovery of the recipient parent genome for the carrier chromosome was observed. An effort was made to determine the critical dose of herbicide to distinguish between heterozygotes and homozygotes for the mutant allele. Results suggested that the mutant can survive up to the 10× field recommended dose of herbicide, and the 8× and 10× herbicide doses can distinguish between the two AHAS mutant genotypes. Finally, implications of this research in sustaining barley productivity in the PNW are discussed.

Generation of doubled haploid transgenic wheat lines by microspore transformation.

Microspores can be induced to develop homozygous doubled haploid plants in a single generation. In the present experiments androgenic microspores of wheat have been genetically transformed and developed into mature homozygous transgenic plants. Two different transformation techniques were investigated, one employing electroporation and the other co-cultivation with Agrobacterium tumefaciens. Different tissue culture and transfection conditions were tested on nine different wheat cultivars using four different constructs. A total of 19 fertile transformants in five genotypes from four market classes of common wheat were recovered by the two procedures. PCR followed by DNA sequencing of the products, Southern blot analyses and bio/histo-chemical and histological assays of the recombinant enzymes confirmed the presence of the transgenes in the T0 transformants and their stable inheritance in homozygous T1∶2 doubled haploid progenies. Several decisive factors determining the transformation and regeneration efficiency with the two procedures were determined: (i) pretreatment of immature spikes with CuSO4 solution (500 mg/L) at 4°C for 10 days; (ii) electroporation of plasmid DNA in enlarged microspores by a single pulse of ∼375 V; (iii) induction of microspores after transfection at 28°C in NPB-99 medium and regeneration at 26°C in MMS5 medium; (iv) co-cultivation with Agrobacterium AGL-1 cells for transfer of plasmid T-DNA into microspores at day 0 for <24 hours; and (v) elimination of AGL-1 cells after co-cultivation with timentin (200-400 mg/L).

Investigating the multi-causal and complex nature of the accident causal influence of construction project features.

Construction project features (CPFs) are organisational, physical and operational attributes that characterise construction projects. Although previous studies have examined the accident causal influence of CPFs, the multi-causal attribute of this causal phenomenon still remain elusive and thus requires further investigation. Aiming to shed light on this facet of the accident causal phenomenon of CPFs, this study examines relevant literature and crystallises the attained insight of the multi-causal attribute by a graphical model which is subsequently operationalised by a derived mathematical risk expression that offers a systematic approach for evaluating the potential of CPFs to cause harm and consequently their health and safety (H&S) risk implications. The graphical model and the risk expression put forth by the study thus advance current understanding of the accident causal phenomenon of CPFs and they present an opportunity for project participants to manage the H&S risk associated with CPFs from the early stages of project procurement.

HIV and hepatocellular and esophageal carcinomas related to consumption of mycotoxin-prone foods in sub-Saharan Africa.

BACKGROUND: Promotion of the HIV epidemic by aflatoxin is postulated but not yet established. Sub-Saharan populations commonly consume food contaminated by mycotoxins, particularly aflatoxins (predominantly found in peanut, maize, rice, and cassava) and fumonisins, which occur primarily in maize. Aflatoxin promotes hepatocellular cancer, and fumonisin may promote esophageal cancer. OBJECTIVES: This analysis was undertaken to test the hypotheses that consumption of mycotoxin-prone staple foods is 1) related to the incidence of HIV infection in Africa and 2) related to "signature" cancer rates confirming exposure to aflatoxins and fumonisins. DESIGN: World Health Organization data for causes of death and the Food and Agriculture Organization per capita consumption data for commodities in sub-Saharan Africa were used. Per capita Gross Domestic Product and the percentage of Muslims (%Muslim) were the socioeconomic data sets exploited. Relations between causes of mortality, consumption of mycotoxin-prone foods, and socioeconomic variables were evaluated. Models for HIV transmission as a function of maize consumption and %Muslim were estimated. RESULTS: HIV and esophageal cancer deaths were significantly related to maize but were inversely related to %Muslim and rice consumption. HIV infections were minimized (74 compared with 435/100,000 people; odds ratio: 2.41; 95% CI: 1.73, 3.24; P < or = 0.0001) by the combination of low maize consumption and above-median % Muslim. Hepatocellular cancer deaths were positively related to rice but negatively related to maize consumption. CONCLUSIONS: HIV transmission frequency is positively associated with maize consumption in Africa. The relation between cancer and food suggests that fumonisin contamination rather than aflatoxin is the most likely factor in maize promoting HIV. Changes to the quality of maize may avoid up to 1,000,000 transmissions of HIV annually.

Evaluation of efficacy and safety of a herbal medicine used for the treatment of malaria.

Resistance of Plasmodium falciparum to chloroquine has been reported in several countries. Other anti-malarial drugs in use are expensive and not readily accessible to most people in malaria endemic countries. This has led to renewed interest in the development of herbal medicines that have the potential to treat malaria with little or no side effects. This study obtained a preliminary information on the safety and effectiveness of a plant decoction (AM-1), used in treating malaria. The AM-1 is formulated from Jatropha curcas, Gossypium hirsutum, Physalis angulata and Delonix regia. Patients with suspected malaria attending a herbal clinic were enrolled in the study on voluntary basis. They were hospitalized for treatment, clinical observation, biochemical and haematological monitoring, and parasite clearance while on AM-1. In addition male and female Sprague Dawley rats were used to evaluate the acute and subchronic toxicity effects of AM-1. The AM-1 eliminated malaria parasites (Plasmodium falciparum and Plasmodium malarie) from the peripheral blood of patients with malaria. In addition the AM-1 did not show any undesired effects in the patients as well as in laboratory rats. The AM-1, however, showed differential effect on the activities of selected cytochrome P450 isozymes (7-pentoxyresorufin-O-depentylation, 7-ethoxyresorufin-O-deethylation and p-nitrophenol hydroxylase) in relation to sex of the laboratory rats. These results indicate that AM-1 could be used to treat malaria. However, it could precipitate interactions with other drugs via their biotransformation and elimination. The obtained data warrant further studies in a large number of malaria subjects with monitoring for possible drug interactions.