Safety and Bioavailability of Complete and Half-Dose Intravitreal Ziv-Aflibercept in an Experimental Model: Contralateral Eye Study.

Ophthalmic Surg Lasers Imaging Retina. 2019 Dec 01;50(12):785-790

Authors: Lashay A, Delrish E, Ashrafi E, Movassat M, Asadi-Amoli F, Dinarvand R, Abrishami M

Abstract
BACKGROUND AND OBJECTIVE: To evaluate the safety and bioavailability of complete and half-dose of intravitreal ziv-aflibercept (IVZ) in an experimental model.
MATERIALS AND METHODS: Thirty-two eyes of 16 male rabbits received one IVZ injection under anesthesia and the operating microscope. All right and left eyes received 1,250 μg/0.05 mL and 625 μg/0.05 mL of ziv-aflibercept, respectively. Then, rabbits were randomly allocated to four groups (four rabbits in each group). The rabbits were euthanized at predesignated intervals (at 24, 168, 336, and 720 hours), and the eyes were enucleated. Indirect ophthalmoscopy, vitreous sampling, and electrophysiological recordings were obtained before euthanization. Histological examination was performed after enucleation. Vitreous samples were evaluated by enzyme-linked immunosorbent assay to measure the concentration of aflibercept.
RESULTS: No serious drug-related ocular inflammation and toxicity or systemic adverse events were identified. Electroretinogram findings showed no significant difference to the baseline measurements. Remaining vitreal concentrations of ziv-aflibercept injection for the 625 μg/mL group were 416 μg/mL, 349 μg/mL, 124 μg/mL, 41.2 μg/mL, and 18.1 μg/mL (± 10 μg/mL) and for the 1,250 μg/mL group were 833 μg/mL, 737 μg/mL, 284 μg/mL, 87.3 μg/mL, and 38.2 μg/mL (± 10 μg/mL), at zero, 24, 168, 336, and 720 hours after injection, respectively. The vitreous concentration of aflibercept was analyzed by one-compartment model. The area under curve from time 0 to the end point (AUC last) was 147,637 hours × μg/mL for the complete dose group (1,250 μg/0.05mL) and 68,498 hours × μg/mL for the half-dose group (625 μg/0.05 mL). The assessed vitreous half-life of ziv-aflibercept was 113 hours in both groups.
CONCLUSIONS: IVZ proved to be safe and well tolerated, even in the complete dose group. It seems to be a cost-effective therapeutic option for the treatment of retinal vascular diseases. However, the long-term safety and efficacy of intravitreal ziv-aflibercept remain unknown. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:785-790.].

PMID: 31877224 [PubMed - in process]

Advanced intrahepatic cholangiocarcinoma treated using anlotinib and microwave ablation: A case report.

Medicine (Baltimore). 2019 Dec;98(52):e18435

Authors: Zhang A, Liu B, Xu D, Sun Y

Abstract
INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) accounts for 10% to 15% of all primary hepatic carcinomas. However, there are no effective drug treatment strategies against ICC, and surgery is currently the only curative treatment. Here, we present a case of ICC successfully treated with anlotinib, a novel oral agent.
PATIENT CONCERNS: The patient was a 66-year-old Han Chinese woman, and she was a retired worker. The patient had no history of hepatitis B infection or hypertension. Physical examination showed no abnormalities, and the patient showed no conscious discomfort. However, ultrasound revealed liver occupation.
DIAGNOSIS: Liver ultrasound and enhanced computed tomography (CT) indicated liver cancer with intrahepatic metastasis. Serum carbohydrate antigen 199 and alpha fetoprotein levels were high at 4270 and 1561 ng/mL, respectively. Pathologic findings of CT-guided liver biopsy revealed an adenocarcinoma. Owing to further immunohistochemical staining and clinical results, a diagnosis of ICC was made.
INTERVENTIONS: The patient had received 5 cycles of transhepatic arterial chemotherapy and embolization and 1 cycle of microwave ablation. Due to rapid tumor progression and loss of liver function, systemic chemotherapy was contraindicated. As second-line therapy, she received anlotinib, a novel tyrosine kinase inhibitor that inhibits tumor angiogenesis and proliferative signaling and has been used to treat refractory advanced non-small-cell lung cancer that shows progression despite treatment with ≥2 chemotherapy regimens.
OUTCOMES: This patient showed a partial response after 2 cycles of treatment with anlotinib (12 mg daily, days 1-14 of a 21-day cycle). Drug-related side effects, such as hypertension and hand foot skin reaction, were observed. After 4 cycles of anlotinib, the efficacy appeared to be stable, and the patient showed a progression-free survival period of almost 4 months. However, the patient's condition worsened and she died of liver failure 6 months after treatment (overall survival, almost 6 months).
CONCLUSION: Some cases of ICC may be responsive to the antiangiogenic drug, anlotinib, when combined with microwave ablation. Randomized clinical studies are required to further confirm the efficacy and safety of anlotinib in the clinical treatment of ICC.

PMID: 31876723 [PubMed - in process]

Antipsychotic Medication Exposure, Clozapine, and Pneumonia: Results from a Self-controlled Study.

Acta Psychiatr Scand. 2019 Dec 25;:

Authors: Rohde C, Siskind D, de Leon J, Nielsen J

Abstract
OBJECTIVE: By using a self-controlled design, we investigated whether antipsychotic medication exposure was associated with increased pneumonia risk and whether patients receiving clozapine were more likely to develop pneumonia than patients receiving other antipsychotic medications.
METHODS: Through nationwide health registers, we identified all outpatients with schizophrenia initiating antipsychotic treatment. First, we estimated whether antipsychotic-naïve patients with schizophrenia increased their risk of pneumonia after initiation of either a first- or second-generation antipsychotic medication using a one-year mirror-image model. Afterwards, similar analyses were made for individual second-generation antipsychotics. Lastly, the rate of pneumonia for patients initiated on clozapine was compared to patients commenced on other second-generation antipsychotics.
RESULTS: In total, 8355 antipsychotic-naïve patients with schizophrenia were initiated on a first-generation antipsychotic medication; 0.95% of the patients had developed pneumonia before exposure, compared to 0.68% after exposure (p=0.057). Similar findings were made for the 8001 antipsychotic-naïve patients with schizophrenia initiated on second-generation antipsychotic medications, with 0.56% developing pneumonia before exposure compared to 0.55% after exposure (p=1.00). Second-generation antipsychotic medications did not increase the pneumonia risk, except for risperidone (increased by 0.32%; p=0.007) and clozapine, which gave the largest absolute increase in pneumonia risk although not significant (increased by 0.64 %; p=0.10). The rate of pneumonia was higher after initiation of clozapine than for other second-generation antipsychotic medications.
CONCLUSION: Most antipsychotic medications were not found to increase the risk of pneumonia. Clozapine exposure might be associated with increased risk of developing pneumonia.

PMID: 31875941 [PubMed - as supplied by publisher]

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events.

World J Stem Cells. 2019 Dec 26;11(12):1020-1044

Authors: Genova E, Cavion F, Lucafò M, Leo L, Pelin M, Stocco G, Decorti G

Abstract
Adverse drug reactions (ADRs) are major clinical problems, particularly in special populations such as pediatric patients. Indeed, ADRs may be caused by a plethora of different drugs leading, in some cases, to hospitalization, disability or even death. In addition, pediatric patients may respond differently to drugs with respect to adults and may be prone to developing different kinds of ADRs, leading, in some cases, to more severe consequences. To improve the comprehension, and thus the prevention, of ADRs, the set-up of sensitive and personalized assays is urgently needed. Important progress is represented by the possibility of setting up groundbreaking patient-specific assays. This goal has been powerfully achieved using induced pluripotent stem cells (iPSCs). Due to their genetic and physiological species-specific differences and their ability to be differentiated ideally into all tissues of the human body, this model may be accurate in predicting drug toxicity, especially when this toxicity is related to individual genetic differences. This review is an up-to-date summary of the employment of iPSCs as a model to study ADRs, with particular attention to drugs used in the pediatric field. We especially focused on the intestinal, hepatic, pancreatic, renal, cardiac, and neuronal levels, also discussing progress in organoids creation. The latter are three-dimensional in vitro culture systems derived from pluripotent or adult stem cells simulating the architecture and functionality of native organs such as the intestine, liver, pancreas, kidney, heart, and brain. Based on the existing knowledge, these models are powerful and promising tools in multiple clinical applications including toxicity screening, disease modeling, personalized and regenerative medicine.

PMID: 31875867 [PubMed]

Nocebo effect in myasthenia gravis: systematic review and meta-analysis of placebo-controlled clinical trials.

Acta Neurol Belg. 2019 Jun;119(2):257-264

Authors: Varma A, Zis P

Abstract
Nocebo refers to the adverse events (AEs) experienced when taking a placebo drug and is believed to be a centrally mediated process. We sought to examine the AEs following placebo administration in Randomised Controlled Trials (RCTs) for Myasthenia Gravis (MG) patients. A systematic literature search was performed on Medline and Web of Science for RCTs for MG pharmacological treatments. We assessed the number of placebo-treated patients reporting at least one AE and the number of dropouts because of AEs. Data were extracted from six RCTs fulfilling the search criteria. Four out of five placebo-treated participants (80.1%) reported at least one AE and one in 40 (2.4%) discontinued placebo treatment because of AE. All patients participating in the MG trials reported similar AEs independent of the study arm to which they belonged (placebo or active treatment). This meta-analysis demonstrates a low nocebo dropout rate in MG compared to central nervous system disorders.

PMID: 31004288 [PubMed - indexed for MEDLINE]

Auricular acupressure: reducing side effects of chemotherapy in women with ovarian cancer.

Support Care Cancer. 2019 Nov;27(11):4155-4163

Authors: Tsao Y, Creedy DK

Abstract
PURPOSE: Many women with ovarian cancer may experience adverse effects from adjuvant chemotherapy after surgery. Non-pharmacological interventions can be used to reduce these side effects. We tested auricular acupressure to reduce treatment side effects in this population.
METHODS: A prospective, quasi-randomized controlled trial was carried out at a publicly-funded hospital in southern Taiwan. Thirty-four women in the intervention group received auricular acupressure at four points (Shenmen, subcortex, endocrine, and heart), three times per day for 3 min per time, for 6 weeks. Thirty-one women in the control group received routine nursing care alone. The M. D. Anderson Symptom Inventory (MDASI) was completed at four time points.
RESULTS: After receiving the third cycle of chemotherapy, side effect severity was elevated among both groups. Auricular acupressure reduced side effects such as disturbed sleep (t = - 11.99; p < .001, eta squared = 0.69), fatigue (t = - 2.57; p < .01, eta squared = 0.10), and lack of appetite (t = - 2.37; p = .024, eta squared = 0.08).
CONCLUSION: Auricular acupressure can reduce adverse side effects of chemotherapy in women with ovarian cancer. Future studies with a larger sample and using some laboratory-based tests (such as C-reactive protein, interleukin-6) are warranted to confirm the results.

PMID: 30796521 [PubMed - indexed for MEDLINE]

Is a new symptom an adverse drug reaction?

Geriatr Nurs. 2019 Nov - Dec;40(6):634-635

Authors: Simonson W

PMID: 31735450 [PubMed - indexed for MEDLINE]

Understanding Parkinson's disease and deep brain stimulation: Role of monkey models.

Proc Natl Acad Sci U S A. 2019 Dec 23;:

Authors: Vitek JL, Johnson LA

Abstract
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder affecting over 10 million people worldwide. In the 1930s and 1940s there was little understanding regarding what caused PD or how to treat it. In a desperate attempt to improve patients' lives different regions of the neuraxis were ablated. Morbidity and mortality were common, but some patients' motor signs improved with lesions involving the basal ganglia or thalamus. With the discovery of l-dopa the advent of medical therapy began and surgical approaches became less frequent. It soon became apparent, however, that medical therapy was associated with side effects in the form of drug-induced dyskinesia and motor fluctuations and surgical therapies reemerged. Fortunately, during this time studies in monkeys had begun to lay the groundwork to understand the functional organization of the basal ganglia, and with the discovery of the neurotoxin MPTP a monkey model of PD had been developed. Using this model scientists were characterizing the physiological changes that occurred in the basal ganglia in PD and models of basal ganglia function and dysfunction were proposed. This work provided the rationale for the return of pallidotomy, and subsequently deep brain stimulation procedures. In this paper we describe the evolution of these monkey studies, how they provided a greater understanding of the pathophysiology underlying the development of PD and provided the rationale for surgical procedures, the search to understand mechanisms of DBS, and how these studies have been instrumental in understanding PD and advancing the development of surgical therapies for its treatment.

PMID: 31871164 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Digital ischaemia with fingertip ulcers during ipilimumab therapy].

Ann Dermatol Venereol. 2019 Dec 18;:

Authors: Zenati N, Charles J, Templier I, Blaise S

Abstract
BACKGROUND: Anti-cancer drugs have many adverse effects including vascular side effects. Herein we present the case of a patient presenting digital ischaemia with high imputability of ipilimumab.
OBSERVATION: A 47-year-old male patient was treated for popliteal melanoma, initially stage IIIA but which subsequently became metastatic (stage IV), and for which ipilimumab was given after the failure of two lines of chemotherapy. During the 4th course of ipilimumab, the patient developed autoimmune hepatitis. Ipilimumab was suspended. Three months later, he developed a drug-like neuropathy followed one month later by ulceration of the right index finger. Causes of embolic, autoimmune and occupational origin (thrombotic microangiopathy, thrombosed aneurysm) were rapidly ruled out. Although a paraneoplastic origin could not be formally excluded, drug-induced immune disorder remained the most plausible origin.
DISCUSSION: This is the first reported case of digital ulceration under ipilimumab.

PMID: 31864764 [PubMed - as supplied by publisher]

Safety Study of Sodium Pentosan Polysulfate for Adult Patients with Mucopolysaccharidosis Type II.

Diagnostics (Basel). 2019 Dec 17;9(4):

Authors: Orii K, Lim A, Tomatsu S, Stapleton M, Suzuki Y, Simonaro CM, Schuchman EH, Fukao T, Matsumoto T

Abstract
Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to a) primarily establish the safety of weekly PPS injections in attenuated MPS II, b) assess the efficacy of treatment on MPS pathology, and c) define appropriate clinical endpoints and biomarkers for future clinical trials. Subcutaneous injections were administered to three male Japanese patients for 12 weeks. Enzyme replacement therapy was continued in two of the patients while they received PPS and halted for two months in one patient before starting PPS. During treatment, one patient experienced an elevation of alanine transaminase, and another patient experienced convulsions; however, these incidences were non-cumulative and unrelated to PPS administration, respectively. Overall, the drug was well-tolerated in all patients, and no serious drug-related adverse events were noted. Generally, PPS treatment led to an increase in several parameters of shoulder range of motion and decrease of the inflammatory cytokines, MIF and TNF-α, which are potential clinical endpoints and biomarkers, respectively. Changes in urine and serum glycosaminoglycans were inconclusive. Overall, this study demonstrates the safety of using PPS in adults with MPS II and suggests the efficacy of PPS on MPS pathology with the identification of potential clinical endpoints and biomarkers.

PMID: 31861164 [PubMed]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A first-in-human Phase I study to evaluate the ERK1/2 inhibitor GDC-0994 in patients with advanced solid tumors.

Clin Cancer Res. 2019 Dec 17;:

Authors: Varga A, Soria JC, Hollebecque A, LoRusso PM, Bendell JC, Huang SA, Wagle MC, Okrah K, Liu L, Murray ER, Sanabria Bohórquez SM, Tagen M, Dokainish H, Mueller L, Burris HA

Abstract
PURPOSE: Extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, Phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors.
EXPERIMENTAL DESIGN: GDC-0994 was administered once daily on a 21-day on/7-day off schedule to evaluate safety, pharmacokinetics, and preliminary signs of efficacy. Patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer (CRC) were enrolled in the expansion stage.
RESULTS: Forty-seven patients were enrolled in 6 successive cohorts (50-800 mg). A single DLT of Grade 3 rash occurred at 600 mg. The most common drug-related adverse events (AE) were diarrhea, rash, nausea, fatigue, and vomiting. PK data showed dose-proportional increases in exposure, with a mean half-life of 23 hours, supportive of once daily dosing. In evaluable paired biopsies, MAPK pathway inhibition ranged from 19-51%. Partial metabolic responses by FDG-PET were observed in 11/20 patients across dose levels in multiple tumor types. Overall, 15/45 (33%) patients had a best overall response of stable disease and 2 patients with BRAF-mutant CRC had a confirmed partial response.
CONCLUSIONS: GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single agent activity was observed in two patients with BRAF-mutant CRC.

PMID: 31848189 [PubMed - as supplied by publisher]

Duvelisib: a new phosphoinositide-3-kinase inhibitor in chronic lymphocytic leukemia.

Future Oncol. 2019 Jul;15(19):2227-2239

Authors: Frustaci AM, Tedeschi A, Deodato M, Zamprogna G, Cairoli R, Montillo M

Abstract
P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across different prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Immune-related effects are the main reason for treatment suspension, thus affecting survival benefit. Nevertheless, the correct management of adverse events, eventually including dose modification, allows patients to remain on treatment. In conclusion, duvelisib represents a promising treatment in chronic lymphocytic leukemia and a salvage therapy after ibrutinib.

PMID: 31137964 [PubMed - indexed for MEDLINE]

Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections.

Clin Cancer Res. 2018 04 15;24(8):1780-1784

Authors: Kim J, Singh H, Ayalew K, Borror K, Campbell M, Johnson LL, Karesh A, Khin NA, Less JR, Menikoff J, Minasian L, Mitchell SA, Papadopoulos EJ, Piekarz RL, Prohaska KA, Thompson S, Sridhara R, Pazdur R, Kluetz PG

Abstract
Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780-4. ©2017 AACRSee related commentary by Nipp and Temel, p. 1777.

PMID: 29237718 [PubMed - indexed for MEDLINE]

66 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Improved muscle function in a phase I/II clinical trial of albuterol in Pompe disease.

Mol Genet Metab. 2019 Dec 10;:

Authors: Koeberl DD, Case LE, Desai A, Smith EC, Walters C, Han SO, Thurberg BL, Young SP, Bali D, Kishnani PS

Abstract
This 24-week, Phase I/II, double-blind, randomized, placebo-controlled study investigated the safety and efficacy of extended-release albuterol in late-onset Pompe disease stably treated with enzyme replacement therapy at the standard dose for 4.9 (1.0-9.4) years and with no contraindications to intake of albuterol. Twelve of 13 participants completed the study. No serious adverse events were related to albuterol, and transient minor drug-related adverse events included muscle spasms and tremors. For the albuterol group, forced vital capacity in the supine position increased by 10% (p < .005), and forced expiratory volume in one second increased by 8% (p < .05); the six-minute walk test increased 25 m (p < .05; excluding one participant unable to complete muscle function testing); the Gross Motor Function Measure increased by 8% (p < .005) with the greatest increases in the Standing (18%; p < .05) and Walking, Running, and Jumping (11%; p < .005) subtests. No significant improvements would be expected in patients with late-onset Pompe disease who were stably treated with enzyme replacement therapy. The placebo group demonstrated no significant increases in performance on any measure. These data support a potential benefit of extended-release albuterol as adjunctive therapy in carefully selected patients with late-onset Pompe disease based on ability to take albuterol on enzyme replacement therapy (NCT01885936).

PMID: 31839530 [PubMed - as supplied by publisher]

Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern.

Autoimmun Rev. 2019 Dec 12;:102455

Authors: Matas-García A, Milisenda JC, Selva-O'Callaghan A, Prieto-González S, Padrosa J, Cabrera C, Reguart N, Castrejón N, Solé M, Ros J, Trallero-Araguas E, Antoniol MN, Vila-Pijoan G, Grau JM

Abstract
BACKGROUND AND OBJECTIVE: Drug-induced myopathy is among the most common causes of muscle disease. An association has recently been described between programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and immune-related adverse events (irAE) affecting the muscle. Here, we report the clinical and pathological findings of nine unrelated patients with PD-1 and PD-L1 inhibitors-associated myopathy.
METHODS: We retrospectively analyzed 317 muscle biopsies performed for diagnostic purposes from January 2017 to June 2019. Patients were attended in two tertiary centers and muscle biopsies were performed and analyzed by two myology experts. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned and stained. Immunohistochemistry studies were also performed as a routine procedure in our lab.
RESULTS: We identified 9 patients receiving anti-PD-1 or PD-L1 inhibitors consulting for either muscle weakness, asthenia, myasthenic-like syndrome or other muscle related-symptoms, along with biopsy-proven inflammatory myopathy. One had concomitant myocarditis. In most of the cases muscle biopsy showed a marked phenomenon of necrosis, macrophagy and muscle regeneration with perivascular inflammatory infiltrates with a large component of macrophagic cells. A tendency to perifascicular atrophy was also noticed. The expression of MHC class I antigens predominated in the perifascicular zones. Raised muscle enzymes were detected in 7 patients.
CONCLUSION: A characteristic clinic-pathological pattern, including a myasthenia gravis-like syndrome plus myositis was found in patients receiving PD-1 and PD-1 L inhibitors. A large component of macrophages resembling granulomas seems to be the pathological hallmark of the syndrome. Further information is required to understand the wide spectrum of immune-related adverse events involving the muscle during or after treatment with anti-PD-1 inhibitors, but the pathological picture seems to be characteristic.

PMID: 31838162 [PubMed - as supplied by publisher]