Symptomatic Events Research Articles

The potential role of Sodium/Glucose Cotransporter 2 inhibitors in the treatment of cystinuria.

The Maillard reaction is a non-enzymatic reaction between an amino acid and carbohydrate. We hypothesized that continuous washing of cystine stones with glucose could theoretically prevent growth of an existing cystine stone or even reduce its size leading to a decrease in stone events. Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors, well known for inducing glucosuria, were used to test this hypothesis in an initial series of patients. Patients with cystinuria from September 2019 to May 2023 who received off-label dapaglifozin (Farxiga™) were identified. Patients were allowed to continue thiol and alkalinizing agents per standard of care. A symptomatic stone event was defined by stone passage or surgical intervention. Ten cystinuric patients were prescribed SGLT2 inhibitors with a median follow up of 13.5 months. Each patients' historic stone event rate was compared to the event rate while prescribed SGLT2 medication. Overall, 70% of patients experienced fewer stone events and half had stable stone volume during therapy. Eight patients had negative cystine capacity at baseline, yet seven experienced fewer stone events while on medication: four experienced no stone growth. One patient was taken off the SGLT2 inhibitor due to an adverse reaction; three others experienced mild, self-resolving effects and yet stayed on the medication. Cystinuric patients treated with a SGLT2 inhibitor experienced fewer stone events while on medication compared to their historic rates and exhibited decreased or stable stone growth. There were few medication related side effects. SGLT2 inhibitors may be a promising long-term therapy for patients with cystinuria.

Abstract 4123563: High Prevalence of Unrecognized Actionable Cardiac Arrhythmias in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease

Background: Patients with chronic obstructive pulmonary disease (COPD) are at high risk for developing arrhythmias due to hypoxemia, right heart failure and use of beta-agonists inhalers. Symptoms related to arrhythmias can often be masked or confounded by symptoms related to COPD exacerbation and remain undiagnosed. Objective: To identify the incidence of actionable arrhythmias in patients with no prior cardiology follow-up and moderate–severe COPD with continuous monitoring. Methods: An automatic referral for electrophysiology (EP) consult was generated in patients with moderate-severe COPD if they answered yes to one of the following: palpitations, dizziness, abnormal ECG, near syncope. Upon consultation with EP specialist, implantation of loop reorder was discussed (ILR) with the patient. Patients were then monitored for 12 months via remote monitoring. Actionable arrhythmia was defined the arrhythmia that correlated with symptoms triggered by the patient, necessitated adjustment of medications (including initiation of anticoagulation), catheter ablation and implantation of implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM). Results: Out of 62 patients referred 22 (35.5%) agreed to undergo ILR implantation. Of the 22 (50.0% female, 62 ± 9.5 years) patients implanted with an ILR, 15 (68.2%) had an actionable arrhythmia after a mean follow-up of 2.7± .3 months. These included 14 symptomatic events requiring medication adjustment (10 atrial tachycardias, 4 ventricular events), 7 cases of atrial fibrillation (requiring initiation of anticoagulation in all cases and catheter ablation in 1), 1 case of sinus node dysfunction requiring pacemaker implantation, and 1 episodes of sustained ventricular tachycardia requiring ICD implantation. Conclusion: Continuous monitoring had high yield in diagnosing significant arrhythmic events in patients with moderate-severe COPD. Awareness should be raised about the high arrhythmic risk of this population and the role of continuous monitoring should be sought in larger studies.

Symptoms Burden as a Clinical Outcomes Assessment in HeartFailure Patients With Atrial Fibrillation.

Safe and effective pharmacologic therapy for atrial fibrillation (AF) in heart failure (HF) is an unmet need. In AF clinical trials, the standard primary endpoint of time to first symptomatic AF event (TTFSE) has several disadvantages, which could theoretically be overcome by measurement of AF-specific symptoms burden during an entire follow-up period. The authors sought to develop and validate a method of measuring symptom burden of AF in a HF population. The authors constructed a patient-reported outcome instrument (Atrial Fibrillation Symptoms Questionnaire [AFSQ]) to function in the setting of AF/HF, and used it to measure symptoms throughout long-term follow-up. The AFSQ queries the presence of 10 new or worsening symptoms, equally divided between those associated with AF or HF. In a 267 patient AF/HF trial comparing 2 AF prevention treatments, the AFSQ was linked to electrocardiography documented AF to form a 2-component clinical outcome assessment (SxBAF) that was subjected to psychometric testing, anchor validation, and endpoint efficiency comparison to TTFSE. SxBAF exhibited greater efficiency than time to first symptomatic event for treatment difference detection, resulting in smaller projected clinical trial sample sizes. SxBAF correlated well with device-detected AF burden (Spearman's ρ=0.74; P< 0.0001), while permitting gradation in symptom severity. SxBAF also identified treatment group differences in cardiovascular serious adverse events and AF interventions and in recent-onset AF provided specificity for AF- or worsening HF-associated symptoms (P< 0.001 for each). Measurement of symptoms burden throughout clinical trial follow-up is feasible in AF/HF and should be useful for evaluating patient-centered outcomes in AF prevention trials. (Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With HeartFailure [GENETIC-AF]; NCT01970501).

Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial.

Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO). This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments. Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P=0.82). The interaction was marginally significant between groups (P=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P<0.001). Other safety outcomes were similar between the 2 treatments. Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411.

Study protocol for LOMCAD Trial: Effect of lomerizine hydrochloride to prevent recurrence of cerebral ischemic events in CADASIL patients

ObjectivesCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common monogenic cerebral small vessel diseases. Our previous observational study suggested that lomerizine hydrochloride, a calcium channel blocker approved in Japan in 1999 for the prevention of migraine headaches, is also effective for preventing recurrent ischemic stroke in CADASIL patients. The aim of this study (LOMCAD trial) is to verify the efficacy of lomerizine hydrochloride. Materials and MethodsThis is a multicenter, prospective, single-arm trial, using a historical control for comparison. CADASIL patients with a history of two or more cerebral ischemic events within the last two years will be administered lomerizine hydrochloride (5-mg tablet twice daily) for 24 months. The primary endpoint is symptomatic cerebral ischemic events during the 24-month period. Using our historical data and Bayesian sample size calculation based on a prior predictive distribution, the planned sample size was determined as 20 subjects. ConclusionWe have planned a clinical trial to verify the effectiveness of lomerizine hydrochloride as prophylaxis to prevent recurrent cerebral ischemic events in CADASIL patients. RegistrationThe LOMCAD trial has been registered in the Japan Registry of Clinical Trials (jRCTs051220072, https://jrct.niph.go.jp/latest-detail/jRCTs051220072).

Statistical properties of items and summary scores from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) in a diverse cancer sample.

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) was developed to capture symptomatic adverse events from the patient perspective. We aim to describe statistical properties of PRO-CTCAE items and summary scores and to provide evidence for recommendations regarding PRO-CTCAE administration and reporting. Using data from the PRO-CTCAE validation study (NCT02158637), prevalence, means, and standard deviations of PRO-CTCAE items, composite scores, and mean and maximum scores across attributes (frequency, severity, and/or interference) of symptomatic adverse events were calculated. For each adverse event, correlations and agreement between attributes, correlations between attributes and composite scores, and correlations between composite, mean, and maximum scores were estimated. PRO-CTCAE items were completed by 899 patients with various cancer types. Most patients reported experiencing one or more adverse events, with the most prevalent being fatigue (87.7%), sad/unhappy feelings (66.0%), anxiety (63.6%), pain (63.2%), insomnia (61.8%), and dry mouth (60.0%). Attributes were moderately to strongly correlated within an adverse event (r = 0.53 to 0.77, all p < 0.001) but not fully concordant (κweighted = 0.26 to 0.60, all p < 0.001), with interference demonstrating lowest mean scores and prevalence among attributes of the same adverse event. Attributes were moderately to strongly correlated with composite scores (r = 0.67 to 0.97, all p < 0.001). Composite scores were moderately to strongly correlated with mean and maximum scores for the same adverse event (r = 0.69 to 0.94, all p < 0.001). Correlations between composite scores of different adverse events varied widely (r = 0.04 to 0.68) but were moderate to strong for conceptually related adverse events. Results provide evidence for PRO-CTCAE administration and reporting recommendations that the full complement of attributes be administered for each adverse event, and that attributes as well as summary scores be reported.

Clinical Outcomes and Relevance of Composite V12 Gy in Patients With Four or More Brain Metastases Treated With Single Fraction Stereotactic Radiosurgery

AimsTissue V12Gy (total brain volume receiving 12Gy including target) can predict for late toxicity in single target benign disease treated with stereotactic radiosurgery (SRS). The value of this metric remains uncertain for multiple brain metastases. This retrospective cohort study reports the outcomes and evaluates the predictors of toxicity in patients with four or more brain metastases treated with single-fraction SRS. Materials and methodsTwo hundred twenty-six patients with 2160 metastases treated from 2014-21 were retrospectively studied. Symptomatic late toxicity (new/progressive neurological symptoms ≥3 months post SRS) with magnetic resonance imaging (MRI) changes suggestive of treatment effect were analysed. Kaplan–Meier and competing risk analysis was used to assess survival and toxicity respectively. Resultsmedian number of metastases/patient was 6 (range: 4-41) and median composite tissue V12Gy (inclusive of planning target volume (PTV)) was 11.3 cc (IQR: 6.1 cc–17.1 cc). Sixteen out of the 226 patients developed symptomatic late radiation adverse event (R-AE), and the cumulative incidence was 4.9% at 1 year and 6.9% at 2 years. The total target volume was significantly predictive of the risk of late R-AE. Volume of the largest lesion, V12Gy and V15Gy did not predict for late R-AE, but plotted graphs showed suggestions of linear relationships between dosimetric parameters and late R-AE. ConclusionWithin the limitations of this study, the cumulative incidence of symptomatic toxicity remains acceptable despite routinely accepting a composite tissue V12Gy in excess of 10 cc to treat multiple brain metastases. Advances in knowledgeV12Gy has limitations as a plan quality metric in multiple brain metastases treated with SRS. There is insufficient evidence to have a defined target limit as <10 cc.

MA10.09 Mapping of Patient-Reported Outcome Items to Symptomatic Adverse Events of Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

MA10.09 Mapping of Patient-Reported Outcome Items to Symptomatic Adverse Events of Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

Rates and risk factors of bleeding after gastric endoscopic submucosal dissection with continuous warfarin or 1-day withdrawal of direct oral anticoagulants.

The 2017 Japanese guidelines recommend continuing warfarin therapy during the perioperative period or discontinuing direct oral anticoagulants (DOACs) only on the day of endoscopic submucosal dissection for early gastric cancer. However, their safety has not been sufficiently explored. This study aimed to validate this management method. This retrospective, multicenter study analyzed the characteristics and outcomes of patients who underwent gastric endoscopic submucosal dissection between July 2017 and June 2019. The patients were categorized according to the use of warfarin or DOACs. Among the 62 eligible patients, 53 (85%) were male (median age, 76years). Warfarin was used in 10 patients (16%) and DOACs in 52 patients (84%). Fourteen patients taking DOACs (27%) used concomitant antiplatelet agents, with seven patients (13%) continuing treatment at the time of the endoscopic procedure. No postprocedural bleeding occurred in patients receiving warfarin (0%), whereas 10 cases (19%) of bleeding occurred in patients receiving DOACs: rivaroxaban, 0% (0/22); dabigatran, 0% (0/2); edoxaban, 43% (6/14); and apixaban, 29% (4/14). The type of anticoagulant (P<0.01) and continuation of antiplatelet therapy (P=0.02) were risk factors for postprocedural bleeding in patients receiving DOACs. Intraprocedural bleeding requiring transfusion or symptomatic thromboembolic events were not reported. Continuous warfarin therapy is preferred. DOAC withdrawal 1day before a procedure is associated with a high bleeding rate, which may differ for different types of anticoagulants. The continuation of antiplatelet medications in patients receiving DOACs carries a high risk of bleeding and is a future challenge.

Biomarkers of bone metabolism in [223Ra] RaCl2 therapy - association with extent of disease and prediction of overall survival

BackgroundThe alpha-emitting radionuclide therapy [223Ra]RaCl2 (Radium-223) improves overall survival (OS) and time to symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence suggests that the effect of Radium-223 is partly exerted through an impact on the surrounding bone matrix. We hypothesized that bone metabolism markers (BMM) could provide predictive information regarding response to Radium-223. Accordingly, the aim of this study was to investigate changes in BMM during Radium-223 therapy and evaluate association with clinical outcome.MethodsProspective study of BMM in patients with mCRPC receiving Radium-223. Blood samples were collected before each administration of Radium-223 and the following BMM were quantified; bone-specific alkaline phosphatase (BALP), osteocalcin, procollagen type I N-propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), receptor-activated nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Clinical outcomes were scintigraphic progression during/after therapy, change in bone scan index (BSI), occurrence of SSE, and OS.ResultsA total of 55 mCRPC patients were included. There was a significant linear association between skeletal extent of disease and CTX-MMP, PINP, BALP, and osteocalcin. No significant association between dynamics in BSI and BMM were detected. Median OS for the cohort was 14 months (95% CI: 10.7–16.8). Baseline levels of Log2-CTX-MMP (HR = 2.15 (95%CI: 1.1–4.1)) and Log2-BALP (HR = 1.59 (95%CI: 1.1–2.1)) were associated with OS. Patients with increasing CTX-MMP during therapy had significantly shorter OS (Median OS = 4 mo. (95%CI: 2.3–5.7)) than patients with stable or decreasing CTX-MMP (Median OS = 12 mo. (95%CI: 10.1–13.9), P < 0.001).ConclusionBMM are significantly associated with scintigraphic extent of skeletal disease and OS in patients with mCRPC. Particularly, the bone resorption marker CTX-MMP is a promising surrogate marker for prediction of outcome in patients receiving Radium-223 therapy and could potentially improve selection of patients for therapy and assessment of response.Trial registrationClinicaltrials.gov, NCT03247010. Registered 10th of August 2017, https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1.

Most Common Symptomatic Adverse Reactions of Cancer Treatments From US Drug Labels (2015-2021) to Inform Selection of Patient-Reported Outcomes

ObjectivesIncorporating patient-reported outcomes (PROs) to assess symptomatic adverse events (AEs) in cancer clinical trials (CTs) is important to characterize treatment tolerability. Cancer therapies approved over the past decade have expanded the types of expected toxicities. To inform future symptomatic AE PRO item selection, we identified the most common symptomatic adverse reactions from recently approved products. MethodsWe reviewed approvals from 2015 to 2021 for lung, breast, and hematologic cancer indications. Using United States Prescribing Information safety data, we recorded symptomatic adverse reactions reported in ≥20% of patients in the experimental arm of CTs supporting approvals. We calculated the proportion of arms reporting each symptomatic adverse reaction. ResultsIn total, 130 experimental arms were included (lung = 30, breast = 10, hematologic = 90). For all cancer types, fatigue and diarrhea were reported in >50% of the arms. Nausea was reported in ≥50% of the arms for all except lung. Vomiting, decreased appetite, and alopecia, were reported in ≥50% of breast cancer arms. Rash, musculoskeletal pain, and cough were reported in >50% of leukemia/lymphoma arms. Cough was common (50%) in multiple myeloma arms. ConclusionsHeterogeneity in symptomatic adverse reactions across CTs supports the use of item libraries when building a PRO strategy to assess tolerability. Fatigue, diarrhea, and nausea were the most frequent symptomatic adverse reactions reported in contemporary cancer CTs and could provide a starting point when selecting PRO symptomatic AE items. Additional symptomatic AE PRO items should be selected based on the mechanism of action, early clinical data, published literature, and patient and clinician input.

Clinical features, hemorrhage risk and epilepsy outcomes of familial cerebral cavernous malformation: A 20-year observational pragmatic single-center study

IntroductionFamilial Cerebral Cavernous Malformations (fCCMs) are rare, hereditary conditions characterized by multiple central nervous system lesions. Despite their rarity, CCMs can cause significant clinical challenges when symptomatic, manifesting as seizure and symptomatic hemorrhage (CASH). Guidelines suggest neurosurgical intervention for symptomatic or previously symptomatic lesions, while conservative management is recommended for new-onset epilepsy. However, the natural history and optimal management remain unclear, necessitating further research. ObjectiveThis study aims to provide a comprehensive analysis of the clinical features, hemorrhage risk, and epilepsy outcomes in fCCM patients over an extended follow-up period, offering a more precise estimate of CASH and epilepsy rates in this population. MethodsThis retrospective longitudinal cohort study included fCCM patients enrolled from 2001 to May 2024. Data collected included demographic information, new neurological symptoms, symptomatic hemorrhages, seizures, and modified Rankin Scale (mRS) scores. Incidence rates of first symptomatic events and Kaplan-Meier survival curves were calculated, with logistic and Cox-proportional hazard regression models used to evaluate outcomes. ResultsA total of 47 patients were included in this study, with a mean age at diagnosis of 37.51 years. At diagnosis, 68 % were symptomatic, with 30 % having CASH and 36 % experiencing seizures without CASH. During a median follow-up of 126.0 months (interquartile range, 110.5 months), 17 % had a new CASH event, 20 % had seizures without CASH, and 60 % remained asymptomatic. The bleeding rate was 1.02 % per patient-year, with new focal neurological symptoms at 2.045 per 1000 patient-years and new CASH at 10.225 per 1000 patient-years. Most patients maintained minimal or no disability (mRS 0 or 1). Presenting with epilepsy at baseline significantly increased the odds of future seizures (OR 18.13, p = 0.001). ConclusionThis study highlights the complex presentation and progression of fCCMs, emphasizing the necessity for long-term monitoring. Baseline epilepsy is a significant predictor of future seizures, underscoring the need for individualized management strategies. Future research with larger cohorts and standardized criteria is essential to refine the understanding and management of fCCMs.

Genetic variants in FCGR2A, PTPN2, VDR as predictive signatures of aggressive phenotypes in cerebral cavernous malformation

ObjectiveThe biological behavior of Cerebral Cavernous Malformation (CCM) is still controversial, lacking a clear-cut signature for a mechanistic explanation of lesion aggressiveness. In this study, we evaluated the predictive capacity of genetic variants concerning the aggressive behavior of CCM and their implications in biological processes. MethodsWe genotyped the variants in VDRrs7975232, VDRrs731236, VDRrs11568820, PTPN2rs72872125 and FCGR2Ars1801274 genes using TaqMan Genotyping Assays in a cohort study with 103 patients, 42 of whom had close follow-up visits for 4 years, focusing on 2 main aspects of the disease: (1) symptomatic events, which included both intracranial bleeding or epilepsy, and (2) the onset of symptoms. The genotypes were correlated with the levels of several cytokines quantified in peripheral blood, measured using the x-MAP method. ResultsWe report a novel observation that the PTPN2rs72872125 CT and the VDRrs7975232 CC genotype were independently associated with an asymptomatic phenotype. Additionally, PTPN2rs72872125 CC genotype and serum level of GM-CSF could predict a diagnostic association with symptomatic phenotype in CCM patients, while the FCGR2Ars1801274 GG genotype could predict a symptomatic event during follow-up. The study also found a correlation between VDRrs731236 AA and VDRrs11568820 CC genotype to the time to the first symptomatic event. ConclusionsThese genetic markers could pave the way for precision medicine strategies for CCM, enhancing patient outcomes by enabling customized therapeutic approaches.

Invasive procedures and surgery following etranacogene dezaparvovec gene therapy in people with hemophilia B

BackgroundLittle information regarding the management of invasive procedures in people with hemophilia B (HB) after undergoing gene therapy is available. Here, we report the management of invasive procedures in people with severe or moderately severe HB who had previously been treated with etranacogene dezaparvovec in the phase 2b and phase 3 Health Outcomes with Padua Gene; Evaluation in Hemophilia B clinical trials (NCT03489291 and NCT03569891). ObjectivesThe objective of this study was to describe the use of exogenous FIX, endogenous FIX activity prior to invasive procedures, and peri- and postoperative bleeds in participants who underwent invasive procedures after receiving etranacogene dezaparvovec gene therapy. MethodsThis retrospective analysis included invasive procedures performed within 3 and 2 years following a single infusion of 2 × 1013 gc/kg of etranacogene dezaparvovec in participants in the phase 2b and Health Outcomes with Padua Gene; Evaluation in Hemophilia B trials, respectively. Data for factor (F)IX dosing, duration of postoperative FIX use, FIX activity prior to invasive procedures, and postoperative bleeds were collected and analyzed. ResultsThe analysis included 64 procedures in 29 participants: 9 major surgeries, 24 minor surgeries, 11 endoscopies, 3 endoscopies with biopsy/polypectomy, and 17 dental procedures. Uncontaminated endogenous FIX activity corresponded to mild hemophilia or normal levels prior to 98% of all procedures, with a median endogenous FIX activity of 43.8 IU/dL (range, 3.1-113 IU/dL). All major surgeries were managed with exogenous FIX, 67% with ≤4 days of FIX infusion. Most minor surgeries (88%), endoscopies (82%), and dental procedures (94%) were managed with no or a single FIX infusion. Postoperative bleeds occurred after 1 minor surgery and 4 dental procedures. There were no symptomatic thrombotic events or FIX inhibitor developments. ConclusionEtranacogene dezaparvovec has the potential to facilitate perioperative management in people with HB by reducing the need for perioperative exogenous FIX and its associated risks.

1599P Symptomatic skeletal events, health-related quality of life and pain in a phase III study of [177Lu]Lu-PSMA-617 in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer: Third interim analysis of PSMAfore

1599P Symptomatic skeletal events, health-related quality of life and pain in a phase III study of [177Lu]Lu-PSMA-617 in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer: Third interim analysis of PSMAfore

Percutaneous transluminal angioplasty and stenting (PTAS) in patients with symptomatic intracranial vertebrobasilar artery stenosis (IVBS)

BackgroundApproximately 20% of all transient ischaemic attacks (TIAs) and ischaemic strokes occur within the posterior circulation, with vertebrobasilar stenosis identified as the cause in roughly 25% of the cases. Studies...

Vascular imaging for Stereoelectroencephalography: A safety and planning study

BackgroundStereoelectroencephalography (SEEG) is a procedure used to localize the epileptogenic zone in patients with medically refractory epilepsy, involving the stereotactic implantation of electrodes into brain parenchyma. Magnetic Resonance Imaging (MRI), Digital Subtraction Angiography, and Computed Tomography have been used preoperatively to prevent Intracranial Hemorrhage (ICH) by identifying electrode-vessel conflicts (EVC’s) on planned electrode trajectories. There is variation in the use of Digital Subtraction Angiography and non-invasive sequences for vascular planning. Digital Subtraction Angiography provides high spatial resolution, but carries risks of arterial dissection, groin and retroperitoneal hematoma, and a 0.5–1.9% risk of stroke. Our group has incorporated Intravenous Cone Beam Computed Tomography (CBCT A/V) Brain into our SEEG workflow, given its effective implementation in other neurosurgical domains. Primary aims include validating the safety of our CBCT A/V sequence for SEEG planning and determining if CBCT A/V is comparable to other modalities in detecting EVC’s. Secondary aims include elucidating the relationship of conflicting vessel calibre with ICH incidence in SEEG using CBCT A/V imaging. MethodsA single-center retrospective study was conducted of 20 patients who underwent preoperative CBCT A/V Brain and MRI Brain with gadolinium enhancement, encompassing 273 electrode implantations from August 2020 − July 2023. The incidence and grade of post-implant, post-explant symptomatic ICH and asymptomatic ICH was noted. The total number of EVC’s identifiable on MRI and CBCT A/V was recorded, along with average diameter of conflicting vessels. ResultsAcross 20 patients and 273 implanted electrodes, there were four ICH events, where two were symptomatic and two were asymptomatic. The mean diameter of EVC’s across all patients was 1.4 mm (±0.5). A significant difference (P < 0.0001) was observed between the number of EVC’s that CBCT A/V could identify (20) compared to MRI (6). Two EVC’s were identified in the region of two symptomatic ICH’s, with the mean diameter of these conflicted vessels being 1.5 mm (±0.4). The two symptomatic ICH-associated EVC’s were observed on CBCT A/V but not MRI. ConclusionsIn our series, CBCT A/V demonstrates an acceptable safety profile for SEEG planning compared to other imaging modalities. CBCT A/V identified significantly more EVC’s compared to MRI, including those contributing to transient symptomatic intracranial hemorrhage. A conflicting vessel calibre of less than 1.2 mm on CBCT A/V did not contribute to ICH in our SEEG series.

Are bone targeted agents still useful in times of immunotherapy? The SAKK 80/19 BTA pilot study

BackgroundPatients with bone metastases from solid tumors often have additional treatment with bone targeted agents (BTAs) to avoid symptomatic skeletal events (SSEs) such as clinically significant pathological fracture leading toradiation therapy or surgery to the bone, spinal cord compression, or hypercalcemia. The absolute value of BTA treatment in the era of immunotherapy (IO) is unknown. MethodsPatients with bone metastases treated with immunotherapy within the Alpine Tumor Immunology Registry were compared based on whether they received an additional BTA such as denosumab or zoledronic acid. The primary endpoint was time to first SSE. Continuous data were summarized as median and range, categorical data using frequency counts and percentages. Kaplan-Meier estimates were used to describe and visualize the effect of categorical variables. ResultsOne hundred and ninety-seven patients with bone metastases and treatment with immunotherapy such as nivolumab (48 %), pembrolizumab (40 %), atezolizumab (12 %), ipilimumab (9 %) and other immunotherapy (5 %) were included. The most frequent tumor types were lung cancer (50 %), malignant melanoma (11 %), renal cell cancer (10 %) and bladder cancer (9 %), respectively. One hundred and twenty-two patients (62 %) received a BTA treatment (91 % denosumab). The median treatment duration of a BTA was 178 days (min: 1 day, max: 2010 days). Out of the 197 patients, 47 (24 %) experienced at least one SSE, 100 (51 %) had bone pain. Ten of the 122 patients (8 %) receiving a BTA developed osteonecrosis of the jaw (ONJ). The percentage of patients without an SSE at fixed time points was higher if treated with a BTA (e.g., at 6 months, 92 % [95 % CI: 84 % - 96 %] versus 88 % [95 % CI: 77 % - 94 %]), but no significant difference in time to first SSE (HR 0.69; 95 % CI 0.34–1.39, log-rank p = 0.29) or time to first bone pain (HR: 0.85; 95 % CI: 0.51–1.43, p = 0.54) between these two groups could be detected. There were differences in OS between patients treated with a BTA and patients not treated with a BTA (HR: 1.46; 95 % CI: 1.01–2.10, p = 0.043). ConclusionNo significant difference in time to first SSE or bone pain was observed between patients who have received a BTA or not when treated with immunotherapy. Based on these retrospective results the indication of BTAs to reduce SSEs in cancer patients under treatment with immunotherapy needs further evaluation.

FILO: Automated FIx-LOcus Identification for Android Framework Compatibility Issues

Keeping up with the fast evolution of mobile operating systems is challenging for developers, who have to frequently adapt their apps to the upgrades and behavioral changes of the underlying API framework. Those changes often break backward compatibility. The consequence is that apps, if not updated, may misbehave and suffer unexpected crashes if executed within an evolved environment. Being able to quickly identify the portion of the app that should be modified to provide compatibility with new API versions can be challenging. To facilitate the debugging activities of problems caused by backward incompatible upgrades of the operating system, this paper presents FILO, a technique that is able to recommend the method that should be modified to implement the fix by analyzing a single failing execution. FILO can also provide additional information and key symptomatic anomalous events that can help developers understand the reason for the failure, therefore facilitating the implementation of the fix. We evaluated FILO against 18 real compatibility problems related to Android upgrades and compared it with Spectrum-Based Localization approaches. Results show that FILO is able to efficiently and effectively identify the fix-locus in the apps.

Aspirin is an Effective Prophylaxis for Venous Thromboembolism After Revision Hip and Knee Arthroplasty

BackgroundVenous thromboembolism (VTE) following revision total joint arthroplasty (TJA) poses significant risks despite prophylactic measures. The optimal VTE prophylaxis agent for revision TJA remains unclear. This study aimed to compare aspirin against various anticoagulant agents regarding efficacy and safety in preventing symptomatic VTE events after revision TJA. MethodsA retrospective analysis included 4,575 patients undergoing revision TJA between 2008 and 2020. Of these, 2,091 received aspirin, while 2,484 received other anticoagulants. Demographic, procedural, and outcome data were collected. Logistic regression models were used to identify predictors of symptomatic VTE. ResultsThe aspirin group showed a significantly lower incidence of symptomatic VTE compared to the other anticoagulant group (0.53 versus 2.54%, P < .001). Logistic regression confirmed a higher risk of VTE with other anticoagulants (odds ratio: 0.2 to 0.26, P < .001), while blood transfusion (odds ratio: 2.72, P = .001) were identified as risk factors. ConclusionsThis study demonstrated that aspirin is a viable and potentially safer option than other anticoagulants, exhibiting comparable efficacy in preventing VTE events in revision TJA. Balancing effectiveness and safety is crucial, considering patient-specific risk factors and bleeding tendencies. This large cohort study demonstrated that aspirin was associated with a more effective and safer VTE prophylaxis agent, compared to other anticoagulants, in patients undergoing revision TJA.