Complete Response To Tislelizumab In A Muscle-Invasive Urothelial Carcinoma After Surgery Associated With Tumor Mutational Burden High: A Case Report

Muscle-invasive urothelial carcinoma (MIUC) is a highly aggressive urothelial carcinoma. Radical cystectomy (RC) is standard of treatment, but still more than 50% patients with cancer invading the muscularis propria or involving the regional lymph nodes will have metastatic recurrence. In CheckMate274 study, programmed cell death-1 (PD-1) inhibitor nivolumab as adjuvant treatment has shown effective for patients with MIUC. Tislelizumab is an anti-human PD-1 monoclonal IgG4 antibody which was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. But there is no report of tislelizumab as adjuvant treatment in MIUC currently. Here, we report a case of MIUC in a patient with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response (CR) receiving tislelizumab therapy after surgery. Progression-free survival (PFS) exceeded 6 months since tislelizumab treatment. To our knowledge, this is the first reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the efficacy of tislelizumab as adjuvant treatment in MIUC and to confirm that TMB is a predicted biomarker of tislelizumab for efficacy.

Advances in Drugs Targeting Lymphangiogenesis for Preventing Tumor Progression and Metastasis

Metastasis of cancer cells from the primary tumor to other organs and tissues in the body is the leading cause of death in patients with malignancies. One of the principal ways cancer cells travel is through lymphatic vessels, and tumor invasion into the regional lymph nodes is a hallmark of early metastasis; thus, the formation of especially peritumoral lymphatic vessels is essential for tumor transportation that gives rise to further progression. In the past few decades, tumor-induced lymphangiogenesis has been testified to its tight correlation with lymphatic metastasis and poor clinical outcomes in multiple types of human malignancies, which warrants novel potential therapeutic targets for cancer treatment. As the understanding of underlying molecular mechanisms has grown tremendously over the years, an inexorable march of anti-lymphangiogenic therapy also aroused terrific interest. As a result, a great number of drugs have entered clinical trials, and some of them exhibited predominant contributions in cancer management. Herein, this review provides an updated summary of the current advances in therapies preventing lymphatic metastasis and discusses the validity of different applications.

Immunotherapy for Cutaneous Squamous Cell Carcinoma: Results and Perspectives

Although initial surgical excision cures 95% of patients, a minority of cutaneous squamous cell carcinomas (cSCCs) are judged to be unresectable, either locally advanced or with unresectable regional lymph nodes or distant metastases. These patients are offered systemic treatments. Response rate to chemotherapy is relatively low and not durable, as well as the results obtained with epidermal growth factor inhibitors (EGFRi). Like other cutaneous tumors, cSCCs have high immunogenicity, driven by the high mutational burden, the ultraviolet signature, and the overexpressed tumor antigens. Two checkpoint inhibitors, cemiplimab and pembrolizumab, achieved high response rate and survival with fewer toxicities than other available systemic agents. These promising results prompted to investigate new combination strategies of systemic therapy and surgery or radiotherapy. Subgroup analysis showed promising role of immunotherapy to facilitate surgery in locally advanced cSCC and, in a small group of patients, long-term survivals without resection. However, some cSCCs treated with immunotherapy develop either early or late resistance, so new drugs and new combinations are in a clinical study to overcome the mechanism underpinning these resistances. The present review focuses on the progress with immunotherapy to date and on new therapeutic strategies for cSCC.

The Bovine Tuberculoid Granuloma

The bovine tuberculoid granuloma is the hallmark lesion of bovine tuberculosis (bTB) due to Mycobacterium bovis infection. The pathogenesis of bTB, and thereby the process of bovine tuberculoid granuloma development, involves the recruitment, activation, and maintenance of cells under the influence of antigen, cytokines and chemokines in affected lungs and regional lymph nodes. The granuloma is key to successful control of bTB by preventing pathogen dissemination through containment by cellular and fibrotic layers. Paradoxically, however, it may also provide a niche for bacterial replication. The morphologic and cellular characteristics of granulomas have been used to gauge disease severity in bTB pathogenesis and vaccine efficacy studies. As such, it is critical to understand the complex mechanisms behind granuloma initiation, development, and maintenance.

Clinical Significance of Stem Cell Biomarkers EpCAM, LGR5 and LGR4 mRNA Levels in Lymph Nodes of Colon Cancer Patients

The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan-Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA copies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12-year follow-up (p = 0.022, p = 0.005 and p = 0.011, respectively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence.

Overall Survival Rate Analysis For Risk Factors In Women With Neuroendocrine Carcinoma of The Cervix Using Surveillance, Epidemiology, And End Results (SEER) Database

Background: Neuroendocrine carcinoma of the cervix is rare and aggressive disease, of which prognosis information and the effectiveness of the therapies is unclear.Methods: A retrospective study using data from the SEER database for the first diagnosed Neuroendocrine carcinoma of the cervix patients was conducted. We performed univariate and multivariate Cox models to screen for independent prognostic factors for overall survival. Subgroup analysis and sensitive analysis were performed for further study, then again univariate and multivariate analyses of Cox regression analysis were performed based on the sensitivity analysis data set.Results: A total of 250 Neuroendocrine carcinoma of the cervix cases was included, tumor subtype, age, marriage, race, number of regional lymph nodes, number of positive lymph nodes, radiotherapy, surgery, and FIGO stage were all factors affecting OS, and multivariate analysis identified FIGO staging (HR, 2.4; 95% CI, 1.505-3.828, P < 0.001) and surgery (HR, 0.467; 95% CI, 0.358-0.609, P < 0.001) treatment as independent indicators. With respect to the factors associated with treatments, we found that patients who underwent surgery (yes vs. no vs. unknown) or radiation (yes vs. no) experienced prolonged survival, both P < 0.001Conclusions: Our investigation shows that for patients with NECC surgery seems to be the effective treatment. Chemotherapy cannot improve the prognosis of NECC patients, and the effectiveness of radiation should be further verified.

Evaluation of the Relationships between Intestinal Regional Lymph Nodes and Immune Responses in Viral Infections in Children

Viral infections increase the risk of developing allergies in childhood, and disruption of mucosal homeostasis is presumed to be involved. However, no study has reported a role for viral infections in such disruption. In this study, we clarified the mechanism of immunoglobulin A (IgA) overproduction in viral infections. Autopsies were performed on 33 pediatric cases, IgA and interferon (IFN)β levels were measured, and histopathological and immunohistochemical examinations were conducted. Furthermore, we cultured human cells and measured IFNβ and IgA levels to examine the effect of viral infections on IgA production. Blood IgA levels in viral infections were higher than in bacterial infections. Moreover, IFNβ levels in most viral cases were below the detection limit. Cell culture revealed increased IgA in gastrointestinal lymph nodes, especially in Peyer’s patches, due to enhanced IFNβ after viral stimulation. Conversely, respiratory regional lymph nodes showed enhanced IgA with no marked change in IFNβ. Overproduction of IgA, identified as an aberration of the immune system and resulting from excessive viral infection-induced IFNβ was observed in the intestinal regional lymph nodes, particularly in Peyer’s patches. Further, increased IgA without elevated IFNβ in the respiratory system suggested the possibility of a different mechanism from the gastrointestinal system.

The role of endoscopic ultrasound investigation in the diagnosis of submucosal neoplasms of the stomach and duodenum (literature review and our clinical observations)

Submucosal neoplasms of the stomach and duodenum include a group of diseases with different etiology, clinical symptoms, diagnosis and management. Conventional gastroduodenoscopy helps detect submucosal formations in 0.36–4 % of cases, while the stomach is the most common site of submucosal lesions (up to 60 %). Endoscopy and ultrasound endoscopic examination are important tools for the diagnosis of submucosal tumors of the esophagus, stomach, duodenum, both benign (polyps, submucosal formations, extraorganic compression, cysts) and malignant neoplasms of the gastrointestinal tract, especially small and accidentally detected. It is important not only to diagnose the tumor, but also to determine from which layers it comes, what level germinates, whether there is damage to regional lymph nodes. Only endoscopic ultrasonography (EUS) can answer these questions. EUS combines the capabilities of two studies: endoscopic and ultrasound, which significantly increased the informativeness of endoscopic examination, as it was possible to determine the site of the pathological process and the degree of intramural invasion, and also made it possible to carry out the differential diagnosis of submucosal tumors and pathological processes in organs adjacent to the esophagus, stomach, duodenum. The article presents examinations of patients with submucous formations of the stomach and duodenum at the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine. With the help of EUS, the diagnosis was confirmed in one patient, and in another one, the submucosal neoplasms was excluded.

New morphological risk factors for metastasis to regional lymph nodes in rectal cancer with invasion into the submucosa

AIM to assess prognostic significance of pathologic features of T1 rectal carcinoma in relation to regional lymph nodes involvement (N+).MATERIAL AND METHODS: surgical specimens (n = 66) from rectal resection for carcinoma pT1 were investigated. Following prognosticators were evaluated: depth of submucosal invasion, grade of differentiation, lymphovascular invasion (LVI), tumor budding (Bd), poorly differentiated clusters (PDC) of tumor and rupture of cancer glands (CGR).RESULTS: lymph nodes metastases were found in 13 (19.7%) specimens. LVI was associated lymphatic spread in great possibility OR 38.0 95% CI 2.1-670 (p < 0.0001). Tumor budding of high grade (Bd3) OR 6.2 95% CI 1.2-31 (p < 0.0001) and poorly differentiated clusters (p = 0,03) also increased risk of lymph node metastases. Depth of submucosal invasion, grade of differentiation, and rupture of cancer glands failed to demonstrate significant association with N+. Logistic regression analysis allowed to determine LVI as independent prognostic factor of lymph node tumor involvement.CONCLUSION: lymphovascular invasion, tumor budding and poorly differentiated clusters of tumor are risk factors of T1 rectal carcinoma lymph node metastases.

THE ROLE OF THE UROKINASE SYSTEM IN LYMPHOGENOUS METASTASIS OF COLORECTAL CANCER

The aim of this work was to study the role and relationship of the levels of the components of the urokinase system with lymphogenous metastasis in patients with colorectal cancer.Materials and methods: the study was carried out on the basis of the Medical Scientific and Educational Center of the Moscow State University named after M.V. Lomonosov from 2019 to 2021. The study included healthy donors (control group) and patients with a verified diagnosis of stage I-III colorectal cancer in accordance with the inclusion criteria; all patients underwent surgical resection of the primary tumor with lymphadenectomy of the appropriate level. All patients underwent determination of the level of uPA and uPAR in blood serum before surgery. We also analyzed the clinical and demographic data of the patients, as well as the pathomorphological characteristics of the tumor.Results. The study included 7 healthy donors and 49 patients with stage I-III colorectal cancer. The average level of serum urokinase in the control group was 2.7±1.04 ng / ml, in the study group – 4, 15±1.9 ng / ml (p = 0.071), the level of the urokinase receptor in the control and study groups was 1.36 ±0.8 ng / ml vs 3.22±2.06 ng / ml (p = 0.05). The average level of serum urokinase in patients without and with lesions of lymph nodes was 3.4±1.4 ng / ml and 4.4±2.3 ng / ml (p = 0.068).Conclusion. There is a tendency to an increase in the level of components of the urokinase system in the peripheral blood in patients with colon neoplasms in the preoperative period, depending on the presence of metastatic lesions of regional lymph nodes, which indicates the need for further research in this area.