ABSTRACT
For locally advanced esophageal squamous cell carcinoma (ESCC), neoadjuvant therapy combined with surgery has become the standard treatment schedule. The application of immunotherapy, represented by programmed death-1 and programmed death-ligand 1 inhibitors, has injected new vitality into neoadjuvant therapy for ESCC. At present, a large number of clinical trials are being carried out and explored, which brings new challenges to the diagnosis of clinical pathologists. Combined with the latest researches at home and abroad and clinical diagnosis problems, the authors summarize the relevant problems and progress of pathological evaluation before and after neoadjuvant immunotherapy from the perspective of pathology, in order to improve the level of clinical pathological diagnosis and provide reference for further optimizing the comprehensive treat-ment strategy.
ABSTRACT
Gastric cancer is one of the most common malignant tumors in the digestive system. At present, surgery is still the main treatment for gastric cancer and the consensus has been reached that D 2 lymph node dissection should be performed for advanced gastric cancer. Laparos-copic distal gastrectomy for locally advanced gastric cancer completed by experienced surgeons was comparable to open surgery in terms of safety and oncology. Laparoscopic spleen preserving splenic hilar lymph node dissection is safety and effective. Adjuvant chemotherapy and neoadjuvant chemo-therapy can prolong postoperative survival time of gastric cancer patients. The common chemo-therapy regimens are single drug S-1, XELOX regimen or S-1 combined with docetaxel. DOS regimen, SOX regimen and FLOT regimen are commonly used neoadjuvant chemotherapy regimens. Molecular targeted drugs or immunotherapeutic drugs has not been approved for the perioperative first-line treatment of locally advanced gastric cancer, but more and more clinical research results suggest that the combination of targeted therapy or immunotherapy can improve the R 0 rate or pathological complete response rate. There is no evidence to support that combination treatment can prolong survival time. The best comprehensive treatment for advanced gastric cancer is not unified, which needs further researches.
ABSTRACT
OBJECTIVES@#To analyze the clinical characteristics and prognosis of children with anti-N-methyl--aspartate receptor (NMDAR) encephalitis and to provide a basis for early clinical identification of this disease.@*METHODS@#The clinical data of 42 cases of anti-NMDAR encephalitis at Department of Pediatrics, Second Xiangya Hospital, Central South University from January 2015 to March 2018 were collected. The clinical features and followed-up outcomes were analyzed retrospectively.@*RESULTS@#There were 15 cases (35.7%) of males and 27 cases (64.3%) of females in 42 children, with a ratio of 1꞉1.8. They were aged from 4 months to 17 years, with an average of (9.20±4.66) years. The most common initial symptoms were seizures (47.6%, 20/42) and mental behavior disorder (35.7%, 15/42). During the course of the disease, 85.7% patients(36/42) had mental and behavior disorder, 85.7% patients (36/42) had epilepsy, 76.2% (32/42) had speech disorder, 66.7% patients (28/42) had dyskinesia, 66.7% patients (28/42) had the decreased level of consciousness, 61.9% patients (26/42) had autonomic instability, and 57.1% (24/42) patients had sleep disorder. All the children had positive antibody against NMDA receptor resistance encephalitis in cerebrospinal fluid. Head MRI showed the abnormal incidence was 50.0% (21/42), and the lesions involved in parietal lobe, frontal lobe, temporal lobe, occipital lobe, midbrain, thalamus, basal ganglia and optic nerve. There was a patient with optic nerve damage combined with myelin oligodendrocyte glycoprotein (MOG) antibody positive. Forty cases were examined by electroencephalogram (EEG), 92.5% cases (37/40) were abnormal, mainly showing diffuse slow waves, and δ brushes could be seen in severe cases. And there was 1 patient (2.4%) complicated with mesenteric teratoma. The mRS score (2.14±1.46) at discharge was significantly lower than the highest mRS score (3.88±1.38) during hospitalization (<0.05). After 3-39 months of follow-up, mRS score at 3 months after discharge was only 0.81±1.29, which was still improved compared with that at discharge, 76.2% cases (32/42) experienced complete or near-complete recovery (mRS score≤2), and 4.8% (2/42) cases relapsed. There was no mortality; the initial time of immunotherapy and the highest mRS score in the course of the disease were the factors affecting the prognosis. The earlier the starting time for immunotherapy and the lower mRS score in the course of the disease were, the better the prognosis was.@*CONCLUSIONS@#Seizures, mental and behavior disorder, dyskinesias, speech disorder and autonomic instability are common clinical manifestations of anti-NMDAR encephalitis in children. The effect of immunotherapy is significant, and the time to start immunotherapy and the severity of the disease are important factors affecting the prognosis. Anti-NMDAR encephalitis can be combined with other autoantibodies, but its clinical significance and mechanism need further study.
Subject(s)
Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Autoantibodies , Electroencephalography , Magnetic Resonance Imaging , Receptors, N-Methyl-D-Aspartate , Retrospective StudiesABSTRACT
Objective: To construct the murine chimeric antigen receptor-redirected T lymphocyte (CAR-T) that can target glypican 3 (GPC3) and express interleukin-12 (IL-12) in an activation-dependent manner, and to explore the anti-cancer efficacy of CAR-T cells in immunocompetent mice bearing GPC3 positive (GPC3+) breast cancer. Methods: Gene recombination technology was used to construct the retroviral vector encoding GPC3-specific CAR (m9.28z) or encoding both GPC3-specific CAR and nuclear factor of activated T cells (NFAT)-IL-12 expression system (m9.28z/IL-12). Murine T cells were retrovirally transduced to develop m9.28z CAR-T cells and m9.28z/IL-12 CAR-T cells. In vitro, the cytotoxicity assay and ELISA assay were used to assess the biological functions of m9.28z/IL-12 CAR-T cells. In vivo, the GPC3+ breast cancer E0771-GPC3 cell subcutaneously transplanted model was established in C57BL/6 mice, and the tumor-bearing mice were injected with 5×106 murine untransduced T cells (mUTD, which served as the negative control), 5×106 m9.28z CAR-T cells, 2×106 m9.28z CAR-T cells, 5×106 m9.28z/IL-12 CAR-T cells and 2×106 m9.28z/IL-12 CAR-T cells, respectively. The growth of xenografts in nude mice was observed, and the expression levels of CD8α and forkhead box protein P3 (FOXP3) in tumor tissues were detected by immunohistochemistry. Results: The retroviral vector encoding m9.28z or m9.28z/IL-12 was constructed, and the m9.28z CAR-T cells and m9.28z/IL-12 CAR-T cells were developed subsequently. In vitro, the m9.28z/IL-12 CAR-T cells killed GPC3+ breast cancer cells specifically and effectively, and secreted more tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) than m9.28z CAR-T cells (both P < 0.05). In vivo, as compared with m9.28z CAR-T cells, the m9.28z/ IL-12 CAR-T cells suppressed the growth of xenografts significantly (P < 0.001), and there were more CD8+ T cells and less regulatory T cells (Treg) in tumor tissues treated with m9.28z/IL-12 CAR-T cells (both P < 0.01). Conclusion: The m9.28z/IL-12 CAR-T cells, which can express IL-12 inducibly, can display more potent anti-cancer activity against GPC3+ tumor than m9.28z CAR-T cells in vitro and in immunocompetent breast cancer transplanted mice.
ABSTRACT
During the past three decades, studies have shown that tumor cells could ″manipulate″host immunity to escape the immune defenses in the tumor microenvironment. One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1 (PD- 1/ PD- L1), which makes PD- 1/PD- L1 blockadea promising target of cancer immune- therapy. Tumors could suppress immuno- response of T cells by activating PD- 1/PD- L1 signaling pathway. Therefore, inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response, there after augmenting the endogenous antitumor force of the immune system. Along these lines, inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors. Recent studies indicated that PD-1/PD- L1 blockade have demonstrated high efficacy and safety against melanoma, lung, kidney and several other solid tumors, as well as hematological malignancies. Nevertheless, the efficacy of this checkpoint blockade approach is not universal. Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected. In this review, we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1, as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.
ABSTRACT
Aim To investigate the anti-EAC breast cancer effects of viable human umbilical vein endothe-lial cells ( HUVECs) vaccine. Methods Subconflu-ent HUVECs were mixed with OK432 to prepare HU-VECs-OK432 vaccine, and the anti-tumor efficacy of HUVECs-OK432 was investigated using a subcutaneous tumor model of EAC breast cancer. ELISA, splenic lymphocyte proliferation assay and cytotoxic T lympho-cytes ( CTL ) killing assay were adopted to detect the humoral and cellular immune responses after HUVECs-OK432 immunization. Results HUVECs-OK432 im-munization significantly inhibited the growth of EAC tumor in mice in the prophylactic procedures. High ti-ter of anti-HUVEC antibody was elicited by HUVECs-OK432 immunization. The proliferation activity of splenocytes from mice immunized with HUVECs-OK432 was significantly increased. T lymphocytes iso-lated from HUVECs-OK432-immunized mice were dose dependently killing HUVECs in vitro. Conclusion Strong humoral and cellular immune responses targeting HUVEC are elicited by HUVECs-OK432 immuniza-tion, which results in a significant inhibition on the growth of EAC tumor in mice.
ABSTRACT
γδT lymphocytes,a numerically small subset of T lymphocytes,have been shown to directly recognize protein antigens without restriction by polymorphic MHC class I or class Ⅱ molecules and their asso-ciated peptide ligands,secrete cytokines,kill tumor cells and display cytolytie activity against various tumors.In osteosarconla patients,γδT lymphocytes can recognize antigens expressed on the surface of osteosarcoma cells,lyse and kill tumor cells.Combined with converntional chemotherapy and surgery,the new γδT lympho-cytes-based cell immunotherapy of osteosarcoma can increase the survival rate greatly.
ABSTRACT
Objective:To investigate the anti-tumor immune responses against renal cell carcinoma induced by dendritic cells(DCs)transfected with survivin gene mediated by recombinant adenovirus.Methods:The DCs derived from human peripheral blood were infected with recombined adenovirus vector carrying the survivin gene.The expression of survivin protein in the infected DCs was examined by Western blotting assay;the surface expression of CD83,MHCⅡ,CD80 and CD86 by flow cytometry(FCM),Interleukin-12(IL-12)in the supernatants of DCs and IFN-? released by the cytotoxic T lymphocytes(CTLs)by ELISA,the ability of DCs in proliferating allo-lymphocytes by mixed lymphocyte reaction(MLR),and specific killing activity of CTLs by MTT assay.Results:The DCs presented mature DCs phenotype after transfection with Ad-svv.The expression of survivin protein in transfected DCs was confirmed by Western blotting analysis.The IL-12 level in the supernatant of DCs transfected with Ad-svv was significantly higher than that transfected with empty vector(Ad-CMV,P