ABSTRACT
Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient-derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain. SIGNIFICANCE STATEMENT Given the invasive nature of glioblastoma (GBM), tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain-penetrant molecules for effective treatment. We show that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor-bearing mouse brains, indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.Copyright © 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.
ABSTRACT
Alcohol use disorder (AUD) is highly prevalent in Australia.(1) However, best practice management of AUD in the community post discharge from hospital is not well articulated in the literature. In particular, given the harmful effects excessive alcohol consumption has on nutritional status there is a need to identify what approaches are being utilised in managing this vulnerable group.(2) Hence the aim of this scoping review was to identify the current approaches and outcomes with respect to nutritional care as identified by the Nutrition Care Process Model (NCPM) for patients discharged from hospital post alcohol withdrawal. This scoping review was registered with OpenScience Framework (words: PubMed, CINAHL, Web of Science and Scopus. Articles included were published between January 1995 and April 2022 Eligible articles were screened independently by pairs of reviewers, and consensus was reached across pairs to provide inter-rater and inter-consensus reliability. Screening and data extraction was conducted using Covidence by reviewers HM, ATM, CM, SG Fourteen articles were eligible for inclusion. Approaches to nutritional care was identified based on the intervention utilised and in comparison to the NCPM.(3) Key findings were screening for nutrition related problems and anthropometry measures were the most evaluated (n = 10), whereas practices of referral providing continuum of care were highlighted in only a minority of studies (n = 3). Education interventions included Motivational Interviewing and cognitive behavioural therapy sessions (4) (n = 7). Few studies (n = 4) which combined harm-reduction counselling with nutritional approaches and education interventions showed significant improvement (p < 0.05) in outcome measures of nutritional care. This was measured through the improvement in nutritional status (positive eating habits, decrease in nutrition-related impact symptoms, and WHO Quality of Life (QoL) health and physical domains) Limitations include varying aims of analysis and a paucity of information in this area. There is a need for further studies to be completed in this area to understand the nature of this complex issue and recommend effective strategies to improve health outcomes for individuals and populations.
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Background: Breast cancer accounts for 35-40% of cancer in women in Lebanese and Arab countries with 50% of patients (pts) diagnosed before age 50. Prevalence of pathogenic BRCA variants in high-risk pts is 5.6-20% (Abulkhair and El Saghir 2021). 7 BRCA1 and 7 BRCA2 pathogenic variants were found in 5.6% of 250 pts with high hereditary risk breast cancer using amplicon sequencing and MLPA (El Saghir 2015;Poulet 2016). We report results of Next Generation Sequencing (NGS) on selected cases based on Manchester Score. First report in ethnic Lebanese Arab pts. Method(s): Pts prospectively enrolled in 2009-2012. IRB approval secured. Pts signed informed consent. Data collected from medical records. Amplicon and MLPA was done on 250 patients. NGS was done on 100 cases with Manchester Score 14-56. DNAs of the 14 pts previously found to have a pathogenic variant (Manchester Score 10-59) were not re-sequenced. NGS on remaining 150 pts was not done due to Covid-19 pandemic and lack of additional funding. Result(s): NGS showed 7 pathogenic variants, 4 in PALB2 and 3 in ATM. No new BRCA variants were found. Two BRCA2 mutations noted by Amplicon/MLPA reported as VUS in 2015 are reclassified as pathogenic. Total BRCA2 pathogenic variants becomes 9. Total pathogenic variants 23. Risk of having hereditary breast cancer in pts with MS 10-59 is 20% (23/ 114), and at least 9.2% in the entire cohort (23/250). Age <=40 with family history (FH) carries 18.9% risk of harboring a pathogenic mutation while no FH, 1.4% (Table 1). All BRCA1 pts had triple negative and 7/9 BRCA2 pts had hormone receptor positive breast cancer. 4 unrelated pts shared the same c.1056_1057delGA PALB2 pathogenic variant thus we suggest this is a founder mutation in Lebanese Ethnic Arab population. Conclusion(s): Mutation rates in high hereditary risk pts with Manchester Score range 10-59 is 20%. Age <=40 with positive FH can be used to select pts for testing when resources are limited. Our data suggests that c.1056_1057delGA is a PALB2 founder mutation. No conflict of interest.Copyright © 2022 Elsevier Ltd. All rights reserved
ABSTRACT
Background: The international, multi-center Pancreatic Cancer Early Detection (PRECEDE) Consortium enrolls high-risk individuals (HRIs) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Enrollment began in 2020, and despite challenges related to the COVID-19 pandemic, the PRECEDE Consortium rapidly accrued a large cohort of HRIs. The purpose of this study is to describe the characteristics of this cohort and assess racial, ethnic, and sex-based disparities. Method(s): The PRECEDE Consortium (NCT04970056) is a prospective, multicenter study focused on improving survival from PDAC through early detection. Data from all HRIs who met criteria for PDAC surveillance and enrolled between May 2020 - March 2022 were collected and included in the analysis. Result(s): During the study period, 1299 HRIs enrolled in PRECEDE at 32 centers. HRIs were excluded if enrollment data was incomplete or criteria for PDAC surveillance were not met. Of 1113 who were included, 47.2% met criteria for familial pancreatic cancer (FPC) and 45.4% had a family history of PDAC along with a PV in a PDAC-risk gene (BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). The remainder had familial atypical mole melanoma syndrome (5.7%), Peutz- Jeghers syndrome (1.6%), or hereditary pancreatitis (0.2%). More females than males enrolled (65.9% vs. 33.5%). The distribution of HRIs by race and ethnicity is depicted;the majority identified as white (87.7%). Study participants were primarily from the US (82.7%), the median age was 61 (27-85) and 18.5% had Ashkenazi Jewish ancestry. Nearly all HRIs consented to allow access to imaging data (99.6%), collection of germline DNA (97.7%), and biosample collection (99.5%). There were no race, ethnicity, or sex-based differences in rates of consent for collection of imaging, DNA, or biosamples. Conclusion(s): Enrollment of HRIs in prospective studies of PDAC surveillance is essential for advancing early detection research in PDAC. A distinct advantage of the PRECEDE Consortium for examining enrollment disparities is that recruitment began in 2020, providing a unique and current snapshot of the international PDAC surveillance landscape. Despite the recent attention on addressing disparities in healthcare delivery, significant racial, ethnic, and sex-based disparities persisted in the cohort of HRIs enrolled in the PRECEDE Consortium. Ensuring that the diversity of participants in the PRECEDE Consortium mirrors the communities served by participating centers is crucial. Further examining and addressing the reasons for these disparities is a major focus of the PRECEDE Consortium moving forward.
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Very early after their discovery, X-rays were used in multiple medical applications, such as treatments against cancer, inflammation and pain. Because of technological constraints, such applications involved X-ray doses lower than 1 Gy per session. Progressively, notably in oncology, the dose per session increased. However, the approach of delivering less than 1 Gy per session, now called low-dose radiation therapy (LDRT), was preserved and is still applied in very specific cases. More recently, LDRT has also been applied in some trials to protect against lung inflammation after COVID-19 infection or to treat degenerative syndromes such as Alzheimer's disease. LDRT illustrates well the discontinuity of the dose-response curve and the counterintuitive observation that a low dose may produce a biological effect higher than a certain higher dose. Even if further investigations are needed to document and optimize LDRT, the apparent paradox of some radiobiological effects specific to low dose may be explained by the same mechanistic model based on the radiation-induced nucleoshuttling of the ATM kinase, a protein involved in various stress response pathways.
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Clinical Information Patient Initials or Identifier Number: Mr. AL Relevant Clinical History and Physical Exam: 59-year-old gentleman. CAD risk factors: Hypertension, Diabetes Mellitus, Dyslipidaemia, Positive family history of CAD. Admitted with Acute Anterior MI & got Tenecteplase. Relevant Test Results Prior to Catheterization: Troponin-I: >50000 ng/L, ECG: ST Elevation in V1-V6, Echo: Anterior wall is hypokinetic with Mild LV systolic dysfunction (EF- 45%). Hb-14.2 gm/dl, Creatinine: 1.12 mg/dl, Na- 135, K- 4.0, Cl- 100 m mol/L, Plasma BNP: 235 pg/ml, COVID-19 RT-PCR- Negative, S. Bilirubin- 0.3 mg/dl, ALT- 45 IU/L, AST- 107 IU/L, Anti-HCV- Negative, Anti-HIV- Negative, HbsAg- Negative, Relevant Catheterization Findings: LMCA: Normal. LAD: Got 90-99% narrowing in its proximal segment followed by 90-99% diffuse disease. DG1 is small and diseased. DG2 has got sub-total occlusion at its origin. LCX: Good size artery with mild ostial narrowing & 50% narrowing in its mid segment. Principal OM has got 50% narrowing in its ostium. RCA: Dominant artery has got 60% narrowing in its proximal segment. PDA is a good size artery & got mild irregular narrowing in its proximal segment. Recommendation: PCI to LAD [Formula presented] [Formula presented] [Formula presented] Interventional Management Procedural Step: LCA was engaged with guiding catheter EBU -3.5 (6F). Sion Blue wire crossed the lesion of LAD, another wire crossed the lesion of Diagonal branch and pre-dilatation was done with 2.0 x 15 mm balloon at 08-10 ATM. Proximal lesion was stented with a 2.75 mm x 18 mm stent (Xience Alpine) at 12-14 ATM. After withdrawing the wire following angiogram showed proximal LAD was well dilated but mid LAD having a long dissection which interrupted the distal flow. So, decided to put stent in mid LAD. Again, repeated ballooning was done in mid LAD to prepare the lesion and a 2.25 mm x 28 mm stent (Xience Xpedition) was taken for mid LAD but stent didn't cross the mid LAD lesion. During stent withdrawal, it was struck in the previous Proximal stent and proximal calcified segment. When trying to pull it back, the delivery system shaft was tear off. Tried to get the shaft by coronary snare but failed to get it back. Finally, he was recommended to retrieve the torn delivery system & stent surgically. [Formula presented] [Formula presented] [Formula presented] Conclusions: • Stent with torn delivery system entrapment might not be rare. • In this situation, emergency decision to tackle the situation and Bail out decision to send the patient for surgical retrieval of the delivery system & stent saved the life of the patient. Take Home Message: • No case is simple in intervention. • Preparedness to tackle any untoward consequence is the key to success and save lives.
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Purpose: National guidelines recommend universal germline genetic testing (GT) for patients with Pancreatic Ductal Adenocarcinoma (PDAC), but rates of testing remain low. Given the aggressiveness of PDAC, the window of opportunity for GT is short and often overshadowed by treatment initiation and other clinical milestones. Thus, there is an unmet need for a model that streamlines GT and makes it available to a wider audience in a rapid fashion. Moreover, in pandemic times, video-based alternatives for medical care are increasingly relevant. Methods: We implemented a novel care delivery model in which a seven-minute educational video describing the benefits, risks, and implications of GT was shown to PDAC patients. The video was shown in lieu of an initial consult with a genetic counselor. Only patients who had not undergone GT or previously met with a genetic counselor were included. After watching the video, patients could elect to pursue GT and get tested on-side or remotely (at home). Genetic counselors disclosed results and provided post-test counseling by phone. Clinical and germline data were collected through medical records on a cohort of PDAC patients seen at the Gastrointestinal Center-MD Anderson during a 2-year enrollment period (May 2019-July 2021), which included the COVID-19 pandemic period. Results: A total of 286 PDAC patients watched the educational video. From 175 patients that watched the video pre-pandemic, 12 declined testing, whereas in the post-pandemic period, none of the 111 patients declined testing (6.9% vs 0%;p<0.004). We excluded data from 29 patients who elected to undergo GT but declined to participate in the registry. From the 241 patients with successfully collected samples, 21 patients (8.7%) had a pathogenic variant (PV), 38 patients (15.8%) had a Variant of Uncertain Significance (VUS), and 182 patients (75.5%) tested negative. The pathogenic variants detected included: BRCA2 (most frequent), ATM, BRCA1, CDKN2A, PALB2 and APC. Conclusions: GT can have tremendously beneficial effects, such as qualifying for targeted treatment options and facilitating cancer prevention in probands' at-risk family members. Comparing uptake of GT pre- versus post-pandemic suggests that patients were more willing to trust information from a video platform, likely due to the global effect of living in a virtual society as a result of the pandemic. We suggest an approach in which every PDAC patient is shown a genetics educational video and given the choice to undergo GT and post-result counseling, greatly reducing the burden on genetic counselors. We report here the feasibility of implementing video-based germline testing in PDAC patients which resulted in unexpectedly high uptake levels, particularly post-pandemic. Further investigations are needed to explore the feasibility of a fully remote GT model in diverse populations to assess additional barriers to universal GT.
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Objective: To describe, to the best of our knowledge, the first case of myelin oligodendrocyte glycoprotein (MOG) antibody syndrome associated with the Moderna COVID-19 mRNA vaccine, and a case of acute transverse myelitis (ATM) associated with the Pfizer COVID-19 mRNA vaccine. Background: Post-vaccination CNS demyelinating syndromes have been reported with different vaccines, most notably the influenza and human papilloma vaccines. Two cases of new-onset multiple sclerosis (MS) and a case of new-onset neuromyelitis optica (NMO) associated with the Pfizer vaccine have been reported. One case of new-onset relapsing-remitting MS was reported after the Moderna vaccine. Design/Methods: NA Results: A 38-year-old man developed left blurry vision, lower extremity weakness/paresthesia and bowel/bladder dysfunction three days after receiving the Moderna vaccine. He was diagnosed with left optic neuritis and longitudinally extensive transverse myelitis;he tested positive for MOG antibody. A 39-year-old woman presented with progressive lower extremity weakness/numbness seven days after receiving the Pfizer vaccine. She was diagnosed with ATM. Both patients improved with intravenous corticosteroids. Conclusions: The association between CNS demyelinating syndromes and vaccination has been reported for many years. The proposed pathogenesis of CNS demyelinating syndromes after vaccines includes molecular mimicry, epitope spreading, bystander activation, polyclonal activation, effects of adjuvants, and depends on vaccine-related factors like type, dose, and route of administration. The adjuvanticity of COVID-19 vaccines is novel in that it involves Toll-like Receptor (TLR) 7 and 9 agonism, and several immune-mediated disorders have been linked to altered nucleic acid metabolism and processing that have stimulated TLR-7 and TLR-9 experimentally. While the risk of CNS demyelinating events is non-negligible, the incidence is very low. The rate of demyelinating events after the COVID-19 infection is higher. Therefore, we feel that the overall benefits of vaccination outweigh the marginal risk. However, providers should be aware of this potential neurological complication of the COVID-19 mRNA vaccines.
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BACKGROUND AND AIMS: Patients with ESRD present high symptom burden and impaired health-related quality of life (HRQoL). While the maintenance of medical Key Performance Indicators (KPIs) within defined ranges has been traditionally the focus for dialysis patients' healthcare, there is now increasing evidence of how selfreported HRQoL data could also significantly impact their outcomes. The inclusion of these data, using Patient-Reported Outcomes Measurements (PROM), to the routine medical practice works in favor of providing personalized treatments and detecting new outcomes' predictive factors. In the present study, we aimed to evaluate possible correlations between demographic and clinical variables as well as the COVID-19 incidence rate with HRQoL scores in a haemodialysis patients' cohort. METHOD: This is a retrospective, observational analysis performed in a total of 47 clinics from Fresenius Medical Care (FMC) Spain in the last quarter of 2021. Patients' demographic and clinical variables were obtained from EuCliD ® (European Clinical database). As part of our Healthcare Quality Improvement Program, HRQoL measurements were assessed using the KDQOLTM-36 questionnaire by an electronic device (ePROM). This questionnaire was developed specifically for patients affected by kidney disease and combines a generic assessment, which evaluates Physical and Mental Composite Scores (PCS and MCS, respectively) and three disease-specific scales where Effects, Burden and Symptoms dimensions are scored (EKD, BKD and SKD) [1]. For all clinics, we also collect data regarding their Spanish region, the presence or not of multidisciplinary teams in their staff and their number of active issues. This last parameter, part of FMC Balanced Scorecard, is calculated according to the number of KPIs below range, where a higher score indicates a higher number of active issues. Finally, the COVID-19 incidence rate adjusted per region was obtained from the Spanish Ministry of Health register. The mean (±SD) for quantitative variables and frequencies (%) for those categorical were calculated. We explored possible correlations between the HRQoL average scores and the different variables included in the study. All tests were performed using IBM ® SPSS ® Statistics V19 software and a P-value < 0.05 was considered statistically significant. RESULTS: A total of 3480 ePROM were completed (patients' response rate = 82.4%, Figure 1). Descriptive parameters for demographic and clinical variables are shown in Table 1. The different KDQOLTM-36 average scores were the following: PCS: 39.3 ± 2.3;MCS: 47 ± 3;EKD: 70 ± 7.4;BKD: 48.1 ± 8.9 and SKD: 81.2 ± 4.3. We found positive correlations between the presence of nutritionist staff with MCS and the quality of dialysis treatment (measured by OCM Kt/V) and the frequency of AVF as vascular access with EKD score. Unexpectedly, the Charlson Comorbidity Index (CCI) showed positively correlation with PCS. Regarding negative correlations, variables as the Spanish region, the proportion of women in the clinics, body composition parameters (ATM and FTM) and serum P concentration were all associated with PCS. We also observed that EKD scores could be affected in those clinics with a higher number of active issues. Moreover, high levels of CRP or Vitamin D may lead to worsening symptoms. Interestingly, we finally observed how a higher incidence rate of COVID-19 in the region could influence the BDK score in patients receiving haemodialysis treatment. CONCLUSION: Although further analyses are needed, our study showed the correlation of HRQoL scores obtained by ePROM with factors of great impact in patients' outcomes. According to provide a higher healthcare quality and personalized treatments for ESRD patients, an integral approach considering their HRQoL data should be essential.
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Background: Multi-gene cancer panels, available since 2013, have been used in routine clinical practice for the past six years. A significant concern in the uptake of panel testing by both clinicians and patients is the possibility of receiving a variant of uncertain significance (VUS). There are no published standard VUS rates, however, labs have anecdotally reported a rate of 1–1.3% per gene. The VUS rate in cancer panels has fallen drastically since the introduction of testing. This rate may continue to fall with the implementation of data sharing platforms, like ClinVar. With the exception of founder mutations, pathogenic variant rates are similar across different ethnic groups, however, VUS rates are significantly higher in non-white ethnic groups. In 2017, our center assessed the VUS rate for our mostly urban, ethnically diverse patient population. At that time, out of 478 patients who underwent multi-gene cancer testing, 162 (33.8%) were found to have at least one VUS;the overall VUS to gene ratio was 1.64%. With this study, we aim to observe our current VUS rate in order to assess whether there is a decrease in VUS in our center similar to that observed nationally. Methods: As part of our routine clinical practice, the results of all patients referred for cancer genetic counseling for a personal or family history of cancer are maintained in a secure, HIPPA-compliant database. The entries of all patients who completed a genetics consultation in 2020 were reviewed. Patients were excluded from analysis if they did not pursue genetic testing or if they pursued single gene or single site testing. Patients who completed any multi-gene cancer panel testing were included. The number of genes included in the panels varied due to reported history and patient preference. Results were analyzed for presence or absence of pathogenic variants and VUS. Results: In 2020, 768 patients completed a cancer genetics consultation. The majority of our patients (624/768 or 81%) reside in the Bronx. 20 patients (3%) reside in other New York City (NYC) boroughs and the remaining 124 patients reside outside of NYC. Of the 768 patients, 450 (59%) had a personal history of cancer and 318 (41%) had a family history of cancer only. A total of 307 were excluded from analysis: 160 patients declined genetic testing. An additional 147 patients were excluded, (26 with abnormal results from testing performed by outside providers, 10 who pursued single site testing, 8 who canceled testing due to billing concerns, 48 who missed their blood draw appointments, and 17 who did not return their saliva kits). Moreover, 1 patient passed away before completing testing and 36 had results pending. Out of 461 patients who completed cancer panel testing, 51 (11%) were found to have a pathogenic variant and 171 (37%) were found to have at least one VUS;a total of 213 VUS were noted, as some patients were found to have more than one VUS. Of note,13 of these individuals were also found to have a pathogenic variant. A total of 17,613 genes were tested through all the cancer panels ordered, which yields a variant rate of 1.21%. The most common identified VUSs were in the following genes: ATM (18/171, 11%, one patient had 2 ATM VUSs);BRCA2 (12/171, 7%);APC (14/171, 8%, one patient had 2 APC VUSs);DICER1 (11/171 or 6%, one patient had 2 DICER1 VUSs);BARD1 (11/171, 6%);CHEK2, MSH2, and RAD51D (each with 10/171, 6%). Discussion: As compared to 2017, the number of patients receiving a VUS on their multi-gene cancer panel testing increased to 37%, as compared to 34%. The variant to gene ratio decreased, however, to 1.2% as compared to 1.6%. One likely explanation for this apparent contradiction is the fact that larger, more comprehensive cancer gene panels are being offered now as compared to the outset of the testing, as many patients and providers favored smaller, more targeted panels and many labs have increased the number of genes on the panels they offer. Therefore, while the overall variant rate per gene has decreased, more of our patients are faced with receiving a VUS result and coping with the anxiety and other negative psychological impacts. Limitations to these data include the COVID-19 pandemic. In 2020, with the suspension of elective procedures and scheduling limitations, the ability of our center to complete cancer consultations was suspended and/or significantly reduced for many months. Therefore, patients seen for cancer genetic counseling may have been more likely to have a personal history of cancer or a stronger family history of cancer, however, it is unclear if this would affect the noted VUS rate. Conclusions: This study highlights the importance of pre and posttest counseling as well as ongoing vigilance with VUS rates, especially in an ethnically diverse population. It also makes the sharing of data between clinical laboratories more imperative in order to attempt to further reduce these rates.