Development, Histological, and Ultrastructural Evaluation of Sheep Hyperimmune Serum Therapy for COVID-19 / Desarrollo, Evaluación Histológica y Ultraestructural de la Terapia con Suero Hiperinmune de Oveja para COVID-19

SUMMARY: In response to the threat posed by new variants of SARS-CoV-2 and the urgent need for effective treatments in the absence of vaccines, the aim of this study was to develop a rapid and cost-effective hyperimmune serum (HS) derived from sheep and assess its efficacy. The utilization of a halal-certified, easily maintained in certain geographic regions, easy-to-handle animal such as sheep could provide a viable alternative to the expensive option of horses. Sheep were immunized with a whole inactivated SARS-CoV- 2 antigen to produce HS, which was evaluated for neutralizing potency using the PRNT50 assay. K18-hACE2 transgenic mice (n=35) were divided into three groups: control, SARS-CoV-2 exposure through inhalation, and SARS-CoV-2 exposed mice treated with HS. HS efficacy was assessed through serum proinflammatory cytokine levels, qRT-PCR analysis, histopathological examination of lungs and hearts, and transmission electron microscopy. Purified HS exhibited significant neutralizing activity (1/24,576). The SARS-CoV-2+HS group showed lower levels of TNF-α, IL-10, and IL-6 (P<0.01) and relatively lower levels of MCP-1 compared to the SARS-CoV-2 group. HS prevented death, reduced viral RNA levels in the lungs and hearts, protected against severe interstitial pneumonia, preserved lung tissue integrity, and prevented myocyte damage, while the SARS-CoV-2 group exhibited viral presence in the lungs. This study successfully developed a sheep-derived HS against the entire SARS-CoV-2 virus, resulting in a significant reduction in infection severity, inflammation, and systemic cytokine production. The findings hold promise for treating severe COVID-19 cases, including emerging viral variants, and immunocompromised patients.

En respuesta a la amenaza que suponen las nuevas variantes del SARS-CoV-2 y la urgente necesidad de tratamientos eficaces en ausencia de vacunas, el objetivo de este estudio fue desarrollar un suero hiperinmune (HS) rápido y rentable derivado de ovejas. y evaluar su eficacia. La utilización de un animal con certificación halal, de fácil mantenimiento en determinadas regiones geográficas y de fácil manejo, como las ovejas, podría proporcionar una alternativa viable a la costosa opción de los caballos. Las ovejas fueron inmunizadas con un antígeno de SARS-CoV-2 completamente inactivado para producir HS, cuya potencia neutralizante se evaluó mediante el ensayo PRNT50. Los ratones transgénicos K18-hACE2 (n = 35) se dividieron en tres grupos: control, exposición al SARS-CoV-2 mediante inhalación y ratones expuestos al SARS-CoV-2 tratados con HS. La eficacia de HS se evaluó mediante niveles de citoquinas proinflamatorias en suero, análisis qRT-PCR, examen histopatológico de pulmones y corazones y microscopía electrónica de transmisión. El HS purificado exhibió una actividad neutralizante significativa (1/24,576). El grupo SARS-CoV-2+HS mostró niveles más bajos de TNF-α, IL-10 e IL-6 (P<0,01) y niveles relativamente más bajos de MCP-1 en comparación con el grupo SARS-CoV-2. HS evitó la muerte, redujo los niveles de ARN viral en los pulmones y el corazón, protegió contra la neumonía intersticial grave, preservó la integridad del tejido pulmonar y evitó el daño de los miocitos, mientras que el grupo SARS-CoV-2 exhibió presencia viral en los pulmones. Este estudio desarrolló con éxito un HS derivado de ovejas contra todo el virus SARS-CoV-2, lo que resultó en una reducción significativa de la gravedad de la infección, la inflamación y la producción sistémica de citocinas. Los hallazgos son prometedores para el tratamiento de casos graves de COVID- 19, incluidas las variantes virales emergentes y los pacientes inmunocomprometidos.

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.

Inmunoterapia para el tratamiento del cáncer de cabeza y cuello ¿dónde estamos y hacia dónde vamos? / Immunotherapy for the treatment of head and neck cancer: where are we and where are we going?

El cáncer de cabeza y cuello comprende a todos aquellos tumores que se desarrollan en el tracto aerodigestivo superior, una de las características de éstos es su diversidad, que no es solo desde el punto de vista histológico y etiológico, sino que incluyen diversas formas de presentación, progresión y enfoques terapéuticos. Son de causa multifactorial, siendo el alcohol y el tabaco los principales factores de riesgo asociados; en los últimos años se ha relacionado a ciertos virus con potencial oncogénico con la génesis tumoral, entre ellos al Virus del Papiloma Humano, lo que ha permitido modificar el sistema de estadificación tumor primario-nodos linfáticos cancerosos-metástasis (TNM); presentándolo ahora en dos grandes grupos acorde a la Proteína supresora de tumores P16: P16+ y P16-,los cuales tienen características y manejo diferente. En vista de la heterogeneidad de la enfermedad, son diversos los tratamientos que se ha empleados para el manejo de la misma, entre ellos cirugía, radioterapia, quimioterapia e/o inmunoterapia; ésta última terapéutica, está dirigida hacia la estimulación del sistema inmune del paciente con la finalidad de generar la destrucción de las células tumorales, se realizan previo a una intervención quirúrgica para reducir el tamaño del tumor. Una forma destacable, es la del bloqueo de puntos de control inmunitarios, especialmente hacia proteínas de control inmune moduladoras de respuesta de células T, como los anti-PD-1 y los anti-CTLA-4. La inmunoterapia cada vez va tomando más protagonismo en oncología, en especial las formas de evasión de las reacciones inmunitarias por parte de las células cancerígenas(AU)

Head and neck cancer includes all those tumors that develop in the upper aerodigestive tract, one of the characteristics of these is their heterogeneity, which is not only from the histological and etiological, but also include various forms of presentation, progression and therapeutic approaches.They have a multifactorial cause, with alcohol and tobacco being the main associated risk factors, however, in recent year scertain viruses with oncogenic potential have been linked to tumor genesis, including HPV, which has made it possible tomodify the TNM staging system; now presenting it in two large groups, P16+ and P16-, which have different characteristics and management. In view of the heterogeneity of the disease, there are various treatments that have been used to manageit, including surgery, radiotherapy, chemotherapy and/ orimmunotherapy which will be determined taking into account the location and tumor extension. The latter treatment, is aimedat stimulating the patient's immune system in order to generate the destruction of tumor cells, are performed prior to a surgical intervention to reduce the size of the tumor. A remarkable therapy is that of blocking immune checkpoints, especially anti-PD-1 and anti-CTLA. Immunotherapy is becoming more and more prominent, however, there is still much to discover, so we believe that we should continue investigating the ways of evasion of immune reactions by cancer cells(AU)

Avaliação por imagem de medidas esplênicas e tímicas como biomarcadores de resposta em pacientes com câncer tratados com imunoterapia / Imaging evaluation of thymic and splenic measurements as response biomarkers in cancer patients treated with immunotherapy

INTRODUÇÃO: Em menos de duas décadas, a imunoterapia consolidou-se como um dos pilares do tratamento do câncer. Apesar da sua potencial elevada eficácia e resposta duradoura, a proporção de pacientes que apresentam resposta objetiva é relativamente baixa e existem poucos biomarcadores para selecionar os pacientes com maior potencial de resposta. OBJETIVO: Nossa hipótese era de que era possível avaliar globalmente o sistema imune do paciente através da mensuração por imagem do timo e do baço e usar essas métricas como fator prognóstico e preditivo de resposta a bloqueadores de checkpoint. RESULTADOS: Os principais resultados foram: 1) As medidas tímicas não se correlacionam com a sobrevida em pacientes tratados com imunoterapia; 2) Há aumento do volume esplênico após o uso de imunoterapia na maior parte dos pacientes, mas o grau de aumento não se correlaciona com resposta à terapia; 3) Maior volume esplênico está associado a pior sobrevida livre de progressão em pacientes com melanoma tratados com imunoterapia, mas essa correlação não pôde ser replicada em outros tipos tumorais. CONCLUSÃO: a espessura tímica não se correlaciona com desfechos clínicos em pacientes oncológicos tratados com imunoterapia. Menor volume esplênico antes de iniciar imunoterapia está relacionada a melhor prognóstico em pacientes com melanoma, mas não em outros tipos tumorais.

INTRODUCTION: In less than two decades, immunotherapy has established itself as one of the pillars of cancer treatment. Despite its potentially high efficacy and long-lasting response, the proportion of patients who have an objective response is relatively low and there are few biomarkers to select patients with the greatest response potential. OBJECTIVE: Our hypothesis was that it was possible to assess the patient's immune system globally by measuring the thymus and spleen by imaging and using these metrics as a prognostic and predictive factor of response to immune checkpoint inhibitors. RESULTS: The main results were: 1) Thymic measurements do not correlate with survival in patients treated with immunotherapy; 2) There is an increase in splenic volume after the use of immunotherapy in most patients, but the degree of increase does not correlate with response to therapy; 3) Greater splenic volume is associated with worse progression free survival in patients with melanoma treated with immunotherapy, but this correlation could not be replicated in other tumor types. CONCLUSION: thymic thickness does not correlate with clinical outcomes in cancer patients treated with immunotherapy. Smaller splenic volume before starting immunotherapy is associated with better prognosis in patients with melanoma, but not other tumor types

Comparação da fadiga relacionada ao câncer de pacientes em tratamento com imunoterápicos ou quimioterápicos / Comparison of cancer-related fatigue in patients undergoing treatment with immunotherapeutic or chemotherapeutic drugs

INTRODUÇÃO: A Fadiga Relaciona ao Câncer (FRC) é uma "sensação persistente e subjetiva de cansaço e esgotamento físico, emocional, e/ou cognitivo, relacionado com o câncer ou o tratamento do mesmo, que não é proporcional à atividade recente e que interfere na capacidade funcional". A FRC, que atinge até 80% dos pacientes, é relatada principalmente por pacientes em tratamento quimioterápico. OBJETIVO: Comparar a fadiga relacionada ao câncer de pessoas com tumores sólidos em tratamento com imunoterapia ou quimioterapia. METODOLOGIA: Foi um estudo observacional transversal analítico, em pacientes adultos, de ambos os sexos, com câncer sólido, que no momento da coleta estavam exclusivamente em tratamento com quimioterápicos ou imunoterápicos. Os voluntários foram separados em dois grupos: grupo Imunoterapia e grupo Quimioterapia. Os instrumentos de avaliação foram: questionário de Avaliação Funcional da Terapia de Doenças Crônicas ­ Fadiga (FACIT-F), que avalia a percepção de fadiga da pessoa em tratamento do câncer. A dinamometria com o dinamômetro Jamar® para avaliar força de preensão manual e teste de velocidade da marcha de 4 metros (VM4M) para avaliar a velocidade da marcha. RESULTADOS: Em relação a velocidade da marcha, o grupo imuno apresentou velocidade média de 1,43 m/s e o grupo quimio apresentou velocidade média de 1,41m/s. Esses resultados apresentam que os pacientes avaliados não apresentaram lentidão de marcha e não tem diferença estatística entre os grupos (p=0.43). Em relação à força de preensão manual, observamos que não tem diferença estatística entre os grupos estudados (p=0,13 mão direita e p=0,10 mão esquerda), porém observamos que o grupo Imunoterapia contém valores maiores de média e mediana para a força de preensão palmar em ambas as mãos, permitindo afirmar que nos pacientes estudados em tratamentos com imunoterápicos apresentaram maior força de preensão manual. Em relação ao inventário de fadiga observa-se que, na amostra estudada, a média do escore final comprova que o grupo Imunoterapia tem menor ocorrência de fadiga (p=0.01). CONCLUSÃO: Não houve diferença estatística entre os grupos na velocidade da marcha e na força de preensão manual. No inventário de fadiga o grupo imunoterapia apresentou menor ocorrência de fadiga com diferença significativa.

INTRODUTION: Cancer Relational Fatigue (CRF) is a "persistent and subjective feeling of tiredness and physical, emotional, and/or cognitive exhaustion, related to cancer or its treatment, which is not proportional to recent activity and which interferes in functional capacity". CRF that meets up to 80% of patients is mainly reported by chemotherapy treatment. Patients being treated with immunotherapics report less fatigue. OBJECTIVE: Compare cancer-related fatigue in people with solid tumors undergoing exclusive immmunotherapy or chemotherapy treatments. This was an observational, cross-sectional and analytical study conducted with adult patients of both genders. The volunteers were distributed in two groups, namely, Immunotherapy and Chemotherapy. The assessment instruments were as follows: Functional Assessment Questionnaire of Chronic Illness Therapy ­ Fatigue (FACIT-F), dynamometry with a Jamar® dynamometer to assess hand grip strength and the 4-meter gait speed (4MGS) test. RESULTS: In relation to gait speed, the Immunotherapy group presented a mean speed of 1.43 m/s while the mean speed in the Chemotherapy group was 1.41 m/s. These results indicate that the patients evaluated did not present low gait speed and do not statistically differ between the groups (p=0.43). In relation to hand grip strength, we did not observe any significant difference between the groups under study (p=0.13 right hand and p=0.10 left hand). However, we noticed that the Immunotherapy group has higher mean and median values for hand grip strength in both hands, allowing us to assert that the patients studied in immunotherapy treatments presented greater hand grip strength. In relation to the fatigue inventory, in the sample studied it is observed that the final score mean proves that the Immunotherapy group presents lower occurrence of fatigue (p=0.01). CONCLUSION: There was no statistical difference between the groups in gait speed and handgrip strength. In the fatigue inventory, the immunotherapy group had a lower occurrence of fatigue with a significant difference.

CAR-T cell therapy for multiple myeloma: a practical toolkit for treatment in Brazil

ABSTRACT Introduction Chimeric antigen receptor T (CAR-T) cell therapy is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) that is a multi-step process involving various stakeholders. Appropriate education on the practical logistics is therefore paramount to ensure treatment success. Methods A group of key opinion leaders met to explore the key elements of setting up and running a CAR-T center in Brazil. For each step in the CAR-T cell therapy process, the experts agreed on basic requirements, gave their key recommendations from practical experience, and considered any remaining unanswered questions. Results This paper presents best-practice recommendations and advice on how to overcome common challenges for each step in the CAR-T cell therapy process, with a focus on the current situation in Brazil. Key themes throughout the process are collaboration within the multidisciplinary team and with the referring physician, along with communication and education for patients and their caregivers. Conclusion We believe that the expert insights presented in this paper, in particular on optimal patient selection and timing of CAR-T cell therapy, will deepen understanding of the CAR-T process and aid implementation of this novel therapy for patients with RRMM in Brazil.

Clinical analysis of immunotherapy rechallenge in advanced gastric cancer / 中华肿瘤杂志

Objective: To evaluate the efficacy and influencing factors of programmed death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with anti-PD-1 rechallenge in Henan Cancer Hospital from January 2020 to December 2021 were collected retrospectively. The progression-free survival (PFS) was defined as the time from the first or second used of anti-PD-1 treatment to the date of disease progression or the last follow-up, named PFS(1) and PFS(2), respectively. Kaplan-Meier method and Log rank test were used for survival analysis, Cox proportional hazard model was used to analyze the influencing factors. Results: A total of 60 patients with anti-PD-1 rechallenge therapy were collected, the median follow-up time was 12.2 months. The median progression-free survival (PFS(2)) of anti-PD-1 rechallenge therapy was 2.9 months, the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS(2) of the first and second anti-PD-1 identical and different rechallenge treatment was 3.5 months and 1.9 months (P=0.007) respectively. The median PFS(2) of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS(2) was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS(1)≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with anti-PD-1 rechallenge therapy with PFS(2) (HR=2.327, 95% CI, 1.066-5.082, P=0.034). The incidence of adverse reactions in grade 1-2 and grade 3-4 of anti-PD-1 rechallenge therapy was 83.3%, and 35.0%, respectively, and the safety was controllable. Conclusion: Rechallenge therapy with anti-PD-1 is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.

Clinical analysis of combined immunotherapy in patients with malignant pleural mesothelioma / 中华肿瘤杂志

Objective: To observe the present situation, efficacy and safety of immunotherapy in patients with malignant pleural mesothelioma (MPM). Methods: The data of 39 patients with MPM in two centers from 2016 to 2021 were collected and the efficacy and safety were evaluated. According to the application of immune checkpoint inhibitors (ICIs), these patients, whose median clinical follow-up amounting to 18.97 months, were divided into immunotherapy group (19 cases) and control group (20 cases). Kaplan-Meier method and Log-rank test were used for the survival analysis. Results: The objective response rate (ORR) and the disease control rate (DCR) in the immunotherapy group is 21.05% and 79.0% respectively, compared with 10.0% and 55.0% in the control group; and the difference was not statistically significant (P>0.05). The median overall survival (OS) in the immunotherapy group was significantly longer than that in the control group (14.53 months vs 7.07 months, P=0.015), but there was no significant difference in the median progression free survival (PFS) between two groups (4.80 months vs 2.03 months, P=0.062). Single factor survival analysis showed that the nature of pleural effusion, pathological subtype and the efficacy of immunotherapy were related to both PFS and OS of the patients with MPM (P<0.05). The incidence of adverse reactions in immunotherapy group was 89.5% (17 out of 19 cases), and the most common adverse event was hematological toxicity (9 cases), followed by nausea and vomiting (7 cases), fatigue (6 cases) and skin damage (6 cases). Five patients had immune checkpoint inhibitors (ICIs) related adverse reactions with grade 1-2. Conclusions: Patients with MPM have begun to receive immunotherapy in more than 2-line mainly combined chemotherapy in the real world, and the median treatment line is 2-line. Either combined with chemotherapy or anti-angiogenesis therapy, ICI inhibitors have significant efficacy, controllable adverse events and good clinical value.

Expert consensus on PD-L1 expression testing in esophageal carcinoma in China / 中华肿瘤杂志

In recent years, immunotherapy represented by immune checkpoint inhibitors programmed death 1 (PD-1) has made great progress in the treatment of esophageal cancer and is rewriting the global paradigm for the treatment of esophageal cancer. According to current data, only a small number of patients with esophageal cancer could benefit from immunotherapy. Therefore, it is a challenge to screen the potential beneficiaries of PD-1 inhibitors. Studies have shown that the expression level of programmed death-ligand 1 (PD-L1) in esophageal cancer is closely associated with the efficacy of PD-1 inhibitors, and PD-L1 is the most important predictive biomarker of the efficacy of PD-1 inhibitors. With the clinical application of different PD-1 inhibitors and PD-L1 protein expression detection platforms, clarifying the clinical significance and timing of detection of PD-L1 protein expression in esophageal cancer, and establishing a standardized PD-L1 testing procedure, are of great significance to improve the accuracy of detection and reduce the difference between laboratories, so as to maximize the therapeutic benefits for patients. This consensus was finally reached, based on the combination of literature, expert experience, and internal discussion and voting of committee members, to provide an accurate and reliable evidence for clinicians to make decisions.

Prevalence and associated factors for thyroid dysfunction among patients on targeted therapy for cancers:A single-center study from Thailand / Journal of the ASEAN Federation of Endocrine Societies

Objective@#This study aimed to explore the prevalence and associated factors of thyroid dysfunction among cancer patients treated with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs).@*Methodology@#A cross-sectional study was done in patients who received TKIs at Rajavithi Hospital in 2019. For patients treated with ICI, a retrospective chart review for patients seen in 2018 to 2019 was conducted. If there were abnormal thyroid function tests (TFT), thyroid autoantibodies were tested.@*Results@#There were 144 patients on TKIs with a mean age of 56.0 years. Thyroid dysfunction was found in 14.6% of patients and most had subclinical hypothyroidism (n=16, 11.1%). Imatinib (n=11, 10.8%) and sunitinib (n=4, 100%) were the 2 most common TKIs given to patients with thyroid dysfunction. Thyroid dysfunction was associated with male sex, chronic kidney disease and hepatitis B virus infection but not with previous thyroid disease and presence of thyroid autoantibodies. There were 18 patients who received ICIs. The mean age was 63.3 years. Twelve patients (66.7%) used programmed cell death protein-1 antibody (anti-PD1), mainly nivolumab. Thyroid dysfunction was found in 50%, which occurred at a median duration of 46 days. Most patients had overt hypothyroidism and 55.6% needed levothyroxine replacement. @*Conclusion@#Thyroid dysfunctions from TKIs were mostly asymptomatic and mild in severity. Some types of TKIs might be associated with thyroid dysfunction. On the other hand, thyroid dysfunction from ICIs usually occurs within 6 months and requires levothyroxine replacement.

Advances in cancer vaccines for immunotherapy of prostate cancer / 中南大学学报(医学版)

Prostate cancer is currently one of the most common malignancies that endanger the lives and health of elderly men. In recent years, immunotherapy, which exploits the activation of anti-cancer host immune cells to accomplish tumor-killing effects, has emerged as a new study avenue in the treatment of prostate cancer. As an important component of immunotherapy, cancer vaccines have a unique position in the precision treatment of malignant tumors. Monocyte cell vaccines, dendritic cell vaccines, viral vaccines, peptide vaccines, and DNA/mRNA vaccines are the most often used prostate cancer vaccines. Among them, Sipuleucel-T, as a monocyte cell-based cancer vaccine, is the only FDA-approved therapeutic vaccine for prostate cancer, and has a unique position and role in advancing the development of immunotherapy for prostate cancer. However, due to its own limitations, Sipuleucel-T has not been widely adopted. Meanwhile, owing to the complexity of immunotherapy and the specificity of prostate cancer, the remaining prostate cancer vaccines have not shown good clinical benefit in large randomized phase II and phase III trials, and further in-depth studies are still needed.

Research status and prospect of immunotherapy in gastrointestinal stromal tumors / 中华胃肠外科杂志

Tyrosine kinase inhibitors (TKI) significantly reduce the risk of recurrence and metastasis and prolong survival in patients with gastrointestinal stromal tumors (GIST), but drug resistance is often inevitable. Immunotherapy has been proven effective in multiple solid tumors, but the efficacy in GIST is unclear. The efficacy of immunotherapy depends on the tumor microenvironment (TME). Tumor-infiltrating immune cells and immune checkpoints are important components of TME, which not only participate in the regulation of tumor immune response but are also the key target of immunotherapy. A comprehensive analysis of them can clarify the mechanism of tumor immune escape. This review found that there are abundant tumor-infiltrating immune cells in GIST, which play an important role in tumor immune surveillance and escape. Although early clinical studies have shown that patients with GIST have a good tolerance to immunotherapy, the curative effect is not satisfactory. Therefore, how to select the responders of immunotherapy and coordinate the relationship between immunotherapy and TKIs is the key issue to be explored. At the same time, the gradual deepening of basic research and large sample prospective clinical trials will certainly provide more strategies for the application of immunotherapy in GIST.

Safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant chemotherapy combined with immunotherapy / 中华胃肠外科杂志

Objective: To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy. Methods: Between November 2020 and April 2021, patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study. Inclusion criteria were: (1) patients who signed the informed consent form voluntarily before participating in the study; (2) age ranging from 18 to 75 years; (3) patients staged preoperatively as cT3-4N+M0 by the TNM staging system; (4) Eastern Collaborative Oncology Group score of 0-1; (5) estimated survival of more than 6 months, with the possibility of performing R0 resection for curative purposes; (6) sufficient organ and bone marrow function within 7 days before enrollment; and (7) complete gastric D2 radical surgery. Exclusion criteria were: (1) history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy; (2) treatment with corticosteroids or other immunosuppre- ssants within 14 days before enrollment; (3) active period of autoimmune disease or interstitial pneumonia; (4) history of other malignant tumors; (5) surgery performed within 28 days before enrollment; and (6) allergy to the drug ingredients of the study. Follow-up was conducted by outpatient and telephone methods. During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy, follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients; follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients. Observation indicators were: (1) condition of enrolled patients; (2) reassessment after preoperative therapy and operation received (3) postoperative conditions and pathological results. Evaluation criteria were: (1) tumor staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system; (2) tumor regression grading (TRG) of pathological results were evaluated with reference to AJCC standards; (3) treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events; (4) tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria; and (5) Clavien-Dindo complication grading system was used for postoperative complications assessment. Results: A total of 30 eligible patients were included. There were 25 males and 5 females with a median age of 60.5 (35-74) years. The primary tumor was located in the gastroesophageal junction in 12 cases, in the upper stomach in 8, in the middle stomach in 7, and in the lower stomach in 3. The preoperative clinical stage of 30 cases was III. Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy, including four cases of CTCAE grade 3-4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis. All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment. Among the 30 patients who underwent surgery, the time from chemotherapy combined with immunotherapy to surgery was 28 (23-49) days. All 30 patients underwent laparoscopic radical gastrectomy, of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection; 10 patients underwent total gastrectomy for gastric cancer, combined with splenectomy in 1 case and cholecystectomy in 1 case. The surgery time was (239.9±67.0) min, intraoperative blood loss was 84 (10-400) ml, and the length of the incision was 7 (3-12) cm. The degree of adenocarcinoma was poorly differentiated in 18 cases, moderately differentiated in 12 cases, nerve invasion in 11 cases, and vascular invasion in 6 cases. The number lymph nodes that underwent dissection was 30 (17-58). The first of gas passage, the first postoperative defecation time, the postoperative liquid diet time, and the postoperative hospitalization time of 30 patients was 3 (2-6) d, 3 (2-13) d, 5 (3-12) d, and 10 (7-27) d, respectively. Postoperative complications occurred in 23 of 30 patients, including 7 cases of complications of Clavien-Dindo grade IIIa or above. Six patients improved after treatment and were discharged from hospital, while 1 patient died 27 days after surgery due to granulocyte deficiency, anemia, bilateral lung infection, and respiratory distress syndrome. The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge. Postoperative pathological examination showed TRG grades 0, 1, 2, and 3 in 8, 9, 4, and 9 cases, respectively, and the number of postoperative pathological TNM stages 0, I, II, and III was 8, 7, 8, and 7 cases, respectively. The pCR rate was 25.0% (8/32). Conclusion: Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible, with satisfactory short-term efficacy. Early detection and timely treatment of related complications are important.

Neoadjuvant immunotherapy for colorectal cancer / 中华胃肠外科杂志

Immunotherapy has been one of the hot topics in the field of colorectal cancer research in recent years. Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) are the main beneficiaries of immunotherapy. The response rate of patients with dMMR/MSI-H colorectal cancer receiving neoadjuvant immunotherapy is nearly 100%, of which the pathological complete response rate approximately accounts for 60%-67%. The prospect of neoadjuvant immunotherapy in dMMR or MSI-H colorectal cancer patients, especially in the rectal cancer patients, lies in achieving sustainable clinical complete response so as to achieve organ preservation and avoid adverse effects on reproductive, sexual, bowel and bladder function after surgery and radiotherapy. Studies have shown that part of the colorectal cancer patients of microsatellite stability (MSS) or mismatch repair proficient (pMMR) can respond to neoadjuvant immunotherapy in combination with other treatment methods such as radiotherapy and chemotherapy. In pMMR or MSS colorectal cancer, optimizing neoadjuvant immunotherapy regimens and finding effective efficacy prediction biomarkers are important research directions. In neoadjuvant immunotherapy, overcoming primary and secondary resistance and identifying the pseudoprogression and hyperprogression of neoadjuvant immunotherapy are clinical challenges that require attention. This paper comprehensively reviews the research progress, controversies,challenges and future research directions of neoadjuvant immunotherapy (mainly immune checkpoint inhibitors) in colorectal cancer.

Advances of Immunotherapy Resistance and Coping Strategies in Non-small Cell Lung Cancer / 中国肺癌杂志

Immunotherapy has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC), however, along with the popularization of immunotherapy, immune resistance has become an unavoidable problem. Immunotherapy can induce extensive cellular and molecular alterations in the tumor microenvironment. Considering the mechanisms of immune resistance are not yet fully understood and the efficacy of standard chemotherapy regimens is limited, more effective coping strategies based on resistance mechanisms are urgently needed. In this review, we intend to summarize the known mechanisms of immune resistance and feasible strategies, so as to provide a foundation for clinicians to develop more individualized and precise regimens and finally improve patients' prognosis.
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Advances in targeted therapy and immunotherapy for esophageal cancer / 中华医学杂志(英文版)

Esophageal cancer (EC) is one of the most common aggressive malignant tumors in the digestive system with a severe epidemiological situation and poor prognosis. The early diagnostic rate of EC is low, and most EC patients are diagnosed at an advanced stage. Multiple multimodality treatments have gradually evolved into the main treatment for advanced EC, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. And the emergence of targeted therapy and immunotherapy has greatly improved the survival of EC patients. This review highlights the latest advances in targeted therapy and immunotherapy for EC, discusses the efficacy and safety of relevant drugs, summarizes related important clinical trials, and tries to provide references for therapeutic strategy of EC.

Estudio exploratorio de eficacia de ivermectina combinada a α- PD-1 en cáncer colorrectal resistente a quimioinmunoterapia / EXPLORATORY EFFECTIVENESS STUDY OF IVERMECTIN COMBINED WITH α-PD-1 IN CHEMOTHERAPY RESISTANT COLORRECTAL CANCER

[RESUMEN]. Las terapias inmunológicas con inhibidores de checkpoints (ICIs) han revolucionado el abordaje del cáncer colorrectal (CCR), pero su efectividad se restringe a tumores inmunorreactivos con deficiencia en la reparación de errores tipo mismatch (dMMR). La ivermectina (IVM), un agente antiparasitario, se propone como posible estrategia terapéutica debido a su impacto en la muerte celular inmunogénica (MCI) y la reversión de resistencia a medicamentos. La investigación evaluó el efecto antineoplásico de IVM combinado con α-PD-1 empleando el modelo murino CT-26, una línea de CCR KRAS-mutada y competentes para MMR. El análisis bioinformático mediante la plataforma GEPIA2 empleandola base TCGA confirmó la expresión diferencial de blancos moleculares de IVM en tejido tumoral versus normal, siendo más alta en tumores con inestabilidad microsatelital baja (MSI-L)/microsatelital estable (MSS) que en inestabilidad microsatelital alta (MSI-H). En experimentos in vitro, CT-26 mostró alta sensibilidad a IVM (IC50: 11 µM, luego de exposición por 72 horas), alterando el metabolismo y aumentando la secreción de IL-6. El análisis proteómico identificó 17 proteínas sobreexpresadas y 8 inhibidas, relacionadas con evasión inmunológica y proliferación celular. En ratones BALB/c portadores de tumores CT-26, la terapia combinada de IVM y α-PD-1 redujo significativamente el crecimiento tumoral y la progresión metastásica. La preinmunización con células CT-26 tratadas con IVM disminuyó la incidencia y la progresión tumoral. IVM podría potenciar la respuesta a ICIs en tumores "fríos". Estos hallazgos sugieren que la combinación de IVM y α-PD-1 puede mejorar la inmunorreactividad y respuesta terapéutica en CCR.

[ABSTRACT]. Matrix Assisted Laser DesorptionIonization ­ Time of Flight ­ MassSpectrometry (MALDI-TOF-MS) has emerged as anoutstandingtechnique in thefieldofclinicalmicrobiology, with a simple methodology and deliveryof precise results in anexceptionally short timeframe. Thistechnology has garnered notable success in recentyears, establishing as a fundamental toolboth in thecharacterizationofmicroorganisms and translationalresearch.Thecombinationoftheinherentfeaturesofthistechniquewiththepotentialof machine learninganalysis has provento be ofgreatvalue in clinicalmicrobiology, particularly in theantibioticresistancefield. Itsapplication has acceleratedbacterial diagnosis and opened new perspectives in criticalareasof medicine, such sepsis and oncology. In Argentina, several research groups actively contributing to its expansión, applying MALDI-TOF-MS in the fight against infectious diseases, including the COVID-19 pandemic. Theseeffortspromiseto continue drivingresearch and clinical diagnosis in the country and worldwide.

Multiple characteristic alterations and available therapeutic strategies of cellular senescence / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Given its state of stable proliferative inhibition, cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis. Cells undergoing senescence are often associated with the alteration of a series of specific features and functions, such as metabolic shifts, stemness induction, and microenvironment remodeling. However, recent research has revealed more complexity associated with senescence, including adverse effects on both physiological and pathological processes. How organisms evade these harmful consequences and survive has become an urgent research issue. Several therapeutic strategies targeting senescence, including senolytics, senomorphics, immunotherapy, and function restoration, have achieved initial success in certain scenarios. In this review, we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.

Research progress in effects of MAGE-A family on gastric cancer / 中南大学学报(医学版)

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and most of the patients are diagnosed at the advanced stage. Most of the treating options are comprehensive treatment, in which immunotherapy plays more and more important role. Melanoma antigen-associated gene-A (MAGE-A) family is a kind of cancer testis antigens. Except in germ cells of testis and trophoblast cells of placenta, MAGE-A family is highly expressed in cancerous tissues and participates in a variety of biological processes, such as cancer cell proliferation, differentiation and metastasis. In addition, cancer testis antigen also possesses good immunogenicity, which can induce humoral and cellular immune responses, is a good target for immunotherapy, and has good application value in the diagnosis, treatment and prognosis of GC. A variety of targeted therapeutic drugs based on MAGE-A are in phase I or II clinical trials, it has good safety and potential clinical application value. With the continuous progress of clinical trials and basic research on MAGE-A targets in GC, it is expected to provide a theoretical basis for clinical transformation and immunotherapy of MAGE-A in the future.