Efficacy and safety of cryoablation combined with lenvatinib and anti-PD-1 monoclonal antibody in treatment of unresectable hepatocellular carcinoma / 临床肝胆病杂志

ObjectiveTo investigate whether anti-PD-1 monoclonal antibody can improve the efficacy and safety of cryoablation combined with lenvatinib in the treatment of unresectable hepatocellular carcinoma （HCC）. MethodsA retrospective analysis was performed for 232 patients with unresectable HCC who were treated at The Fifth Medical Center of Chinese PLA General Hospital from January 2018 to December 2022， among whom 128 received cryoablation combined with lenvatinib （double combination） and 104 received cryoablation combined with lenvatinib and anti-PD-1 monoclonal antibody （triple combination）. Propensity score matching was performed at a ratio of 1∶1， and finally there were 86 patients in each group. The two groups were evaluated in terms of objective response rate （ORR）， disease control rate （DCR）， overall survival （OS）， progression-free survival （PFS）， and adverse events （AEs）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical data between two groups. Survival curves were plotted， and the Kaplan-Meier method was used to calculate the survival rate of patients in both groups， while the log-rank test was used for comparison between the two groups. The Cox regression model was used to calculate hazard ratio （HR） and 95% confidence interval （CI） and perform the univariate and multivariate analyses of influencing factors for prognosis. ResultsThe median follow-up time was 28 months， and there were 33 deaths （38.0%） in the triple combination group and 40 deaths （46.0%） in the double combination group. Compared with the double combination group， the triple combination group had significantly higher ORR （35.6% vs 14.5%， P=0.008） and DCR （86.1% vs 64.1%， P=0.003）. OS and PFS in the triple combination group were significantly higher than those in the double combination group （P=0.045 and 0.026）. The univariate and multivariate Cox proportional-hazards regression model analyses showed that treatment regimen （HR=0.60， P=0.038） and alpha-fetoprotein level （HR=2.37， P=0.001） were independent risk factors for OS， and treatment regimen （HR=0.65， P=0.025）， diabetes mellitus （HR=1.94， P=0.005）， whether or not to have received local treatment （HR=0.63， P=0.014）， and distant metastasis （HR=0.58， P=0.009） were independent risk factors for PFS. There was no significant difference in the incidence rate of AEs between the two groups （P>0.05）. ConclusionFor patients with unresectable HCC， the triple combination of cryoablation， lenvatinib， and anti-PD-1 monoclonal antibody significantly improves the treatment outcome and survival of patients compared with the double combination of cryoablation and lenvatinib， without increasing AEs， which provides a clinical basis for optimizing the treatment regimen for unresectable HCC.

Psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors

Abstract PD-1 (programmed Death-1) immune checkpoint inhibitors have provided significant benefits to tumor patients. However, a considerable proportion of the patients develop immune-related adverse events (irAEs), of which cutaneous irAEs (cirAEs, e.g., psoriasis) occur relatively early. This review provides an overview of the current progress in psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. It not only describes the relevant influencing factors but also theoretically analyzes the immunological mechanisms that lead to the onset or exacerbation of psoriasis. Finally, the authors present guidelines for the treatment of psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. The review is intended to assist dermatologists in the early recognition and effective individualized management of such cirAE, which is helpful to continue or adjust the tumor-targeted immunotherapy on the basis of ensuring the quality of life of tumor patients.

Cetoacidosis diabética secundaria a inmunoterapia / Diabetic ketoacidosis secondary to immunotherapy

Resumen Los inhibidores de puntos de control inmune (ICIs) son anticuerpos monoclonales cada vez más utilizados en tratamientos oncológicos. A medida que aumenta la experiencia en el uso de inmunoterapia, se conoce cada vez más su perfil de seguridad y los efectos adversos inmunomediados. Entre ellos se encuentra la cetoaci dosis diabética (CAD), complicación infrecuente, grave y potencialmente mortal. En este trabajo describimos los casos de tres pacientes que se presentaron con episo dios de CAD durante el tratamiento con ICIs, dos de los cuales manifestaron con formas fulminantes, llevando un curso agudo con valores de hemoglobina glicosilada inicialmente normales. Asimismo, realizamos una revi sión de la literatura sobre la CAD asociada a ICIs a fines de resaltar la importancia de advertir estas complica ciones potencialmente fatales e instaurar rápidamente la terapéutica apropiada.

Abstract Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used in cancer treat ments. As experience in the use of immunotherapy increases, more is known about its safety profile and immune-mediated adverse effects. Among them is dia betic ketoacidosis (DKA), a rare but serious fatal compli cation of treatment. In this paper we describe the cases of three patients who presented with episodes of DKA during treatment with ICIs, two of which manifested with fulminant forms, leading to an acute course with initially normal glycosylated hemoglobin values. In ad dition, we conducted a review of the literature on DKA associated with ICIs in order to highlight the importance of noticing these potentially fatal complications and promptly establishing appropriate therapy.

Vitreous metastasis from cutaneous melanoma: diagnosis and management / Metástase vítrea de melanoma cutâneo: diagnóstico e tratamento

ABSTRACT Purpose: To report the clinical findings, treatments, and outcomes in a series of patients with vitreous metastasis from cutaneous melanoma. Methods: This single-center, retrospective, interventional case series included patients with biopsy-confirmed vitreous metastasis from cutaneous melanoma diagnosed between 1997 and 2020. Standard 23- or 25-gauge pars plana vitrectomy was performed for diagnostic sampling. Sclerotomies were treated with double or triple freeze-thaw cryotherapy. Perioperative intravitreal injections of melphalan (32 µg/0.075 mL) were administered, when indicated. Visual acuity, intraocular pressure, and systemic and ocular treatment responses were reported. Results: Five eyes of five patients with unilateral vitreous metastasis from cutaneous melanoma were identified. The median age at diagnosis was 84 (range, 37-88) years. The median follow-up after ophthalmic diagnosis was 28 (8.5-36) months; one patient did not have a follow-up. The initial visual acuity ranged from 20/30 to hand motions. Baseline clinical findings included pigmented or non-pigmented cellular infiltration of the vitreous (5/5), anterior segment (4/5), and retina (3/5). Four patients had secondary glaucoma. Systemic therapy included checkpoint inhibitor immunotherapy (n=3, all with partial/complete response), systemic chemotherapy (n=2), surgical resection (n=3), and radiation (n=2). The median time from primary diagnosis to vitreous metastasis was 2 (2-15) years. One patient had an active systemic disease at the time of vitreous metastasis. The final visual acuity ranged from 20/40 to no light perception. Ophthalmic treatment included vitrectomy in all five patients, intravitreal administration of melphalan in three, and intravitreal administration of methotrexate in one. One patient required enucleation, and histopathology revealed extensive invasion by melanoma cells. Conclusions: Vitreous metastasis from cutaneous melanoma can present as a diffuse infiltration of pigmented or non-pigmented cells into the vitreous and may be misdiagnosed as uveitis. Diagnostic pars plana vitrectomy and periodic intravitreal chemotherapy may be indicated.

RESUMO Objetivo: Descrever os achados clínicos, tratamentos, e desfechos em uma série de pacientes com me tástases vítreas de melanoma cutâneo. Métodos: Série retrospectiva de casos de único centro com intervenção. Pacientes incluídos tiveram seu diagnóstico de MVMC confirmado por biópsia entre 1997 e 2020. Vitrectomia via pars plana com 23 ou 25 gauge foram realizadas para obter espécimens. Esclerotomias foram tratadas com crioterapia em duplo ou triplo congelamento. Injeção intravítrea perioperatória de melfalano (32 ug/0,075 mL) foi administrada quando necessário. Foram relatados acuidade visual, pressão intraocular, resposta terapêutica sistêmica e ocular. Resultados: Cinco olhos de 5 pacientes com metástases vítreas de melanoma cutâneo unilateral foram identificados. Idade média de diagnóstico foi 84 anos (variando de 37-88). Seguimento médio após diagnóstico oftalmológico foi 28 (8,5-36) meses; 1 paciente não teve acompanhamento. Acuidade visual inicial variou de 20/30 a movimentos de mão. Achados clínicos iniciais incluíram infiltração de células pigmentadas e não-pigmentadas no vítreo (5/5), segmento anterior (4/5), e retina (3/5). Quatro pacientes tiveram glaucoma secundário. Tratamento sistêmico incluiu imunoterapia com inibidores da via de sinalização (3 - todos com resposta parcial/completa), quimioterapia sistêmica (2), ressecção cirúrgica (3), e irradiação (2). Intervalo médio entre diagnóstico primário e metástases vítreas foi 2 (2-15) anos. Um paciente teve doença sistêmica ativa simultânea as metástases vítreas. Acuidade visual final variou entre 20/40 e SPL. Tratamento oftalmológico incluiu vitrectomia nos 5 pacientes, melfalano intravítreo em 3 e metotrexato intravítreo em 1. Um paciente precisou de enucleação. A histopatologia revelou invasão celular extensa de melanoma. Conclusões: Metástases vítreas de melanoma cutâneo pode se manifestar como uma infiltração difusa de células pigmentadas e não-pigmentadas no vítreo e erroneamente diagnosticada como uveites. Vitrectomia diagnóstica e quimioterapia intravítrea periódica podem estar indicadas.

Toxicidad sistémica y pulmonar por inmunoterapia. Revisión narrativa a propósito de un caso

En el último tiempo, la inmunoterapia se ha convertido en una opción terapéutica para diversos tipos de neoplasias, aumentando la sobrevida en muchos casos, pero también los efectos adversos asociados. Existen tres tipos de inmunoterapia utilizados en cáncer: Terapia de células T con receptor de antígeno quimérico (CAR-T), destacando como reacciones adversas el síndrome liberador de citoquinas (CRS) y el síndrome de neurotoxicidad (ICANS); Anticuerpos monoclonales (AcM), cuyos efectos adversos más comunes están relacionados con reacciones de hipersensibilidad; y los Inhibidores de puntos de control inmunitario (ICI) con toxicidad pulmonar claramente reportada. Para un correcto manejo de estas reacciones adversas se requiere un alto índice de sospecha, un adecuado diagnóstico diferencial y un tratamiento oportuno, basado principalmente en corticoides y guiado por criterios de gravedad. Se presenta el caso de un paciente con reacción granulomatosa sarcoidea posterior al uso de Nivolumab.

In recent times, immunotherapy has emerged as a therapeutic option for various neoplasms, significantly improving survival rates in many cases, albeit with associated adverse effects. There are three types of immunotherapy commonly used in cancer treatment: Chimeric Antigen Receptor T-cell Therapy (CAR-T), notable for adverse reactions such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); Monoclonal Antibodies (mAbs), with the most common adverse effects being hypersensitivity reactions; and Immune Checkpoint Inhibitors (ICI), with well-documented pulmonary toxicity. Adequate management of these adverse reactions requires a high index of suspicion, accurate differential diagnosis, and timely treatment, primarily based on corticosteroids and guided by severity criteria. We present a case of a patient with granulomatous sarcoid-like reaction following the use of Nivolumab.

Diabetes mellitus tipo 1 de presentación súbita inducida por inhibidores del punto de control inmunitario en el tratamiento de cáncer avanzado. Serie de casos / Sudden onset type 1 diabetes mellitus induced by immune checkpoint inhibitors in the treatment of advanced cancer. Cases report

Tres pacientes con cáncer avanzado en tratamiento con inhibidores del punto de control inmunitario (inmune checkpoint inhibitors, ICIs), sin antecedentes de diabetes mellitus (DM), ingresaron al Servicio de Urgencias con poliuria, polidipsia y pérdida de peso, y diagnóstico de cetoacidosis diabética, sin evidencia clínica de infección. Fueron tratados con líquidos e infusión de insulina pasando luego a un régimen de insulina bolo basal que continuó después del alta. Las pruebas de detección de autoanticuerpos para DM resultaron negativas, y se les diagnosticó DM inducida por ICIs, pembrolizumab en dos de ellos y nivolumab en el otro. El propósito de esta serie de casos es demostrar el desarrollo de la DM1 en forma aguda en pacientes tratados con inhibidores de PD-1. Sobre la base de estos casos y la literatura revisada, se buscaron determinar las características clínicas, y sugerir estrategias para la identificación, control, tratamiento precoz y seguimiento de los pacientes tratados con ICIs a fin de minimizar el impacto de la disfunción autoinmune.

Three patients with advanced cancer, treated with inmune checkpoint inhibitors (ICIs), with no history of diabetes mellitus (DM), were admitted to the Emergency Department with polyuria, polydipsia, and weight loss and a diagnosis of diabetic ketoacidosis without clinical evidence of infection. They were treated with fluids and insulin infusion transitioning to a basal-bolus insulin regimen, which continued after discharge. Autoantibody detection tests for DM were negative and they were diagnosed with DM induced by ICIs, pembrolizumab in two of them, and nivolumab in another. The purpose of this case report is to show the development of DM1 in an acute form in patients treated with PD-1 inhibitors. Based on these cases and the reviewed literature, we seek to identify clinical characteristics and suggest strategies for the proper identification, control, treatment, and follow-up of patients treated with ICIs to minimize the impact of autoimmune dysfunction.

Merkel cell carcinoma: epidemiology, clinical features, diagnosis and treatment of a rare disease

Abstract Merkel cell carcinoma is a rare skin cancer with neuroendocrine differentiation. The risk factors include sun exposure, advanced age, immunosuppression (such as transplant recipients, patients with lymphoproliferative neoplasms, or patients with HIV), and Merkel cell polyomavirus infection. Clinically, Merkel cell carcinoma appears as a cutaneous or subcutaneous plaque or nodule, but this tumor diagnosis is rarely made clinically. Therefore, histopathology and immunohistochemistry are usually necessary. Primary tumors without evidence of metastases are treated with complete surgical excision and appropriate surgical margins. The presence of occult metastasis in a lymph node is frequent and a sentinel lymph node biopsy should be performed. Postoperative adjuvant radiotherapy increases local tumor control. Recently, agents that block the PD-1/PD-L1 pathway have shown objective and durable tumor regression in patients with advanced solid malignancies. The first anti-PD-L1 antibody used in patients with Merkel cell carcinoma was avelumab, but pembrolizumab and nivolumab have also shown efficacy. This article describes the current state of knowledge of the epidemiology, diagnosis, and staging of Merkel cell carcinoma, as well as new strategies for its systemic treatment.

Chinese multidisciplinary expert consensus on combined immunotherapy for hepatocellular carcinoma(2023 version) / 中华肝脏病杂志

Immune checkpoint inhibitors (ICIs)-based immunotherapy combined with other treatment for hepatocellular carcinoma (HCC) has achieved significant efficacy in clinical research and practice, and has become the most commonly used and mainstay therapy for the treatment of unresectable HCC. In order to help clinicians administrating immunotherapy drugs and regimens rationally, effectively and safely, we organized a multidisciplinary expert team to adopt the "Delphi" consensus formation method, and finally revised and completed the "Multidisciplinary Expert Consensus on Combination Therapy Based on the Immunotherapy for Hepatocellular Carcinoma (2023 Edition)" on the basis of the 2021 version. This consensus mainly focuses on the principles and methods of clinical application of combination therapy based on the Immunotherapy, aiming to summarize the recommendations for clinical application based on the latest research and expert experience, and provide application guidance for clinicians.

Research progress of the methods for predicting the efficacy of immune checkpoint inhibitors in hepatocellular carcinoma treatment / 中华肝胆外科杂志

In recent years, immune checkpoint inhibitors (ICIs) have emerged as a significant advancement in the treatment of advanced hepatocellular carcinoma (HCC), providing benefits to a subset of patients. At present, there are still many problems with ICIs treatment for HCC, such as limited objective remission rate, high treatment cost, frequent treatment-related adverse events, and tumor hyperprogression. In this context, it is important to find indicators that can predict the efficacy of ICIs treatment in order to optimize patients’ selection and maximize clinical benefits, further avoiding unnecessary toxic side effects and economic losses. This article discusses biochemical and cytological indicators, tumor-related markers, imaging indicators, and immune-related adverse events in order to guide clinical treatment.

Research progress in immune checkpoint inhibitors treatment of advanced biliary tract cancer / 中华消化外科杂志

Biliary tract cancer is a highly lethal disease composed of diverse epithelial tumors, of which incidence is increasing. Nearly two-thirds of patients with biliary tract cancer are in local advanced stage or metastasized at diagnosis. Systemic therapies are the primary treat-ment options, but the prognosis is poor. In recent years, the emergence of immune checkpoint inhibitors has changed the treatment prospects for advanced solid tumors, and multiple clinical trials and related studies have been conducted worldwide. Based on clinical experiences and pertinent researches in the field, the authors expound upon the research progress in immune checkpoint inhibitors treatment of advanced biliary tract cancer.

Clinical research advance in immunotherapy of pancreatic cancer / 中华消化外科杂志

Pancreatic cancer is one of the most common tumors in digestive system, which is characterized by insidious clinical symptoms, strong invasion, easy metastasis and high mortality. In recent years, immunotherapy is a new direction to the treatment of solid tumors, but its applica-tion in pancreatic cancer is limited by tumor microenvironment of pancreatic cancer. The authors systematically analyze the tumor microenvironment of pancreatic cancer, summarize the clinical researches related to pancreatic cancer immunotherapy, and discuss the prospect of pancreatic cancer immunotherapy.

Gut microbiome and tumor immunotherapy / 国际肿瘤学杂志

Neoplasms immunotherapy has made a major breakthrough in the clinical practice of refractory tumor. However, there are still individual differences in treatment results and drug resistance in clinical application. Gastrointestinal microbiome is gradually recognized as an immunoregulatory factor in recent years, and more and more studies have focused on its influences on the efficacy of tumor immunotherapy. Targeting gastrointestinal microbiota to improve the response of tumor patients to immunotherapy has potential clinical application value.

Clinical research progress of immunotherapy for nasopharyngeal carcinoma / 国际肿瘤学杂志

Immunotherapy mainly uses the effector units of the body's immune system to overcome the immune escape or adaptive immune resistance of tumors, accurately identify and remove tumor cells, and normalize or enhance the function of the immune system, which mainly includes cytokine therapy, immune checkpoint inhibition therapy, adoptive cell immunotherapy, tumor vaccine and antibody targeted therapy. The immune characteristics of nasopharyngeal carcinoma make the patients potentially suitable for immunotherapy or combined therapy with radiotherapy and chemotherapy. In recent years, PD-1 inhibitors alone and in combination with chemotherapy have shown good anti-tumor activity and safety in the treatment of recurrent/metastatic nasopharyngeal carcinoma. The incorporation of immune checkpoint inhibitors into the treatment paradigms of nasopharyngeal carcinoma has become a clinical research hot spot.

Prognostic predictors of immunotherapy in patients with small cell lung cancer / 国际肿瘤学杂志

The emergence of immune checkpoint inhibitors holds new promise for patients with small cell lung cancer. Studies have found that PD-L1 expression, tumor mutation burden, genomic characteristics, peripheral blood parameters and other indicators can be used as prognostic predictors in patients with small cell lung cancer receiving immunotherapy. Further exploration and evaluation of relevant predictors can provide a reference for screening patients with potential benefits of immunotherapy.

Research progress in immune-related liver injury caused by immune checkpoint inhibitors / 国际生物医学工程杂志

In recent years, immune checkpoint inhibitors (ICIs) have made great progress in the treatment of tumor patients, prolonging their survival. However, the expansion of immunity against tumors with ICIs may also cause an imbalance in immune tolerance, leading to immune-related adverse events (irAEs). Immune-mediated liver injury caused by ICIs (ILICI) is one of the more common types of irAEs. In this review paper, the definition, epidemiology, risk factors, pathogenesis, pathology, clinical manifestations, treatment, recurrence, and re-treatment of ILICI were summarized to provide a basis for clinical diagnosis and treatment.

Prospect of Tumor Treatment in the Post-PD-1/PD-L1 Inhibitor Era / 肿瘤防治研究

Immune checkpoint inhibitors restart and maintain cancer-immunity circulation to normalize the anti-tumor immunity. Currently, anti-PD-1/PD-L1 antibodies, as new milestone in immunotherapy, have significantly improved the prognosis of patients with various malignant tumors. However, anti-PD-1/PD-L1 antibody alone exhibited a low response rate, and the combination of anti-PD-1/PD-L1 antibody with traditional therapies such as surgery, chemotherapy, radiotherapy and targeted therapy have shown great potential. As new immune checkpoint inhibitors or in combination therapy are on the way, tumor immunotherapy is entering the era of post-anti-PD-1/PD-L1 antibody. The methodology of combination therapy and biomarker screening remain the focus. This paper reviews the current status of immune checkpoint inhibitor therapy and makes a perspective for the future of post-anti-PD-1/PD-L1 antibody era.

Biomarkers related to the treatment of melanoma with immune checkpoint inhibitors / 中华皮肤科杂志

Recently, great breakthroughs have been made in the treatment of melanoma with immune checkpoint inhibitors. However, only a small proportion of patients show a long-lasting response to immunotherapy, and risks of immune-related adverse events and drug resistance have been also increasing along with the emergence of combination treatment. This review summarizes biomarkers related to the efficacy of immune checkpoint inhibitors in the treatment of melanoma, aiming to predict and screen out patients who may benefit from immunotherapy, guide individualized clinical treatment, and reduce the occurrence of drug resistance and adverse reactions.

Gut microbiota and immune checkpoint inhibitor treatment of melanoma / 中华皮肤科杂志

A growing number of studies have shown that gut microbiota affects the development of melanoma through various mechanisms, and plays a vital role in the treatment of melanoma. This review summarizes the relationship between gut microbiota and the development of melanoma, the effect of gut microbiota on the checkpoint blockade immunotherapy of melanoma and related adverse effects.

Roles of PD-1/PD-L1 immune checkpoint in thyroid diseases / 中华核医学与分子影像杂志

Programmed cell death receptor 1 (PD-1)/PD-1 ligand (PD-L1) maintains immune tolerance of normal tissues and mediates immune escape of tumors. For autoimmune thyroiditis, thyroid follicular epithelial cells inhibit the damage of T cells by up-regulating PD-L1 expression. With the application of immune checkpoint inhibitors (ICIs) in the field of cancer therapy, the incidence of immune-related thyroid disorders caused by ICIs has increased. Thyroid function should be monitored during and after ICIs treatment to promptly diagnose primary and (or) secondary thyroid disorders. The PD-1/PD-L1 signaling directly stimulates thyroid cancer cells, and exerts inhibitory effects on tumor-infiltrating immune cells. Combination of ICIs targeting PD-1/PD-L1 with chemo-radiotherapy or targeted therapy is a promising therapeutic strategy in the treatment of refractory thyroid cancers.

Short-term efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy for the treatment of non-small cell lung cancer / 中国胸心血管外科临床杂志

@#Objective    To explore the short-term efficacy and safety of pembrolizumab combined with chemotherapy in the neoadjuvant treatment of non-small cell lung cancer. Methods    The clinical data of 11 male patients with non-small cell lung cancer who underwent pembrolizumab combined with neoadjuvant chemotherapy in the Department of Thoracic Surgery, the First Affiliated Hospital of Xi'an Jiaotong University from December 2019 to June 2021 were retrospectively analyzed. The average age of the patients was 52.0-79.0 (62.0±6.9) years. The imaging data and pathological changes before and after neoadjuvant treatment were compared, and adverse reactions during neoadjuvant treatment were recorded. Objective remission rate (ORR) and main pathological remission rate (MPR) and pathological complete remission rate (pCR) were the main observation endpoints. Results    After preoperative neoadjuvant therapy with pembrolizumab combined with platinum or paclitaxel, all patients successfully underwent thoracoscopic radical resection of lung cancer. The ORR was 72.7%, and the MPR was 81.8%. Among them, 45.5% of patients achieved pCR. The main adverse reactions were hypoalbuminemia, decreased appetite and nausea. The mortality rate within 30 days after surgery was 0, and no tumor metastasis was observed. Conclusion    Pembrolizumab combined with neoadjuvant chemotherapy is safe and feasible to treat non-small cell lung cancer, and the short-term efficacy is beneficial.