Safety Profile of Monoclonal Antibodies and Subsequent Drug Developments in the Treatment of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disease characterized by intravascular hemolysis due to the targeting of affected red blood cells by the complement system. Eculizumab and ravulizumab are two monoclonal antibodies that inhibit the complement system's components and have been shown to significantly improve survival and quality of life. This review describes the role of these monoclonal antibodies in the treatment of PNH with an emphasis on their safety profile. The challenges in the use of these drugs and new drugs in various stages of drug development are also described, which may be helpful in addressing some of these challenges.

Circumstances and implications of conversion from minimally invasive to open liver resection: a multi-center analysis from the AMILES registry.

BACKGROUND: Minimally invasive approaches to liver resection (MILR) are associated with favorable outcomes. The aim of this study was to determine the implications of conversion to an open procedure on perioperative outcomes. METHODS: Patients who underwent MILR at 10 North American institutions were identified from the Americas Minimally Invasive Liver Resection (AMILES) database. Outcomes of patients who required conversion were compared to those who did not. Additionally, outcomes after conversion due to unfavorable findings (poor visualization/access, lack of progress, disease extent) versus intraoperative events (bleeding, injury, cardiopulmonary instability) were compared. RESULTS: Of 1675 patients who underwent MILR, 102 (6.1%) required conversion. Conversion rate ranged from 4.4% for left lateral sectionectomy to 10% for right hepatectomy. The primary reason for conversion was unfavorable findings in 67 patients (66%) and intraoperative adverse events in 35 patients (34%). By multivariable analysis, major resection, cirrhosis, prior liver surgery, and tumor proximity to major vessels were identified as risk factors for conversion (p < 0.05). Patients who required conversion had higher blood loss, transfusion requirements, operative time, and length of stay, (p < 0.05). They also had higher major complication rates (23% vs. 5.2%, p < 0.001) and 30-day mortality (8.8% vs. 1.3%, p < 0.001). When compared to those who required conversion due to unfavorable findings, patients who required conversion due to intraoperative adverse events had significantly higher major complication rates (43% vs. 14%, p = 0.012) and 30-day mortality (20% vs. 3.0%, p = 0.007). CONCLUSIONS: Conversion from MILR to open surgery is associated with increased perioperative morbidity and mortality. Conversion due to intraoperative adverse events is rare but associated with significantly higher complication and mortality rates, while conversion due to unfavorable findings is associated with similar outcomes as planned open resection. High-risk patients may benefit from early conversion in a controlled fashion if difficulties are encountered or anticipated.

Diurnal Variation in Visual Simple Reaction Time between and within Genders in Young Adults: An Exploratory, Comparative, Pilot Study.

Simple reaction time (SRT) is the minimum time required to respond to a stimulus; it is a measure of processing speed. Our study aimed to determine the variation in visual SRT with time among individuals of the same gender and between genders. We carried out a prospective, parallel group, pilot study involving ten male and ten female medical students aged 18-25 years. After obtaining written informed consent, the participants were familiarized with the procedures, and each completed a single practice session of a computerized visual SRT which was administered using Psychology Experiment Building Language Version 2.0 software. On a predetermined day, the participants completed the exercise at 10 a.m., 1 p.m., and 5 p.m. The results showed no statistically significant difference in SRT based on time of day between genders (χ 2(2) = 4.300, p=0.116) as well as within gender (males (χ 2(2) = 0.600, p=0.741); females (χ 2(2) = 5.000, p=0.082). Our study showed that visual SRT does not change significantly at different times of the day and within and between genders. Intraindividual variations in visual SRT can mask the presence of a small but significant difference; hence, further studies are warranted.

MRI-Guided Interstitial Laser Ablation for Intracranial Lesions: A Large Single-Institution Experience of 133 Cases.

BACKGROUND: Managing difficult-to-access lesions or surgically accessible lesions in fragile patients is a central problem in neurosurgery. MRI-guided interstitial laser ablation (ILA) is a minimally invasive option that may provide a safe means of treating these challenging patients. OBJECTIVE: We aim to (1) evaluate safety, efficacy, and preliminary outcomes within a diverse and large series of ILA treatments; and (2) report technical details and operative trends that proved useful over time in the authors' experience and that may be of use to neurosurgeons who perform ILA. METHODS: A retrospective evaluation of ILA patients was performed in terms of demographics, surgical techniques, and clinical outcomes. RESULTS: A total of 133 intracranial lesions in 120 patients were treated with ILA, including glioblastomas (GBM), other gliomas, metastases, epilepsy foci, and radionecrosis. The rate of complications/unexpected readmission was 6.0%, and the mortality rate was 2.2%. With high-grade tumors, tumor volumes >3 cm in diameter trended toward a higher rate of complication (p = 0.056). Median progression-free survival (PFS) and overall survival (OS) for recurrent GBM were 7.4 and 11.6 months, respectively. As a frontline treatment for newly diagnosed GBM, median PFS and OS were 5.9 and 11.4 months, respectively. For metastases, median PFS was not yet reached, and OS was 17.2 months. CONCLUSION: Our series suggests that ILA is a safe and efficacious treatment for a variety of intracranial pathologies, can be tailored to treat difficult-to-access lesions, and may offer a novel alternative to open craniotomy in properly selected patients.

Laser interstitial thermal therapy for subependymal giant cell astrocytoma: technical case report.

Subependymal giant cell astrocytoma (SEGA) is a rare tumor occurring almost exclusively in patients with tuberous sclerosis complex. Although open resection remains the standard therapy, complication rates remain high. To minimize morbidity, less invasive approaches, such as endoscope-assisted resection, radiosurgery, and chemotherapy with mTOR pathway inhibitors, are also used to treat these lesions. Laser interstitial thermal therapy (LITT) is a relatively new modality that is increasingly used to treat a variety of intracranial lesions. In this report, the authors describe two pediatric cases of SEGA that were treated with LITT. In both patients the lesion responded well to this treatment modality, with tumor shrinkage observed on follow-up MRI. These cases highlight the potential of LITT to serve as a viable minimally invasive therapeutic approach to the management of SEGAs in the pediatric population.

Utilizing personalized stereotactic frames for laser interstitial thermal ablation of posterior fossa and mesiotemporal brain lesions: a single-institution series.

OBJECTIVE The precision of laser probe insertion for interstitial thermal therapy of deep-seated lesions is limited by the method of stereotactic guidance. The objective of this study was to evaluate the feasibility of customized STarFix 3D-printed stereotactic platforms to guide laser probe insertion into mesiotemporal and posterior fossa targets. METHODS The authors conducted a retrospective review of 5 patients (12-55 years of age) treated with laser interstitial thermal therapy (LITT) in which STarFix platforms were used for probe insertion. Bone fiducials were implanted in each patient's skull, and subsequent CT scans were used to guide the design of each platform and incorporate desired treatment trajectories. Once generated, the platforms were mounted on the patients' craniums and used to position the laser probe during surgery. Placement of the laser probe and the LITT procedure were monitored with intraoperative MRI. Perioperative and follow-up MRI were performed to identify and monitor changes in target lesions. RESULTS Accurate placement of the laser probe was observed in all cases. For all patients, thermal ablation was accomplished without intraoperative complications. Of the 4 patients with symptomatic lesions, 2 experienced complete resolution of symptoms, and 1 reported improved symptoms compared with baseline. CONCLUSIONS Customized stereotactic platforms were seamlessly incorporated into the authors' previously established LITT workflow and allowed for accurate treatment delivery.

Characterization of postoperative fevers after hemispherotomy.

OBJECTIVE: Patients who have undergone hemispherotomy for intractable epilepsy tend to develop postoperative fevers, which can be severe and/or prolonged, for unclear reasons. The purpose of this paper is to characterize postoperative fever curves after hemispherotomy based on factors including seizure etiology, perioperative blood loss, and the presence or absence of ventricular drainage. METHODS: We present 72 patients who underwent hemispherotomy at our institution between 1995 and 2013 by four surgeons. Data including daily maximum body temperature, seizure etiology, ventricular drain use, steroid and antipyretic use, and seizure control were gathered retrospectively based on electronic records including operative summaries, nursing notes, discharge summaries, and follow-up clinic notes. RESULTS: Seventy-two patients from 11 weeks to 21 years old (mean 7.4 years old) underwent hemispherotomy between 1995 and 2013. Sixty (83%) had fevers postoperatively, while the remainder were afebrile. Patients without external ventricular drains had higher and more prolonged fevers compared to those with drains (p = 0.003). Patients with Rasmussen's encephalitis tended to have higher postoperative fevers than patients with other seizure etiologies (p = 0.005), while patients with cortical dysplasia and polymicrogyria tended to have less severe fevers (p = 0.027 and 0.017, respectively). Fifty-five patients (76%) had freedom from disabling seizures (Engel class I), and 96% showed worthwhile improvement or better (Engel classes I-III). CONCLUSION: Postoperative fever can be anticipated in hemispherotomy patients, may vary based on certain seizure etiologies, and may be mitigated by routinely utilizing external ventricular drainage. Hemispherotomy is an effective surgical procedure for intractable epilepsy in selected patients.

Microsurgical confirmation of perforating arteries arising from the fundus of a posterior communicating artery aneurysm.

Perforating arteries rarely project from the fundus of an aneurysm. We present the case of a 35-year-old woman who was found to have a right posterior communicating artery (PCOM) aneurysm via catheter angiography. Superselective microcatheter angiography revealed that perforating arteries arose from the aneurysm fundus that supplied the anterolateral thalamus. Microsurgical exploration confirmed several small perforating arteries arising from the aneurysm dome as well as an atretic distal PCOM artery. Given the complex anatomy, the lesion was unsuitable for clipping. We propose that this aneurysm represents a developmental variant whereby the proximal PCOM artery becomes atretic and terminates in PCOM perforators. The video can be found here: http://youtu.be/iDcp9fsDjq4.

The safety of aeroplane travel in patients with symptomatic carotid occlusion.

OBJECTIVE: Patients with carotid stenosis or occlusion may be at increased risk for stroke during air travel. Records from the Carotid Occlusion Surgery Study (COSS), a randomised trial of surgical revascularisation for complete carotid artery occlusion and haemodynamic ischaemia, were examined for evidence of stroke related to air travel. METHODS: COSS subjects who travelled by aeroplane to a regional Positron Emission Tomography (PET) centre for a screening of cerebrovascular haemodynamic evaluation were identified. Maximum altitude and total flight time were estimated based on the distance between origin and destination. Ischaemic events were determined by a structured telephone interview within 24 h of travel. Patient demographics, comorbidities, oxygen extraction fraction (OEF) data and 24 h interview responses were recorded. RESULTS: Seventy-seven patients with symptomatic carotid occlusion travelled by aeroplane to a single PET centre (174 flights). Fifty-two (67.5%) were men and 25 (32.5%) were women. The average age was 58.7±1.4 years. Twenty-seven patients (35.1%) demonstrated evidence of ipsilateral haemodynamic cerebral ischaemia as measured by PET OEF, while 50 (64.9%) had normal OEF. Patients flew an average distance of 418.9±25.9 miles for 107.1±4.7 min per trip. No patient reported symptoms of a transient ischaemic attack or stroke during or within 24 h after aeroplane travel (95% CI 0% to 2.0%). CONCLUSIONS: The risk of stroke as a consequence of air travel is low, even in a cohort of patients at high risk for future stroke owing to haemodynamic impairment. These patients with symptomatic carotid occlusion should not be discouraged from air travel.

Assessment of learning styles of undergraduate medical students using the VARK questionnaire and the influence of sex and academic performance.

While there are several tools to study learning styles of students, the visual-aural-read/write-kinesthetic (VARK) questionnaire is a simple, freely available, easy to administer tool that encourages students to describe their behavior in a manner they can identify with and accept. The aim is to understand the preferred sensory modality (or modalities) of students for learning. Teachers can use this knowledge to facilitate student learning. Moreover, students themselves can use this knowledge to change their learning habits. Five hundred undergraduate students belonging to two consecutive batches in their second year of undergraduate medical training were invited to participate in the exercise. Consenting students (415 students, 83%) were administered a printed form of version 7.0 of the VARK questionnaire. Besides the questionnaire, we also collected demographic data, academic performance data (marks obtained in 10th and 12th grades and last university examination), and self-perceived learning style preferences. The majority of students in our study had multiple learning preferences (68.7%). The predominant sensory modality of learning was aural (45.5%) and kinesthetic (33.1%). The learning style preference was not influenced by either sex or previous academic performance. Although we use a combination of teaching methods, there has not been an active effort to determine whether these adequately address the different types of learners. We hope these data will help us better our course contents and make learning a more fruitful experience.

Assessment of safety profile of secukinumab in real-world scenario using United States food and drug administration adverse event reporting system database.

Secukinumab is an anti-IL-17 monoclonal antibody approved for treating psoriasis and various arthritides. A comprehensive evaluation of its safety, especially in a real-world setting, is necessary. This study aimed to describe the adverse events (AE) associated with secukinumab use using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. FAERS data files containing AE reports from 2015 to 2021 were downloaded for data mining. Primary or secondary suspect medications indicated for psoriasis were identified and analyzed. Medical dictionary for regulatory activities (MedDRA version 24.1) was used to analyze the AE terms. To detect potential safety signals of AE from secukinumab use, disproportionality analysis was used. A total of 365,590 adverse event reports were identified; of these, 44,761 reports involved the use of secukinumab. Safety signals were identified for ocular infections and gastrointestinal adverse events at the standardised MedDRA query level. Safety signals for oral candidiasis, oral herpes, conjunctivitis, eye infections, and ulcerative colitis were identified at the preferred term level. The findings of our study are consistent with those of earlier studies, such as the increased risk of infections and inflammatory bowel disease. However, our study also identified additional safety signals that need to be further evaluated.

A descriptive study of new drug approvals during 2017-2021 and disease morbidity and mortality patterns in India.

Aim: Studies show the presence of a mismatch between drug research and disease burden. A study conducted in the European Union found that new drug development was restricted to certain diseases. A study of biosimilar approvals in India found that 87% of drugs were for treating noncommunicable diseases. This study aimed to determine the new drugs approved in India from 2017 to 2021 and the top ten causes of morbidity and mortality and detect the presence of any discordance between these. Methods: A descriptive study was conducted using data on new drug approvals accessed from the Central Drugs Standard Control Organization website. The top ten causes of mortality and morbidity in India from 2015 to 2019 were identified from the Global Burden of Diseases database. Descriptive statistics were used to compare the drug approvals and the leading diseases. Results: One hundred twenty-six drugs were approved during the study period. Antineoplastic drugs constituted 19.84% of the approvals, antimicrobials 18.25%, and cardiovascular drugs 9.52%. Ischemic heart disease and chronic obstructive pulmonary disease were the two leading causes of morbidity and mortality. Diarrheal diseases, lower respiratory tract infection, and drug-susceptible tuberculosis were among the top ten causes. Ten antibacterials, including four antitubercular drugs, were approved during this period. Two drugs were approved for rare diseases. Conclusion: Our study showed that the drugs approved were largely in line with the prevalent disease burden, and there was no significant discordance observed. Some diseases, such as ischemic stroke/intracranial hemorrhage, require further efforts in bringing forth newer pharmacotherapy options.

Burden of death and disability due to adverse effects of medical treatment in India: An analysis using the global burden of disease 2019 study data.

Unsafe patient care can result in an adverse event that may lead to hospitalization, disability, or death. India has a vast and diverse population with varying degrees of access to tertiary healthcare. However, there is a lack of studies analyzing the burden of healthcare-related adverse events. We aimed to determine the burden of adverse effects of medical treatment (AEMT) in India from 2010 to 2019 using the global burden of disease (GBD) 2019 study database. Using the GBD data, we computed estimates for deaths and disability-adjusted life years (DALY) due to AEMT at the national level and stratified them based on age and gender. AEMT contributed to less than 0.01 % of death and DALY rates due to all causes in India. From 2010 to 2019, there was a decrease in the death rate from 2.34 (1.75-2.66) to 2.33 (1.73-2.86) per 100000 population. The number of deaths and DALYs was highest in the 50-74-year age group and in females. There has been a decrease in the death and DALY rates in India over the past decade. AEMT accounts for only a small percentage of deaths due to all causes; however, the potential underreporting and the impact of medical treatment-related adverse events on the public perception regarding healthcare services need to be studied.

A Systematic Review of the Economic Burden of Proton Therapy in Head and Neck Cancer.

BACKGROUND: Radiation therapy is used to treat head and neck cancer (HNC) patients. Proton beam therapy (PBT) is one of the newer treatment options. This systematic review will describe the cost and cost-effectiveness of PBT compared with other first-line treatment options based on available literature and provide a better understanding of its usage in HNC in the future. METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches were conducted in PUBMED, EMBASE and SCOPUS till February 2022. Original pharmacoeconomic articles written in English that considered PBT for HNC were included; the title, abstract and full text of the search items were screened. The included studies were critically appraised using the Drummond Checklist followed by data extraction. RESULTS: Eight of the ten included studies were of good quality; most were cost-effectiveness or cost comparison studies and used the Markov model and lifetime horizon. The dominant comparator was intensity-modulated radiotherapy. The willingness to pay threshold ranged from $30,828 to $150,000 per QALY. The incremental cost-effectiveness ratio (ICER) was between $4,436.1 and $695,000 per QALY. In HNC patients with human papillomavirus infection, the ICER was lower ($288,000/QALY) from the payer's perspective, but much higher ($390,000/QALY) from the societal perspective. CONCLUSION: Our systematic review showed that appropriate patient selection can make PBT cost-effective. HPV-associated tumors can be cost-effectively treated with PBT. From the payer's perspective, PBT is a cost-effective treatment option. In younger patients, PBT can result in lesser incidence of adverse effects, and hence, can reduce the subsequent need for long-term supportive care. Lower fractionation schedules can also make PBT a cost-effective treatment.

Knowledge of pharmacovigilance among healthcare professionals and the impact of an educational intervention.

Aim: To determine the knowledge regarding various aspects of pharmacovigilance among doctors and nurses of a tertiary care teaching hospital and to evaluate the effect of an educational intervention. Methods: A cross-sectional study was conducted among doctors and nurses of a tertiary care teaching hospital. The participants attended a one-hour educational session during which the concept of pharmacovigilance, the Pharmacovigilance Program of India, the need for reporting ADRs, and the method of reporting were explained by a subject expert. A 20-item questionnaire was used to assess their knowledge regarding pharmacovigilance before and after an educational session. The pre-post comparisons were done using Wilcoxon's signed-rank test. A p-value less than 0.05 was considered statistically significant. Results: Forty-two doctors and 115 nurses participated in the study. A significant improvement in the participant scores was seen following the educational intervention in both doctors (Z = -5.344, p < 0.001) and nurses (Z = -8.808, p < 0.001). Lack of knowledge/awareness was perceived as the major barrier for ADR reporting among nurses as well as doctors. Conclusion: There is need for education and training among doctors and nurses to enhance their knowledge about drug safety and reporting practices. Educational intervention is likely to improve the knowledge regarding pharmacovigilance, and thereby enhance reporting by healthcare professionals.

Clinical pharmacology and pharmacogenomics for implementation of personalized medicine.

With the aim of integrating clinical pharmacology with pharmacogenomics and providing a platform to gather clinicians, academicians, diagnostic laboratory personnel and scientists from related domains, the International Conference on Clinical Pharmacology and Pharmacogenomics 2023 (ICCPP 2023) was jointly organized by the Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, India and the CANSEARCH research platform in Pediatric Oncology and Hematology, University of Geneva, Geneva, Switzerland. The conference was held on 31 August and 1 September 2023, as a continued Indo-Swiss scientific exchange event series. In this report we describe the proceedings of this conference for the benefit of peers who could not attend the conference but are interested in knowing about the scientific program in detail.

Gastrointestinal stromal tumour of the duodenum: single institution experience.

BACKGROUND: Primary gastrointestinal stromal tumours (GISTs) of the duodenum are rare. The aim of this study was to review the surgical management of GISTs in this anatomically complex region. METHODS: Retrospective review from January 1999 to August 2011 of patients with primary GISTs of the duodenum. RESULTS: Forty-one patients underwent resection of duodenal GISTs. All operations were performed with intent to cure with negative margins of resection. The most common location of origin was the second portion of the duodenum. Local excision (n= 19), segmental resection with primary anastomosis (n= 11) and a pancreatoduodenectomy (n= 11) were performed. Two patients underwent an ampullectomy with local excision. Peri-operative mortality and overall morbidity were 0 and 12, respectively. Patients with high-risk GISTs (P= 0.008) and those who underwent a pancreatoduodenectomy (P= 0.021) were at a greater risk for morbidity. The median follow-up was 18 months. Eight patients developed recurrence. High-risk GISTs and neoplasms with ulceration had the greatest risk for recurrence (P= 0.017, P= 0.029 respectively). The actuarial 3- and 5-year survivals were 85% and 74%, respectively. CONCLUSION: The choice and type of resection depends on the proximity to the ampulla of Vater, involvement of adjacent organs and the ability to obtain negative margins. The morbidity depends on the type of procedure for GIST.

Doxycycline use and adverse pregnancy or neonatal outcomes: A descriptive study using the United States Food and Drug Administration Adverse Event Reporting System database.

Background and Aims: Doxycycline is recommended for use in rickettsial diseases. The available evidence regarding its safety for rickettsial infection in pregnancy is limited. Our study aimed to describe the adverse events of doxycycline when used during pregnancy for any indication, in terms of adverse maternal and/or neonatal outcomes, using the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We used the OpenVigil software for extracting the safety reports from the United States submitted to the FAERS from 2004 to 2021. We manually reviewed reports of doxycycline use resulting in adverse pregnancy outcomes or congenital anomalies to describe the patient and safety event characteristics. Results: From 2004 to 2021, 59 individual case safety reports containing preferred terms indicative of drug exposure during pregnancy or drug-induced adverse fetal outcomes were identified in the FAERS database. Following deduplication and manual review, 20 relevant adverse event reports were obtained. Doxycycline was the suspect medication in 13/20 (65%) reports. The common adverse event terms reported were premature delivery/baby in 6 reports, spontaneous abortion in 6, intrauterine death in 2, and various congenital anomalies in the rest. Fifty percent of the safety reports contained other medications which could have potentially caused the outcome. Conclusions: The number of reported events in the FAERS database of adverse pregnancy/neonatal outcomes following doxycycline use is small, similar to the numbers reported from large cohort or surveillance studies. Given the presence of concomitant medications that could have contributed to the outcome, there does not seem to be a strong signal of harm, although this needs to be confirmed by surveillance studies.

A Review of the Safety of Interleukin-17A Inhibitor Secukinumab.

Secukinumab is an anti-interleukin (IL)-17A IgG1-κ monoclonal antibody approved for psoriasis, psoriatic arthritis, and ankylosing spondylitis. Its efficacy is well documented, but the complete safety profile of secukinumab, especially on long-term use, needs to be studied. IL-17 inhibitors increase the risk of infections, especially respiratory tract infections and candidiasis, and inflammatory bowel disease; the causal relationships are well described. However, evidence regarding the other adverse events is scarce, and causal associations between the adverse events and the biologic remain unresolved. This review aims to present a narrative perspective on the safety of secukinumab and identify some key areas where the safety of secukinumab may potentially be useful in understanding the scope of secukinumab therapy and making informed clinical decisions.

Role of Drug Transporters in Elucidating Inter-Individual Variability in Pediatric Chemotherapy-Related Toxicities and Response.

Pediatric cancer treatment has evolved significantly in recent decades. The implementation of risk stratification strategies and the selection of evidence-based chemotherapy combinations have improved survival outcomes. However, there is large interindividual variability in terms of chemotherapy-related toxicities and, sometimes, the response among this population. This variability is partly attributed to the functional variability of drug-metabolizing enzymes (DME) and drug transporters (DTS) involved in the process of absorption, distribution, metabolism and excretion (ADME). The DTS, being ubiquitous, affects drug disposition across membranes and has relevance in determining chemotherapy response in pediatric cancer patients. Among the factors affecting DTS function, ontogeny or maturation is important in the pediatric population. In this narrative review, we describe the role of drug uptake/efflux transporters in defining pediatric chemotherapy-treatment-related toxicities and responses. Developmental differences in DTS and the consequent implications are also briefly discussed for the most commonly used chemotherapeutic drugs in the pediatric population.