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Molecular Therapy : the Journal of the... Jun 2024Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial...
Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial (NCT04771676) to investigate the efficacy and safety of oncolytic adenovirus H101 and virotherapy-induced immune response in 25 patients with malignant ascites. Oncolytic virotherapy achieved an increased median time to repeat paracentesis of 45 days (95% confidence interval 16.5-73.5 days), compared with the preset control value of 13 days. Therapy was well-tolerated, with pyrexia, fatigue, nausea, and abdominal pain as the most common toxicities. Longitudinal single-cell profiling identified marked oncolysis, early virus replication, and enhanced CD8 T cells-macrophages immune checkpoint crosstalk, especially in responsive patients. H101 also triggered a proliferative burst of CXCR6 and GZMKCD8 T cells with promoted tumor-specific cytotoxicity. Further establishment of oncolytic virus-induced T cell expansion signature (OiTE) implicated the potential benefits for H101-responsive patients from subsequent anti-PD(L)1 therapy. Patients with upregulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A dendritic cells and GZMKCD8 T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provides insights into the relevant cellular processes following oncolytic virotherapy.
Topics: Humans; Oncolytic Virotherapy; Oncolytic Viruses; Ascites; Female; Male; Middle Aged; Adenoviridae; Aged; Single-Cell Analysis; CD8-Positive T-Lymphocytes; Adult; Treatment Outcome; Longitudinal Studies; Virus Replication
PubMed: 38659226
DOI: 10.1016/j.ymthe.2024.04.029 -
Journal of Nanobiotechnology Apr 2024The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in...
The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone II (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal-organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.
Topics: Metal-Organic Frameworks; Liver Neoplasms; Carcinoma, Hepatocellular; Animals; Mice; Humans; Programmed Cell Death 1 Receptor; Cell Line, Tumor; Immune Checkpoint Inhibitors; Tumor Microenvironment; Mice, Inbred BALB C; Saponins; Lymphocytes, Tumor-Infiltrating
PubMed: 38658950
DOI: 10.1186/s12951-024-02469-6 -
Frontiers in Immunology 2024Malignant ascites indicates ovarian cancer progression and predicts poor clinical outcome. Various ascites components induce an immunosuppressive crosstalk between tumor...
INTRODUCTION
Malignant ascites indicates ovarian cancer progression and predicts poor clinical outcome. Various ascites components induce an immunosuppressive crosstalk between tumor and immune cells, which is poorly understood. In our previous study, imbalanced electrolytes, particularly high sodium content in malignant ascites, have been identified as a main immunosuppressive mechanism that impaired NK and T-cell activity.
METHODS
In the present study, we explored the role of high concentrations of ascites proteins and immunoglobulins on antitumoral NK effector functions. To this end, a coculture system consisting of healthy donor NK cells and ovarian cancer cells was used. The anti-EGFR antibody Cetuximab was added to induce antibody-dependent cellular cytotoxicity (ADCC). NK activity was assessed in the presence of different patient ascites samples and immunoglobulins that were isolated from ascites.
RESULTS
Overall high protein concentration in ascites impaired NK cell degranulation, conjugation to tumor cells, and intracellular calcium signaling. Immunoglobulins isolated from ascites samples competitively interfered with NK ADCC and inhibited the conjugation to target cells. Furthermore, downregulation of regulatory surface markers CD16 and DNAM-1 on NK cells was prevented by ascites-derived immunoglobulins during NK cell activation.
CONCLUSION
Our data show that high protein concentrations in biological fluids are able to suppress antitumoral activity of NK cells independent from the mechanism mediated by imbalanced electrolytes. The competitive interference between immunoglobulins of ascites and specific therapeutic antibodies could diminish the efficacy of antibody-based therapies and should be considered in antibody-based immunotherapies.
Topics: Humans; Killer Cells, Natural; Ascites; Female; Antibody-Dependent Cell Cytotoxicity; Ovarian Neoplasms; Cell Line, Tumor; Immunoglobulins; Receptors, IgG; Cell Degranulation; Antigens, Differentiation, T-Lymphocyte; Cetuximab
PubMed: 38646521
DOI: 10.3389/fimmu.2024.1360615 -
Annals of Palliative Medicine Apr 2024Malignant ascites (MA) is common in patients with advanced cancer, and about 60% of patients with MA experience distressing symptoms. In addition, MA has been identified...
BACKGROUND AND OBJECTIVE
Malignant ascites (MA) is common in patients with advanced cancer, and about 60% of patients with MA experience distressing symptoms. In addition, MA has been identified as a poor prognostic factor, therefore, making the management of MA an important issue. We aimed to review literature describing MA provide a narrative synthesis of relevant studies.
METHODS
A literature search of articles published between 1971 and May 2023 was performed in PubMed, and Cochrane library using the words "ascites/malignant ascites" and the theme of each section. Authors independently selected the articles used and summarized. Finally, this manuscript was obtained consensus through discussed among all authors.
KEY CONTENT AND FINDINGS
The pathophysiological mechanism of ascites formation involves increased vascular permeability and impaired fluid drainage through the lymphatic system, which explain the occurrence of peritoneal carcinomatosis, portal hypertension due to liver tumors, liver cirrhosis in the background of hepatocellular carcinoma, and Budd-Chiari syndrome caused by tumor occlusion of the hepatic vein. The efficacy and safety of various treatments and procedures have been investigated previously; however, no treatment guidelines have been established yet. Diuretics and paracentesis are often selected as the first lines of treatment. Intraperitoneal drug administration (catumaxomab, bevacizumab, aflibercept, hyperthermic intraperitoneal chemotherapy, triamcinolone), indwelling peritoneal catheters, peritoneovenous shunting, and cell-free and concentrated ascites reinfusion therapy are commonly used to manage refractory ascites. A new device for this purpose is alfapump, which transfers ascites fluid from the peritoneum into the urinary bladder. In addition, thoracic epidural analgesia may be effective for managing ascites-related symptoms.
CONCLUSIONS
Despite these options, no standard treatment for MA has been established yet because few trials have been conducted in this area. There are many issues to be investigated, and future research and treatment development are expected.
PubMed: 38644553
DOI: 10.21037/apm-23-554 -
BMC Women's Health Apr 2024Primary lymphoma of the female genital tract (PLFGT) is a rare malignant tumor in the female reproductive system, with a low incidence and few clinical reports. The aim...
BACKGROUND
Primary lymphoma of the female genital tract (PLFGT) is a rare malignant tumor in the female reproductive system, with a low incidence and few clinical reports. The aim of this study is to report our institutional experience with this rare malignancy and emphasize the need for increasing the awareness about PLFGT presenting with gynecologic symptoms.
METHODS
The medical records of patients diagnosed with PLFGT from March 2014 to November 2022 in the First Affiliated Hospital of Wannan Medical College were reviewed. Histological classification and staging were based on the World Health Organization and Ann Arbor systems, respectively.
RESULTS
There were 13 patients with diagnosis of PLFGT and the median length of follow-up was 31 months (0-102 months). The main clinical symptoms included postmenopausal vaginal bleeding, pelvic mass and abdominal pain. Serum LDH increased in 10 patients and serum CA125 elevated in 2 patients. The tumor of ovarian or uterine presented as solid masses in CT or MRI, and ascites was rare. The histological subtypes were diffuse large B-cell (n = 12) and follicular (n = 1) lymphoma. Tumors were located in ovary (n = 8), uterus (n = 3), and cervix (n = 2). According to the Ann Arbor staging system, 6 cases were classified as stage II and 7 cases were classified as stage IV, respectively. A total of 10 patients underwent surgery. Combination chemotherapy was used in 10 patients. Eight patients had tumor-free survival, 1 patient had recurrent disease, 3 patients died and 1 patient lost to follow-up. The median survival time was 32 months (1-102 months).
CONCLUSION
PLFGT usually presents as gynecological symptoms and solid masses in pelvis. Surgery or biopsy was the way to obtain the pathologic diagnosis, and combination chemotherapy is the efficient method for PLFGT. Making an accurate preoperative diagnosis is of paramount importance to avoid radical gynecologic surgery.
Topics: Female; Humans; Genital Neoplasms, Female; Lymphoma, Large B-Cell, Diffuse; Genitalia, Female; Gynecologic Surgical Procedures; Neoplasm Staging
PubMed: 38637800
DOI: 10.1186/s12905-024-03037-8 -
Revista Espanola de Enfermedades... Apr 2024A 62-year-old woman, originally from Peru, with rheumatoid arthritis under treatment with anti-tumor necrosis factor (anti-TNF) therapy, was admitted due to...
A 62-year-old woman, originally from Peru, with rheumatoid arthritis under treatment with anti-tumor necrosis factor (anti-TNF) therapy, was admitted due to constitutional syndrome and suspicion of neoplasia. Computed tomography (CT) scan revealed involvement of three segments of the colon, ascites, and likely peritoneal implants. Ascitic fluid analysis showed elevated adenosine deaminase (ADA) levels and lymphocytosis. The patient presented with hematemesis and hematochezia with hemodynamic instability. Upper gastrointestinal endoscopy identified an extensive ulcer in the middle esophagus with a granular base, elevated and defined edges, indeterminate for malignancy and without blood residues. Colonoscopy also revealed multiple extensive ulcers in the transverse colon, with whitish bases and thickened and necrotic-looking surrounding mucosal edges. Histology showed granulomas and yeast-like fungal structures with methenamine silver staining in both tissues, consistent with disseminated histoplasmosis. Antifungal treatment was initiated with good clinical evolution.
PubMed: 38634865
DOI: 10.17235/reed.2024.10432/2024 -
Nature Medicine May 2024Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions....
Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions. Leveraging cytological images from 57,220 cases at four tertiary hospitals, we developed a deep-learning method for tumor origin differentiation using cytological histology (TORCH) that can identify malignancy and predict tumor origin in both hydrothorax and ascites. We examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets. In both internal and external testing sets, TORCH achieved area under the receiver operating curve values ranging from 0.953 to 0.991 for cancer diagnosis and 0.953 to 0.979 for tumor origin localization. TORCH accurately predicted primary tumor origins, with a top-1 accuracy of 82.6% and top-3 accuracy of 98.9%. Compared with results derived from pathologists, TORCH showed better prediction efficacy (1.677 versus 1.265, P < 0.001), enhancing junior pathologists' diagnostic scores significantly (1.326 versus 1.101, P < 0.001). Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P = 0.006). Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted.
Topics: Humans; Deep Learning; Neoplasms, Unknown Primary; Female; Male; Aged; Middle Aged; ROC Curve; Adult; Cytodiagnosis; Aged, 80 and over; Ascites; Cytology
PubMed: 38627559
DOI: 10.1038/s41591-024-02915-w -
British Journal of Cancer Jun 2024Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-β (TGF-β) in ascites or tumour immune...
BACKGROUND
Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-β (TGF-β) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-β and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models.
METHODS
BA is a first-in-class bifunctional inhibitor of TGF-β and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models.
RESULTS
Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-β and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls.
CONCLUSIONS
Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.
Topics: Female; Animals; Killer Cells, Natural; Ovarian Neoplasms; Mice; Transforming Growth Factor beta; B7-H1 Antigen; Humans; Cell Line, Tumor; Tumor Microenvironment; Disease Models, Animal
PubMed: 38622286
DOI: 10.1038/s41416-024-02677-9 -
Clinical Case Reports Apr 2024Struma ovarii (SO), is a rare and specialized ovarian teratoma. The treatment is controversial depending on the risk of recurrence and metastasis. Here a SO with...
KEY CLINICAL MESSAGE
Struma ovarii (SO), is a rare and specialized ovarian teratoma. The treatment is controversial depending on the risk of recurrence and metastasis. Here a SO with papillary thyroid carcinoma is reported and the approach is thoroughly discussed.
ABSTRACT
Struma ovarii (SO) is a highly specialized ovarian teratoma primarily composed of thyroid tissue. Clinical features associated with SO include lower abdominal discomfort, unusual vaginal bleeding, ascites, and hyperthyroidism. While SO rarely transforms into malignancy, the optimal degree of treatment remains controversial due to the varying risks of recurrence and metastasis. In this report, we present the case of a 64-year-old woman experiencing abdominal pain and diagnosed with SO, accompanied by papillary thyroid carcinoma. We thoroughly discuss the evaluation and management of this rare condition.
PubMed: 38617068
DOI: 10.1002/ccr3.8610