Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study.

BACKGROUND: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct. PATIENTS AND METHODS: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations. RESULTS: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded. CONCLUSIONS: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

On the robustness of model-based algorithms for photoacoustic tomography: Comparison between time and frequency domains.

For photoacoustic image reconstruction, certain parameters such as sensor positions and speed of sound have a major impact on the reconstruction process and must be carefully determined before data acquisition. Uncertainties in these parameters can lead to errors produced by a modeling mismatch, hindering the reconstruction process and severely affecting the resulting image quality. Therefore, in this work, we study how modeling errors arising from uncertainty in sensor locations affect the images obtained by matrix model-based reconstruction algorithms based on time domain and frequency domain models of the photoacoustic problem. The effects on the reconstruction performance with respect to the uncertainty in the knowledge of the sensors location are compared and analyzed both in a qualitative and quantitative fashion for both time and frequency models. Ultimately, our study shows that the frequency domain approach is more sensitive to this kind of modeling errors. These conclusions are supported by numerical experiments and a theoretical sensitivity analysis of the mathematical operator for the direct problem.

Validation of an algorithm of time-dependent electro-clinical risk stratification for electrographic seizures (TERSE) in critically ill patients.

OBJECTIVE: The clinical implementation of continuous electroencephalography (CEEG) monitoring in critically ill patients is hampered by the substantial burden of work that it entails for clinical neurophysiologists. Solutions that might reduce this burden, including by shortening the duration of EEG to be recorded, would help its widespread adoption. Our aim was to validate a recently described algorithm of time-dependent electro-clinical risk stratification for electrographic seizure (ESz) (TERSE) based on simple clinical and EEG features. METHODS: We retrospectively reviewed the medical records and EEG recordings of consecutive patients undergoing CEEG between October 1, 2015 and September, 30 2016 and assessed the sensitivity of TERSE for seizure detection, as well as the reduction in EEG time needed to be reviewed. RESULTS: In a cohort of 407 patients and compared to full CEEG review, the model allowed the detection of 95% of patients with ESz and 97% of those with electrographic status epilepticus. The amount of CEEG to be recorded to detect ESz was reduced by two-thirds, compared to the duration of CEEG taht was actually recorded. CONCLUSIONS: TERSE allowed accurate time-dependent ESz risk stratification with a high sensitivity for ESz detection, which could substantially reduce the amount of CEEG to be recorded and reviewed, if applied prospectively in clinical practice. SIGNIFICANCE: Time-dependent electro-clinical risk stratification, such as TERSE, could allow more efficient practice of CEEG and its more widespread adoption. Future studies should aim to improve risk stratification in the subgroup of patients with acute brain injury and absence of clinical seizures.

Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children with epilepsy.

PURPOSE: The objective of the study was to compare the psychiatric and behavioral side effect (PBSE) profiles of both older and newer antiepileptic drugs (AEDs) in children and adolescent patients with epilepsy. METHOD: We used logistic regression analysis to test the correlation between 83 non-AED/patient related potential predictor variables and the rate of PBSE. We then compared for each AED the rate of PBSEs and the rate of PBSEs that led to intolerability (IPBSE) while controlling for non-AED predictors of PBSEs. RESULTS: 922 patients (≤18 years old) were included in our study. PBSEs and IPBSEs occurred in 13.8% and 11.2% of patients, respectively. Overall, a history of psychiatric condition, absence seizures, intractable epilepsy, and frontal lobe epilepsy were significantly associated with increased PBSE rates. Levetiracetam (LEV) had the greatest PBSE rate (16.2%). This was significantly higher compared to other AEDs. LEV was also significantly associated with a high rate of IPBSEs (13.4%) and dose-decrease rates due to IPBSE (6.7%). Zonisamide (ZNS) was associated with significantly higher cessation rate due to IPBSE (9.1%) compared to other AEDs. CONCLUSION: Patients with a history of psychiatric condition, absence seizures, intractable epilepsy, or frontal lobe epilepsy are more likely to develop PBSE. PBSEs appear to occur more frequently in adolescent and children patients taking LEV compared to other AEDs. LEV-attributed PBSEs are more likely to be associated with intolerability and subsequent decrease in dose. The rate of ZNS-attributed IPBSEs is more likely to be associated with complete cessation of AED.

Cosmetic side effects of antiepileptic drugs in adults with epilepsy.

OBJECTIVE: Cosmetic side effects (CSEs) such as weight gain and alopecia are common, undesirable effects associated with several AEDs. The objective of the study was to compare the CSE profiles in a large specialty practice-based sample of patients taking both older and newer AEDs. METHODS: As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 1903 adult patients (≥16years of age) newly started on an AED. Cosmetic side effects were determined by patient or physician report in the medical record and included acne, gingival hyperplasia, hair loss, hirsutism, and weight gain. We compared the overall rate of CSEs and intolerable CSEs (ICSEs-CSEs that led to dosage reduction or discontinuation) between different AEDs in both monotherapy and polytherapy. RESULTS: Overall, CSEs occurred in 110/1903 (5.8%) patients and led to intolerability in 70/1903 (3.7%) patients. Weight gain was the most commonly reported CSE (68/1903, 3.6%) and led to intolerability in 63 (3.3%) patients. Alopecia was the second most common patient-reported CSE (36/1903, 1.9%) and was intolerable in 33/1903 (1.7%) patients. Risk factors for CSEs included female sex (7.0% vs. 4.3% in males; p<0.05) and any prior CSE (37% vs. 2.9% in patients without prior CSE; p<0.001). Significantly more CSEs were attributed to valproic acid (59/270; 21.9%; p<0.001) and pregabalin (14/143; 9.8%; p<0.001) than to all other AEDs. Significantly less CSEs were attributed to levetiracetam (7/524; 1.3%; p=0.002). Weight gain was most frequently associated with valproic acid (35/270; 13.0%; p<0.001) and pregabalin (12/143; 8.4%; p<0.001). Hair loss was most commonly reported among patients taking valproic acid (24/270; 8.9%; p<0.001). Finally, gingival hyperplasia was most commonly reported in patients taking phenytoin (10/404; 2.5%; p<0.001). Cosmetic side effects leading to dosage change or discontinuation occurred most frequently with pregabalin and valproic acid compared with all other AEDs (13.3 and 5.6% vs. 2.3%; p<0.001). For patients who had been on an AED in monotherapy (n=677), CSEs and ICSEs were still more likely to be attributed to valproic acid (30.2% and 17.1%, respectively) than to any other AED (both p<0.001). SIGNIFICANCE: Weight gain and alopecia were the most common patient-reported CSEs in this study, and weight gain was the most likely cosmetic side effect to result in dosage adjustment or medication discontinuation. Particular attention should be paid to pregabalin, phenytoin, and valproic acid when considering cosmetic side effects. Female patients and patients who have had prior CSE(s) to AED(s) were more likely to report CSEs. Knowledge of specific CSE rates for each AED found in this study may be useful in clinical practice.

Clinical outcomes following prolonged refractory status epilepticus (PRSE).

BACKGROUND: To define the clinical profile and outcome of patients in prolonged refractory status epilepticus (PRSE), and investigate possible predictors of outcome. METHODS: We reviewed 63 consecutive patients with PRSE cared for in the medical and neurointensive care units of three academic medical centers over a 9-year period. For this multi-center retrospective cohort study, PRSE was defined as SE that persisted despite at least 1 week of induced coma. Variables examined for their relationship to outcome included etiology, EEG, neuroimaging, and age. RESULTS: Forty-two (66%) of 63 patients in PRSE survived to discharge from hospitalization. Fourteen (22%) patients had a good outcome (mRS ≤ 3) at last available follow up (at least 6 months post-PRSE). Of these, 6 (10%) individuals had no significant disability and were able to carry out all usual activities (mRS = 1). Normal neuroimaging and a reactive EEG at onset of PRSE were associated with good outcome. Good or excellent clinical outcomes were possible in patients in PRSE for up to 79 days, and in patients up to 69 years old. CONCLUSIONS: Good outcome is not unusual in PRSE, including in some older patients, in a variety of diagnoses, and despite months of coma.

Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it.

The Third Injection Technique Workshop in Athens (TITAN).

The first Injection Technique workshop brought together endocrinologists and injection experts from around the world in Strasbourg in 1997. From its work came groundbreaking recommendations which advanced best practices in areas such as the use of a skin fold when injecting. The second Injection Technique workshop, with an expanded format including nurses and diabetes educators, took place in Barcelona in 2000. The initial stimulus to use shorter injecting needles can be said to date from this meeting. The third Injection Technique workshop was held in Athens in September 2009 and involved 127 experts from across the globe. After a comprehensive review of all publications since 2000 as well as several unpublished studies, the attendees divided into smaller groups to debate and draft new injecting recommendations based on the new data and their collective experience. This paper summarizes all the formal presentations given at this practical consensus workshop.

New injection recommendations for patients with diabetes.

AIM: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. METHODS: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. RESULTS: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. CONCLUSION: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections.

Clinical use of ictal SPECT in secondarily generalized tonic-clonic seizures.

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Cortical and subcortical networks in human secondarily generalized tonic-clonic seizures.

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Cross-sensitivity of skin rashes with antiepileptic drug use.

OBJECTIVE: To determine rates of cross-sensitivity of rash among commonly used antiepileptic drugs (AEDs) in patients with epilepsy. METHODS: The incidence of AED-related rash was determined in 1875 outpatients (> or =12 years), taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproic acid (VPA), or zonisamide (ZNS). We compared rates of rash for each AED in patients with vs those without a rash to 1) another specific AED; 2) any other AED; 3) any two other AEDs; and 4) any non-epilepsy medication. RESULTS: A total of 14.3% (269/1,875) of patients had a rash attributed to at least one AED; 2.8% had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 59), 57.6% had a rash to PHT (abbreviated as CBZ --> PHT: 57.6%); of patients who had a rash to PHT and were also prescribed CBZ (n = 81), rate of rash was 42% (i.e., PHT --> CBZ: 42%). Other results: CBZ --> LTG: 20% (n = 50); LTG --> CBZ: 26.3% (n = 38); CBZ --> OXC: 33% (n = 15); OXC --> CBZ: 71.4% (n = 7); CBZ --> PB: 26.7% (n = 30); PB --> CBZ: 66.7% (n = 12); LTG --> PHT: 38.9% (n = 36); PHT --> LTG: 18.9% (n = 74); PB --> PHT: 53.3% (n = 15); PHT --> PB: 19.5% (n = 41); OXC --> LTG: 37.5% (n = 8); LTG --> OXC: 20% (n = 15). There was evidence of specific cross-sensitivity between CBZ and PHT, and between CBZ and PB. CONCLUSION: Cross-sensitivity rates between certain antiepileptic drugs (AEDs) are high, especially when involving carbamazepine and phenytoin. Specific cross-sensitivity rates provided here may be useful for AED selection and counseling in individual patients.

Electrographic seizures and periodic discharges after intracerebral hemorrhage.

OBJECTIVE: To determine the frequency and significance of electrographic seizures and other EEG findings in patients with intracerebral hemorrhage (ICH). METHODS: We reviewed 102 consecutive patients with ICH who underwent continuous electroencephalographic monitoring (cEEG). Demographic, clinical, radiographic, and cEEG findings were recorded. Using multivariate logistic regression analysis, we determined factors associated with 1) electrographic seizures, 2) periodic epileptiform discharges (PEDs), and 3) poor outcome (death, vegetative or minimally conscious state) at hospital discharge. RESULTS: Seizures occurred in 31% (n = 32) of patients with ICH, prior to cEEG in 19 patients. Eighteen percent (n = 18) of patients had electrographic seizures; only one of these patients also had clinical seizures while on cEEG. After controlling for demographic and clinical predictors, only an increase in ICH volume of 30% or more between admission and 24-hour follow-up CT scan was associated with electrographic seizures (33% vs 15%; OR 9.5, 95% CI 1.7 to 53.8). PEDs were less frequently seen in those with hemorrhages located at least 1 mm from the cortex (8% vs 29%; OR 0.2, 95% CI 0.1 to 0.7). PEDs were independently associated with poor outcome (65% vs 17%; OR 7.6, 95% CI 2.1 to 27.3). In patients with electrographic seizures, the first seizure was detected within the first hour of cEEG monitoring in 56% and within 48 hours in 94%. CONCLUSIONS: Seizures occurred in one third of patients with intracerebral hemorrhage (ICH) and over half were purely electrographic. Electrographic seizures were associated with expanding hemorrhages, and periodic discharges with cortical ICH and poor outcome. Further research is needed to determine if treating or preventing seizures or PEDs might lead to improved outcome after ICH.

Nonconvulsive seizures: developing a rational approach to the diagnosis and management in the critically ill population.

Originally described in patients with chronic epilepsy, nonconvulsive seizures (NCSs) are being recognized with increasing frequency, both in ambulatory patients with cognitive change, and even more so in the critically ill. In fact, the majority of seizures that occur in the critically ill are nonconvulsive and can only be diagnosed with EEG monitoring. The semiology of NCSs and the associated EEG findings are quite variable. There are a number of periodic, rhythmic or stimulation-related EEG patterns in the critically ill of unclear significance and even less clear treatment implications. The field struggles to develop useful diagnostic criteria for NCSs, to standardize nomenclature for the numerous equivocal patterns, and to devise studies that will help determine which patterns should be treated and how aggressively. This review surveys the evidence for and against NCSs causing neuronal injury, and attempts to develop a rational approach to the diagnosis and management of these seizures, particularly in the encephalopathic population.

Comparison and predictors of rash associated with 15 antiepileptic drugs.

OBJECTIVE: To determine predictors and relative incidence of antiepileptic drug (AED)-related rash in patients taking all common AEDs. METHODS: We reviewed 1,890 outpatients. Eighty-one variables were tested as potential predictors of rash. We compared the rate of rash attributed to each AED (AED rash) with the average rate of rash attributed to the other AEDs in all adults (aged > or =16 years; n = 1,649) when taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproate (VPA), or zonisamide (ZNS). We repeated this analysis for patients with and without the identified nondrug predictors of AED rash. RESULTS: The average rate of AED rash was 2.8%. The only nondrug predictor significant in multivariate analysis was occurrence of another AED rash (odds ratio 3.1, 95% CI 1.8 to 5.1; p < 0.0001); the rate of rash in this subgroup was 8.8%, vs 1.7% in those without another AED rash. Higher AED rash rates were seen with PHT (5.9% overall, p = 0.0008; 25.0% in those with another AED rash, p = 0.001), LTG (4.8%, p = 0.00095; 14.4%, p = 0.025), and CBZ (3.7%, not significant; 16.5%, p = 0.01). Lower rates were seen with LEV (0.6% overall; p = 0.00042), GBP (0.3%, p = 0.00035), and VPA (0.7%, p = 0.01). Rash rates were also low (<1% overall) with FBM, PRM, TPM, and VGB (not significant). These AED differences remained similar in patients with and without other AED rashes. There were four cases of Stevens-Johnson syndrome involving four AEDs. CONCLUSIONS: The rate of an antiepileptic drug (AED) rash is approximately five times greater in patients with another AED rash (8.8%) vs those without (1.7%). Rash rates were highest with phenytoin, lamotrigine, and carbamazepine and low (<1%) with several AEDs.