Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment.

The characteristics of COVID-19 vaccine-related headache: Clues gathered from the healthcare personnel in the pandemic

Introduction Headache is a frequent adverse event after viral vaccines. We aimed to investigate the frequency and clinical associations of COVID-19 vaccine-related headache. Methods The characteristics, associations of this headache, main comorbidities, headache history following the influenza vaccine and during COVID-19 were investigated using a web-based questionnaire. Results A total of 1819 healthcare personnel (mean age: 44.4 ± 13.4 years, 1222 females), vaccinated with inactivated virus, contributed to the survey; 209 (11.4%) had been infected with COVID-19. A total of 556 participants (30.6%) reported headache with significant female dominance (36.1% vs. 19.3%), 1.8 ± 3.5 (median: 1; IQR: 0–2) days following vaccination. One hundred and forty-four participants (25.9%) experienced headache lasting ≥3 days. Headache was mostly bilateral without accompanying phenomena, less severe, and shorter than COVID-19-related headache. The presence of primary headaches and migraine were significantly associated with COVID-19 vaccine-related headache (ORs = 2.16 [95% CI 1.74–2.68] and 1.65 [1.24–2.19], respectively). Headache during COVID-19 or following influenza vaccine also showed significant association with headache following COVID-19 vaccine (OR = 4.3 [95% CI 1.82–10.2] and OR = 4.84 [95% CI 2.84–8.23], respectively). Only thyroid diseases showed a significant association (OR = 1.54 [95% CI 1.15–2.08]) with vaccine-related headache among the common comorbidities. Conclusion Headache is observed in 30.6% of the healthcare workers following COVID-19 vaccine and mostly experienced by females with pre-existing primary headaches, thyroid disorders, headache during COVID-19, or headache related to the influenza vaccine.

MO255LONG-TERM MAINTENANCE TREATMENT WITH RITUXIMAB IN ANCA-ASSOCIATED VASCULITIS: A RETROSPECTIVE COHORT STUDY

Background and Aims There is limited guidance and evidence for the ideal duration of maintenance treatment in ANCA-associated vasculitis (AAV) with rituximab (RTX). This study aimed to describe the efficacy and safety of long-term maintenance treatment with RTX, in a cohort of patients with AAV. Method Retrospective, descriptive study of 62 patients with AAV. We included 42 patients, who received RTX maintenance treatment in a newly diagnosed or a relapsed disease. We recorded the duration, dosage, and adverse events (infections, infusion-related events, relapses, late onset leukopenia, malignancy and hypogammaglobulinemia). Results 43 patients (average age 60.33 years, 49% women) received fixed interval dosing with RTX maintenance 1000 mg every 6 months. The most frequent organ involvement (74%) was lung and/or kidney. 33% (14/43) of the patients received RTX maintenance in a relapsed disease. The RTX regimen was followed after induction treatment with rituximab (47%), cyclophosphamide (33%), combination cyclophosphamide and rituximab (14%) or methotrexate/MMF (6%). Median total duration of maintenance treatment was 24 months (range 6-72 months). The most frequent adverse event was serious infections in 23% of the patients, including SARS-CoV-2 in two patients, while four of these patients died. We also recorded: hypogammaglobulinemia in 14%, malignancy in 5% and infusion-related events in 2%. The rate of the major relapses in our cohort during RTX maintenance was quite low at 7% (3/43), the time between 24-60 months, and the rate of the major relapses dependent on the induction treatment was quite the same: cyclophosphamide group vs rituximab group (7 vs 10%, p=0.786). Conclusion In our cohort long-term maintenance treatment in AAV with rituximab maintains remission for longer time, with a quiet safety profile. This could suggest that in selected patients, extended periods of rituximab treatment might be safe.

Surgical Outcomes of Gonioscopy-Assisted Transluminal Trabeculotomy (GATT) in Patients with Open-Angle Glaucoma – A Retrospective Case Series

Purpose To evaluate the outcome of gonioscopy-assisted transluminal trabeculotomy (GATT) in patients with open-angle glaucoma (OAG). Participants and Methods A retrospective case series of patients with uncontrolled OAG treated by GATT at the cantonal Hospital Lucerne, a tertiary referral center, between October 2018 and July 2019 with a minimal 6-month follow-up period. Main outcome measures were intraocular pressure (IOP), number of antiglaucoma medications, and complications. Results Thirty-one eyes of 29 patients with a mean age of 70.9 years and a minimal follow-up period of 6 months were included in this study. Twenty eyes were treated for pseudoexfoliation (64.5%), seven for primary open-angle (22.6%), three for pigmentary (9.7%), and one for traumatic (3.2%) glaucoma. Twenty-six eyes had data at the 6-month follow-up and 12 eyes at the 12-month follow-up. Twenty-two eyes (70.9%) were pseudophakic prior to the operation. Mean preoperative IOP was 33 mmHg (standard deviation [SD] 8.0 mmHg). The postoperative IOP was 13.9 mmHg [SD 2.2] at the 6- and 13.9 mmHg [SD 3.1] at the 12-month follow-up. The postoperative IOP evolution translated into a 58% decrease between 6 and 12 months (p < 0.001). Thirteen patients (41.9%) were treated with oral Diamox prior to GATT. The number of antiglaucoma medications decreased from a preoperative average of 2.9 [SD 1.2] to postoperative 1 [SD 1] drug (p < 0.001). The most frequent adverse event was the occurrence of postoperative hyphema. Hyphema was observed in 21 (68.0%), 7 (22.6%), and 2 (6.4%) eyes at days 1, 7, and 30 after GATT, respectively. Intraocular hypertension over 25 mmHg was seen in eight eyes (25.8%), and in four of them, a steroid response was suspected. One patient developed an anterior uveitis and a macular edema. Conclusion GATT is an effective and safe intervention for OAG, particularly in pseudoexfoliation glaucoma (PEX). The advantages of GATT compared to filtration surgery are the low rate of long-term complications and that the intervention is feasible even when difficult conjunctival conditions are encountered.

Mab-Mig: Registry of the Spanish Neurological Society of Erenumab for Migraine Prevention. Three-Months Results

Background Erenumab was approved in Europe for migraine prevention in patients with ≥4 monthly migraine days (MMD). In Spain, Novartis started a personalized managed access program which allowed free access to erenumab before official reimbursement. The Headache Study Group of the Spanish Neurological Society started a registry to monitor real-world safety and efficacy, and all Spanish headache experts were invited to participate. Methods Patients fulfilled ICHD3 criteria for migraine and had ≥ 4MMD. Sociodemographic and clinical data were registered as well as MMD, headache frequency (MHD), prior and concomitant preventive treatment, medication overuse headache (MOH), migraine evolution, adverse events, and PROs: HIT6, MIDAS, and PGIC. A >50% reduction of MMD after 3 months was considered as response. Results We included 210 patients (female 86.7%, mean age 46.4 years old) from 22 hospitals from February 2019 – to – June 2020. Most patients (89.5%) suffered from chronic migraine with a mean evolution of 8.6 years. MOH was present in 70% of patients, and 17.1% had migraine with aura. Average of prior preventive treatment failure was >7 (BoNT/A had been used by 95.2%). Most patients (67,6%) started with erenumab 70mg. 61% of patients were also taking oral preventive drugs or getting simultaneous BoNT/A (27.6%). Responder rate was 37.1% and the mean reduction of MMD was -6.28 and MHD: -8.6. Regarding PROs: MIDAS: -35 p., HIT6: -11.6 p., PIGC: 4.7 p. Predictors of good response were: HIT6 score ( p =0.01), prior preventive treatment failures ( p =0.026), absence of MOH ( p =0.039), and simultaneous BoNT/A treatment ( p <0.001). 20% had adverse event, but only two of them were severe (0.9%) which led to treatment discontinuation. Mild constipation was the most frequent adverse event (8.1%). Conclusion In real-life, in a personalized managed access program, erenumab shows a good profile of efficacy and an excellent safety in migraine prevention in our cohort of refractory patients.

Causes of Pruritus in Patients Treated With Immune Checkpoint Inhibitors for Melanomas or Skin Carcinomas

Background: Pruritus is a frequent adverse event during the use of immune checkpoint inhibitors (ICIs), with a frequency estimated to be between 11 and 47%. The underlying causes remain poorly understood.Objectives: The main goal was to search for putative causes of pruritus occurring in patients treated with ICIs for melanomas and cutaneous carcinomas. Other objectives were to assess the association between the occurrence of pruritus and survival and between the occurrence of pruritus and other adverse events.Methods: A monocentric retrospective descriptive study was performed using data for patients treated with ICIs (nivolumab, pembrolizumab, ipilimumab, and cemiplimab) between August 2010 and November 2019.Results: A total of 181 patients were included (mean age: 69 years). Pruritus was reported by 25 patients (13.8%). We were able to determine three subgroups of pruritus causes under ICI use: pruritus directly related to immunotherapy, pruritus indirectly related through other pruritus-inducing side effects and pruritus unrelated to ICIs. In 6/25 patients, no more specific cause of pruritus was found at the onset of pruritus or in their backgrounds, other than ICI use.Limitations: The study has some limitations due to unicentric and retrospective design.Conclusion: Pruritus was found in 25/181 patients in this series; only in 6/25 patients no potential cause other than ICI could be found, and pruritus was not associated with differences in survival.

Retrospective analysis of risk factors of hypotensive bradycardic events during shoulder arthroscopic surgery under interscalene blockade in the sitting position

Background: Hypotensive bradycardic events (HBEs) are a frequent adverse event in patients who underwent shoulder arthroscopic surgery under interscalene block (ISB) in the sitting position. This retrospective study was conducted to investigate the independent risk factors of HBEs in shoulder arthroscopic surgery under ISB in the sitting position. Methods: A total of 2549 patients who underwent shoulder arthroscopic surgery under ISB and had complete clinical data were included in the study. The 357 patients who developed HBEs were included in the HBEs group, and the remaining 2192 in the non-HBEs group. The potential risk factors for HBEs, such as age, sex, past medical history, anesthetic characteristics, and intraoperative medications were collected and compared between the groups. Statistically significant variables were included in a logistic regression model to further evaluate the independent risk factors for HBEs in shoulder arthroscopic surgery under ISB. Results: The incidence of HBEs was 14.0% (357/2549). Logistic regression analysis revealed that the intraoperative use of hydralazine (odds ratio [OR] 4.2; 95% confidence interval [CI] 2.9–6.3), propofol (OR 2.1; 95% CI 1.3–3.6), and dexmedetomidine (OR 3.9; 95% CI 1.9–7.8) before HBEs were independent risk factors for HBEs in patients who received shoulder arthroscopic surgery under ISB. Conclusions: The intraoperative use of antihypertensives such as hydralazine and sedatives such as propofol or dexmedetomidine leads to increased risk of HBEs during shoulder arthroscopic surgery under ISB in the sitting position.

STMO-01 Cerebral edema and perioperative epilepsy due to placement of BCNU wafer for malignant glioma

Introduction: Cerebral edema is the most frequent adverse event of BCNU wafer, which is used as local chemotherapy of malignant glioma. However, predictive factor of this event is unknown. Moreover, there is no consensus about cerebral edema and perioperative seizure, which is often observed in glioma. Here, we report risk factor of cerebral edema with BCNU placement and relationship with perioperative seizure in malignant glioma cases. Material and Method: Thirty-one case of adult malignant glioma who underwent BCNU placement in our institute between March 2013 to March 2019 were investigated. The patients were dichotomized to two groups; patient with postoperative transient cerebral edema (CE+ group) and patient without postoperative transient cerebral edema (CE- group). Result: Postoperative cerebral edema associated with placement of BCNU was observed in 9 out of 31 patients (29%). Tumor malignancy was significant parameter for postoperative cerebral edema (p=0.003). Other factors such as, age, gender, laterality, tumor location, primary or recurrent, number of BCNU wafers, duration of recurrence were not significant for postoperative cerebral edema. Seizure was seen in 14 patients (45%), and cerebral edema was not significant parameter for seizure. Tumor malignancy was significant parameters for postoperative cerebral edema. Tumor malignancy was significant parameters for seizure (p=0.0004). Although postoperative seizure was observed in 4 patients (44%) with CE+ group, neither maximum volume (mean 61.1 ml) nor change ratio (mean 354%) of FLAIR-high-intensity region were not related with postoperative seizure. Conclusions: Tumor malignancy was important factor for patients who underwent placement of BCNU wafer with postoperative cerebral edema and seizure. On the other hand, there were no relationship between postoperative cerebral edema and perioperative seizure in patients treated with BCNU wafer.

An Analysis of 2019 FDA Adverse Events for Two Insulin Pumps and Two Continuous Glucose Monitors

US Food and Drug Administration adverse event data for 2019 were analyzed for two insulin pumps and two continuous glucose monitors (CGMs). The analyses were selective—they were guided by the text described in the adverse events. They included (1) percent using auto mode for the Medtronic 670G pump, (2) distributions of hyper and hypo glucose values for Medtronic and Tandem pumps, (3) a Parkes error grid for Dexcom CGM vs glucose meter when the complaint was inaccuracy, and (4) the most frequent events for Abbott Freestyle. We found that for the 670G pump, there were more hypo events when auto mode was on than when auto mode was off. With Dexcom CGMs, users complained about inaccurate result when most results were in the B zone. With the Abbott Freestyle, the most frequent adverse event was an allergic skin reaction.

Hypoglycemia after Bariatric Surgery in Mice and Optimal Dosage and Efficacy of Glucose Supplementation

The Roux-en-Y Gastric Bypass (RYGB) mouse model is a vital tool for studying the pathophysiology of bariatric surgery and contributes greatly to research on obesity and diabetes. However, complications including postsurgical hypoglycemia can have profoundly negative effects. Unlike in humans, blood glucose (BG) is not typically managed in postoperative rodents, despite their critical role as translational models; without this management, rodents can experience hypoglycemia, potentially impairing wound healing, decreasing survivability, complicating interpretation of research data, and limiting translational utility. In this project, we sought to identify an optimal method for minimally invasive administration of dextrose in C57BL/6N (n = 16; 8 male, 8 female) mice. To do so, we characterized BG pharmacokinetic profiles after subcutaneous and oral–transmucosal (OTM) administration of dextrose. Compared with OTM dosage, the subcutaneous route provided more consistent and reliable delivery of glucose and did not cause significant adverse reactions. We then evaluated the frequency of hypoglycemic events after RYGB in C57BL/6N mice (n = 16; 8 male, 8 female) and the effects of subcutaneous dextrose supplementation on morbidity and mortality. BG measurement and behavioral pain assessment (grimace test) were performed for 3 d after surgery. Hypoglycemic (BG ≤ 60 mg/dL) animals were assigned to dose (5% dextrose SC) or no-dose treatment groups. Nearly all (87%) mice became hypoglycemic; 2 of these mice died. No significant intergroup difference in grimace score or mortality was detected. Overall, our results demonstrate that hypoglycemia is a frequent adverse event after RYGB in mice and that subcutaneous injection of dextrose is a safe and effective way to manage hypoglycemia. Further studies are necessary to optimize the intervention threshold and optimal dosage; regardless, we recommend glycemic management after RYGB surgery in mice.