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Oncogene Sep 2023PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors...
PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.
Topics: Animals; Female; Humans; Mice; Angiogenesis Inhibitors; Cell Line, Tumor; DNA Repair; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Rad51 Recombinase; Tumor Microenvironment; Saponins
PubMed: 37550562
DOI: 10.1038/s41388-023-02785-5 -
BMC Women's Health Sep 2023Struma ovarii (SO) is a rare tumor and may transform into ovarian strumal carcinoid (OSC) and/or malignant struma ovarii (MSO), but the incidence, clinical...
BACKGROUND
Struma ovarii (SO) is a rare tumor and may transform into ovarian strumal carcinoid (OSC) and/or malignant struma ovarii (MSO), but the incidence, clinical characteristics, and survival outcomes have not been well defined.
METHODS
We conducted a retrospective study of patients with ovarian strumal diseases treated in the our hospital between 1980 and 2022. Subgroup analyses of SO, OSC, and MSO were subsequently performed.
RESULTS
A total of 275 cases (2.14%) were identified in a cohort of 12,864 patients with ovarian teratomas, where SO, OSC, and MSO accounted for 83.3%, 12.0%, and 4.7% of cases, respectively. There were no significant differences in age, tumor sizes, elevated tumor markers, and ascites among the three subgroups. At initial treatment, all patients with SO or OSC had FIGO stage I disease except one SO patient presenting metastatic disease, ten patients had MSO confined to the ovary, whereas other three patients had metastatic diseases. Two patients with SO respectively relapsed at peritoneum and anterior mesorectum, while none of the OSC patients presented tumor recurrence or death despite different surgical procedures employed. The 5-year recurrence-free survival rate was 88.9%, and only one death occurred at 9.5 years after diagnosis in patients with MSO. Radioiodine therapy showed satisfactory therapeutic efficacy, but these patients showed poor responses to the chemotherapy.
CONCLUSION
2.14% of ovarian teratoma could be classified as SO, of which 12.0% and 4.7% of SO may transform into OSC and MSO, repsectively. The survival outcomes were excellent even after SO transformed into OSC or MSO.
SYNOPSIS
SO occupied 2.14% of ovarian teratoma, where 12.0% and 4.7% of SO may transform into OSC and MSO, respectively, and had excellent survival outcomes.
Topics: Female; Humans; Ovarian Neoplasms; Struma Ovarii; Retrospective Studies; Carcinoid Tumor; Incidence; Iodine Radioisotopes; Neoplasm Recurrence, Local; Teratoma
PubMed: 37726744
DOI: 10.1186/s12905-023-02624-5 -
Annals of Surgery Nov 2023To compare minimally invasive (MILR) and open liver resections (OLRs) for hepatocellular carcinoma (HCC) in patients with metabolic syndrome (MS).
OBJECTIVE
To compare minimally invasive (MILR) and open liver resections (OLRs) for hepatocellular carcinoma (HCC) in patients with metabolic syndrome (MS).
BACKGROUND
Liver resections for HCC on MS are associated with high perioperative morbidity and mortality. No data on the minimally invasive approach in this setting exist.
MATERIAL AND METHODS
A multicenter study involving 24 institutions was conducted. Propensity scores were calculated, and inverse probability weighting was used to weight comparisons. Short-term and long-term outcomes were investigated.
RESULTS
A total of 996 patients were included: 580 in OLR and 416 in MILR. After weighing, groups were well matched. Blood loss was similar between groups (OLR 275.9±3.1 vs MILR 226±4.0, P =0.146). There were no significant differences in 90-day morbidity (38.9% vs 31.9% OLRs and MILRs, P =0.08) and mortality (2.4% vs 2.2% OLRs and MILRs, P =0.84). MILRs were associated with lower rates of major complications (9.3% vs 15.3%, P =0.015), posthepatectomy liver failure (0.6% vs 4.3%, P =0.008), and bile leaks (2.2% vs 6.4%, P =0.003); ascites was significantly lower at postoperative day 1 (2.7% vs 8.1%, P =0.002) and day 3 (3.1% vs 11.4%, P <0.001); hospital stay was significantly shorter (5.8±1.9 vs 7.5±1.7, P <0.001). There was no significant difference in overall survival and disease-free survival.
CONCLUSIONS
MILR for HCC on MS is associated with equivalent perioperative and oncological outcomes to OLRs. Fewer major complications, posthepatectomy liver failures, ascites, and bile leaks can be obtained, with a shorter hospital stay. The combination of lower short-term severe morbidity and equivalent oncologic outcomes favor MILR for MS when feasible.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Ascites; Metabolic Syndrome; Hepatectomy; Propensity Score; Liver Failure; Length of Stay; Laparoscopy; Retrospective Studies; Postoperative Complications
PubMed: 36994755
DOI: 10.1097/SLA.0000000000005861 -
Journal of Cell Communication and... Sep 2023The tumor microenvironment (TME) and its complex role in cancer progression have been hotspots of cancer research in recent years. Ascites, which occurs frequently in... (Review)
Review
The tumor microenvironment (TME) and its complex role in cancer progression have been hotspots of cancer research in recent years. Ascites, which occurs frequently in patients with ovarian cancer especially in advanced stages, represents a unique TME. Malignant ascites contains abundant cellular and acellular components that play important roles in tumorigenesis, growth, metastasis, and chemoresistance of ovarian cancer through complex molecular mechanisms and signaling pathways. As a valuable liquid biopsy sample, ascites fluid is also of great significance for the prognostic analysis of ovarian cancer. The components of ovarian cancer ascites are generally considered to comprise tumor-promoting factors; however, in recent years studies have found that ascites also contains tumor-suppressing factors, raising new perspectives on interactions between ascites and tumors. Malignant ascites directly constitutes the ovarian cancer microenvironment, therefore, the study of its components will aid in the development of new therapeutic strategies. This article reviews the current research on tumor-promoting and tumor-suppressing factors and molecular mechanisms of their actions in ovarian cancer-derived ascites and therapeutic strategies targeting ascites, which may provide references for the development of novel therapeutic targets for ovarian cancer in the future.
PubMed: 36227507
DOI: 10.1007/s12079-022-00698-8 -
The Korean Journal of Gastroenterology... Feb 2024Hepatic hydrothorax is a pleural effusion (typically ≥500 mL) that develops in patients with cirrhosis and/or portal hypertension in the absence of other causes. In... (Review)
Review
Hepatic hydrothorax is a pleural effusion (typically ≥500 mL) that develops in patients with cirrhosis and/or portal hypertension in the absence of other causes. In most cases, hepatic hydrothorax is seen in patients with ascites. However, ascites is not always found at diagnosis and is not clinically detected in 20% of patients with hepatic hydrothorax. Some patients have no symptoms and incidental findings on radiologic examination lead to the diagnosis of the condition. In the majority of cases, the patients present with symptoms such as dyspnea at rest, cough, nausea, and pleuritic chest pain. The diagnosis of hepatic hydrothorax is based on clinical manifestations, radiological features, and thoracocentesis to exclude other etiologies such as infection (parapneumonic effusion, tuberculosis), malignancy (lymphoma, adenocarcinoma) and chylothorax. The management strategy involves a stepwise approach of one or more of the following: Reducing ascitic fluid production, preventing fluid transfer to the pleural space, fluid drainage from the pleural cavity, pleurodesis (obliteration of the pleural cavity), and liver transplantation. The complications of hepatic hydrothorax are associated with significant morbidity and mortality. The complication that causes the highest morbidity and mortality is spontaneous bacterial empyema (also called spontaneous bacterial pleuritis).
Topics: Humans; Hydrothorax; Ascites; Pleural Effusion; Liver Cirrhosis; Liver Transplantation
PubMed: 38389460
DOI: 10.4166/kjg.2023.107 -
Journal of Ayub Medical College,... 2023Primary ovarian Burkitt lymphoma (BL) is a very rare and aggressive malignancy. We report an 18-year-old female patient who presented with a large, tender abdomen, and...
Primary ovarian Burkitt lymphoma (BL) is a very rare and aggressive malignancy. We report an 18-year-old female patient who presented with a large, tender abdomen, and highly de-ranged renal and liver functions. Ultrasonography showed hepatosplenomegaly, mild ascites, dilated biliary channels and a heterogeneous pelvic mass of size ~15106.4 cm. Immunohistochemical (IHC) staining of the biopsy sample excised from the left ovary demonstrated reactivity for CD20 and CD10, and negativity for CD3, Bcl-2 and TdT. The C-myc translocation was positive in 60% of tumour cells. Moreover, the proliferation index was ~90%. These features were consistent with BL. After haemodialysis, the patient was planned for multiagent chemotherapy, including cyclophosphamide, doxorubicin, vincristine and prednisone. This case supports the hypothesis that primary ovarian BL is an aggressive malignancy that appears to respond promisingly to multi-agent chemotherapy.
Topics: Female; Humans; Adolescent; Burkitt Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Vincristine; Prednisone; Doxorubicin
PubMed: 38406915
DOI: 10.55519/JAMC-S4-12410 -
United European Gastroenterology Journal Oct 2023Transjugular intrahepatic portosystemic shunts (TIPS) in patients with hepatocellular carcinoma (HCC) may improve access to curative therapies, treat portal hypertension...
BACKGROUND/AIMS
Transjugular intrahepatic portosystemic shunts (TIPS) in patients with hepatocellular carcinoma (HCC) may improve access to curative therapies, treat portal hypertension (PH)-related complications without worsening liver function, and increase overall survival. Data on the efficacy and safety of TIPS to treat PH complications in HCC patients, as well as the HCC treatment response, were evaluated.
METHODS
Studies reporting efficacy in controlling bleeding/ascites or response to HCC therapy, safety, and survival in patients with HCC and TIPS were searched systematically on PubMed and Embase. An extraction of articles using predefined data fields and quality indicators was used.
RESULTS
We selected 19 studies and found 937 patients treated for ascites/bleeding and 177 evaluating HCC treatment response. Over half were under 5 cm and solitary lesions, and most studies included tumours with portal vein thrombosis. Regarding PH studies, TIPS resolved bleeding/ascites in >60% of patients, more effective for bleeding. There were no lethal complications reported and procedural bleeding occurred in <5%. Hepatic encephalopathy occurred in 15%-30% within three months. In the HCC treatment-response studies, major complication rates were low with no mortality. In the studies that evaluated the response to transarterial chemoembolization, complete response rate of patients with TIPS varied from 16% to 75%. Liver transplantation rate varied from 8% to 80%, with >40% rate in half of the studies.
CONCLUSIONS
In the published studies, TIPS is effective in treating PH complications in patients with HCC. Prospective studies on TIPS placement in patients with HCC are urgently needed to evaluate the efficacy and safety of TIPS in this setting.
Topics: Humans; Carcinoma, Hepatocellular; Portasystemic Shunt, Transjugular Intrahepatic; Liver Neoplasms; Ascites; Prospective Studies; Esophageal and Gastric Varices; Treatment Outcome; Chemoembolization, Therapeutic; Hypertension, Portal
PubMed: 37736854
DOI: 10.1002/ueg2.12454 -
International Journal of Molecular... Dec 2023Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic... (Review)
Review
Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.
Topics: Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metformin; Ascites; Ovarian Neoplasms; Insulin; Immunotherapy; Cholesterol; Tumor Microenvironment
PubMed: 38203494
DOI: 10.3390/ijms25010323 -
Proceedings of the Japan Academy.... 2024This review seeks to highlight and celebrate Professor Tomizo Yoshida's famous work on "Establishment and characterization of a rat ascites sarcoma, later named "Yoshida... (Review)
Review
This review seeks to highlight and celebrate Professor Tomizo Yoshida's famous work on "Establishment and characterization of a rat ascites sarcoma, later named "Yoshida ascites sarcoma". Considering the tremendous contribution of this ascites tumor system to the subsequent promotion of research on cancer biology and cancer chemotherapy, his paper should be regarded as a monumental one in the cancer field. The research was carried out during 1943 and the results were submitted to this Journal in October 1944, when Japan was approaching a debilitating defeat in World War II in August 1945. In 1947, when "Research on Ascites sarcoma" was first comprehensively introduced to researchers in a special lecture at the Annual Meeting of the Japanese Society of Pathology, the whole audience was deeply impressed and was encouraged to resume scientific activity in Japan.
Topics: Animals; Sarcoma; Rats; Humans; History, 20th Century; Ascites; Japan
PubMed: 38866478
DOI: 10.2183/pjab.100.021 -
Clinical Chemistry and Laboratory... Jun 2024Ascites is the pathological accumulation of fluid within the peritoneal cavity. It often occurs as results of liver cirrhosis, malignant neoplasia, tuberculous... (Review)
Review
Ascites is the pathological accumulation of fluid within the peritoneal cavity. It often occurs as results of liver cirrhosis, malignant neoplasia, tuberculous infection, cardiac insufficiency, renal diseases, etc. Determining the etiology is an essential step in the management of patients with new-onset ascites. Abdominal paracentesis with appropriate ascitic fluid analysis is probably the most cost-effective method of determining the cause of ascites. We performed a literature search of PubMed and identified articles published in the field of ascites, to evaluate diagnostic values of various parameters in defining the etiologies of ascites and then provides diagnostic algorithm for patients with new-onset ascites. In patients with ascites, the constituent ratio of underlying etiology varies between developed and developing countries. It is a challenge to define the etiologies of ascites in developing countries. Routine ascitic fluid analysis should include the serum ascites albumin gradient (SAAG), total protein concentration, cell count and differential. Optional ascitic fluid analysis includes cholesterol, fluid culture, cytology, tumor markers, lactate dehydrogenase, adenosine deaminase (ADA), triglyceride, amylase, glucose, brain natriuretic peptide (BNP), etc. Our review evaluated diagnostic values of the above parameters in defining the etiologies of ascites. Diagnostic algorithm established in this review would provide a practical and convenient diagnostic strategy for clinicians in diagnosing patients with new-onset ascites.
Topics: Humans; Ascites; Ascitic Fluid; Algorithms; Diagnosis, Differential
PubMed: 38112289
DOI: 10.1515/cclm-2023-1112