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Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.

Background High-grade serous tubo-ovarian cancer (HGSTOC) is characterised by extensive inter- and intratumour heterogeneity, resulting in persistent therapeutic resistance and poor disease outcome. Molecular subtype classification based on bulk RNA sequencing facilitates a more accurate characterisation of this heterogeneity, but the lack of strong prognostic or predictive correlations with these subtypes currently hinders their clinical implementation. Stromal admixture profoundly affects the prognostic impact of the molecular subtypes, but the contribution of stromal cells to each subtype has poorly been characterised. Increasing the transcriptomic resolution of the molecular subtypes based on single-cell RNA sequencing (scRNA-seq) may provide insights in the prognostic and predictive relevance of these subtypes. Methods We performed scRNA-seq of 18,403 cells unbiasedly collected from 7 treatment-naive HGSTOC tumours. For each phenotypic cluster of tumour or stromal cells, we identified specific transcriptomic markers. We explored which phenotypic clusters correlated with overall survival based on expression of these transcriptomic markers in microarray data of 1467 tumours. By evaluating molecular subtype signatures in single cells, we assessed to what extent a phenotypic cluster of tumour or stromal cells contributes to each molecular subtype. Results We identified 11 cancer and 32 stromal cell phenotypes in HGSTOC tumours. Of these, the relative frequency of myofibroblasts, TGF-β-driven cancer-associated fibroblasts, mesothelial cells and lymphatic endothelial cells predicted poor outcome, while plasma cells correlated with more favourable outcome. Moreover, we identified a clear cell-like transcriptomic signature in cancer cells, which correlated with worse overall survival in HGSTOC patients. Stromal cell phenotypes differed substantially between molecular subtypes. For instance, the mesenchymal, immunoreactive and differentiated signatures were characterised by specific fibroblast, immune cell and myofibroblast/mesothelial cell phenotypes, respectively. Cell phenotypes correlating with poor outcome were enriched in molecular subtypes associated with poor outcome. Conclusions We used scRNA-seq to identify stromal cell phenotypes predicting overall survival in HGSTOC patients. These stromal features explain the association of the molecular subtypes with outcome but also the latter’s weakness of clinical implementation. Stratifying patients based on marker genes specific for these phenotypes represents a promising approach to predict prognosis or response to therapy.

High‐grade serous tubo‐ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP‐ribose) polymerase inhibitors (PARPis) and anti‐PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single‐cell RNA and single‐cell T‐cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRβ+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1‐expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRβ+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti‐CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA‐4/LAG‐3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF‐1/CSF‐1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi‐resistant HRD and refractory HRP tumors. A comprehensive single‐cell atlas of homologous recombination deficient (HRD) and homologous recombination proficient (HRP) ovarian cancer is depicted. Through verification of mIHC and in‐vivo xenograft validation, the distinct tumor immune microenvironment is unveiled, the promising targets specifically for HRD and HRP tumors are proposed, providing novel insights for developing effective clinical therapies customized for HRD and HRP patients.

Exosomes are natural nanovesicles with unique characteristics, such as long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent systemic toxicity. Mesenchymal stem cells produce large amounts of exosomes with regenerative properties and more stability in human plasma. TUBO breast cancer cell lines overexpress rat HER2/neu protein. Targeted exosomes were isolated from transduced bone marrow mesenchymal stem cells. Doxorubicin was encapsulated into exosomes by electroporation. Flow cytometry was used to assess the attachment of exosomes to the target cells. The in vitro cytotoxicity effect of targeted doxorubicin-loaded exosomes on TUBO cells was determined using MTT assay. Selective delivery of doxorubicin to tumor tissues was analyzed by measuring the auto-fluorescence of doxorubicin by in vivo imaging system. Moreover, tumor growth inhibition and body weight were monitored following injection of free doxorubicin, and targeted and untargeted doxorubicin-loaded exosomes in a TUBO breast cancer model. Finally, mouse tissues were examined for the presence of intrinsic fluorescence of doxorubicin. Flow cytometry results revealed significant differences in binding of targeted exosomes to HER2-positive (46.05%) and HER2-negative (13.9%) cells. The results of MTT assay showed that cytotoxicity of targeted doxorubicin-loaded exosomes was higher than free doxorubicin at 72 hours. Selective distribution of targeted doxorubicin-loaded exosomes in the target tissues of the murine breast cancer model suggested specific delivery of doxorubicin by targeted exosomes, rather than untargeted exosomes. Free doxorubicin and untargeted doxorubicin-loaded exosomes showed insignificant effects, whereas targeted doxorubicin-loaded exosomes reduced the tumor growth rate. Herein, we report efficient delivery of targeted doxorubicin-loaded exosomes in vitro, corroborated with a significant reduction of murine breast cancer model tumor growth rate.

Tubo-ovarian abscess (TOA), a serious complication of pelvic inflammatory disease, poses a serious risk to sexually active women, characterized by high rates of morbidity and mortality. Despite antibiotic therapy being the primary treatment for non-ruptured, stable TOA cases, failure rates of medical management remain as high as 30%. This study investigates the potential of systemic inflammatory markers, particularly the systemic immune-inflammation index (SII), in predicting the necessity for surgical intervention following the failure of medical treatment in TOA patients. A retrospective analysis was conducted on 101 patients diagnosed with TOA at the Bağcılar Training and Research Hospital's Department of Obstetrics and Gynecology between January 2019 and June 2023. Data collected included demographic details, obstetric history, chronic conditions, clinical history (including intrauterine interventions), and preoperative admission laboratory parameters (CBC, CRP, Neutrophil-to-Lymphocyte Ratio (NLR), and Systemic Immune-Inflammation Index (SII)). Patients were categorized based on treatment outcomes: successful medical treatment versus surgical intervention. A multivariable logistic regression analysis was conducted to assess the predictive value of these markers and to identify independent predictors of medical treatment failure. The surgical group had significantly higher SII, NLR, and CRP levels compared to the medically managed group. An SII cut-off value of 1750 was a significant predictor of medical treatment failure, with an area under the curve (AUC) of 0.749 (95% CI: 0.649-0.850), yielding a sensitivity of 73.2% and specificity of 76.7%. Similarly, NLR demonstrated predictive value with a cut-off value of 4.3, achieving an AUC of 0.694 (95% CI: 0.590-0.798), with 80.5% sensitivity and 58.3% specificity. In the multivariable analysis, SII (OR: 1.002), NLR (OR: 0.706), length of hospital stay (OR: 1.181), and history of curettage (OR: 7.018) were identified as independent predictors of medical treatment failure. Although the mean abscess diameter was larger in the surgical group (64.0 mm vs 57.5 mm), this difference did not reach statistical significance (p=0.079). Systemic inflammatory markers -particularly, the Systemic Immune-Inflammation Index (SII)- appear to be robust, cost-effective, and readily available tools for predicting medical treatment failure in patients with TOA. Predictive performance is enhanced when SII is interpreted in conjunction with NLR and relevant clinical history, especially prior curettage. Integrating these independent predictors into clinical decision-making may facilitate earlier identification of high-risk patients and expedite escalation to surgical intervention, thereby minimizing delays and improving patient outcomes.

During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10−4) by Kaplan–Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10−4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10−4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.

Background: Tuboovarian abscess is a serious complication of pelvic inflammatory disease. Pelvic ac- tinomycosis may correlate with long term use of intra-uterine device (IUD), but is uncom- mon cause of inflammation, except in postmenopausal IUD users.1, 2 Tuboovarian abscess complicated with cerebritis is relatively uncommon condition. Methods: We present a rare case of a 56-years-old woman with IUD, developing tuboovarian abscess that complicated with cerebritis. Twenty days before admittance to the Gynecologic clinic, she complained of fatigue and nausea, anorexia, vomiting and diarrhea. After an initial improvement for 5 days her symptoms recurred, profounded with sweating and fever up to 40 °C, leg weakness and walking difficulties, and weight loss. In that condition she was presented to our emergency room. There was no history of chronic disease. The patient had an IUD for the past 30 years. On physical examination the abdomen was tender, but without signs of peritoneal irritation. Laboratory studies revealed elevated CRP (107 mg/L), ESR (65mm/h) and normal number of leukocytes (7.8 × 109/L). Ultrasound showed 8x4 cm left infraumbilical septated mass suspect for tubo-ovarian abscess.. She was hospitalized, IUD was removed and Metronidazol, Ciprofloxacin and Gentamycin were started parenterally. Tumor markers were negative. On the next day she developed neurologic symptoms with blindness and left-hemiparesis. MR angiography and CT of the head revealed local brain edema, suspect for cerebritis. Although the laboratory findings of inflammation were de- creasing, we changed the antimicrobial therapy with Cefotaxime and Kloksacilin (Orbenin) instead of Metronidazol and Ciprofloxacin because of better blood-brain barrier transport. Cerebrospinal fluid tests for HSV, neurotropic viruses, malignant cells, TBC, echinoccocus, toxoplasmosis, cysticercosis, pathogenic bacteria, fungi, TILR2, and TNF alfa were nega- tive. A brain biopsy was preformed and no pathologic changes were found, except a group of beta amyloides. Rectoscopy ruled out malignancy. Because of enlargement of the brain edema Mannitol and Dexamethazon were added in the therapeutic regimen. Temporar- ily stabilizing the increment of brain edema, we performed exploratory laparotomy that revealed a left retroperitoneal abscess infiltrating the sigmoid colon and left parameters. Left fallopian tube and ovary were modified in a solid tumor. A total hysterectomy with bilateral salpingoophorectomy with Hartmann resection of sigmoid colon was performed. After operation general inhalation anesthesia was initiated at Central Intensive care unit (CIT). Control brain CT showed diffuse bilateral brain edema. Brain biopsy was performed and the histology results were negative. Vancomycin and Ceftriakson were added in therapy for 15 days. After this therapy, CT revealed a decrease in the brain edema and isolated bilateral hypodense parietoocipital formations and a right frontal paramedial hypodense formation. The patient was kept sedated and intubated. Approximately one month later a try of awaking the patient from general anesthesia was unsuccessful. Our neurologic team proposed either a repeat of the brain lesion biopsy or intrathecal empiric antimicrobial therapy. On the next day, before performing either of proposed procedures, the patient completely awaked and was contactable but with left-sided hemiparesis. According to the hystologic and microbyologic findings the patient was transferred to Intensive Care unit of our Department where Imipenem was started, and later transferred to Infectology for further treatment. Approximately one year after the hospitalization, long-term use of intravenous antibiotics and rehabilitation, the patient fully recovered with minimal consequences of brain damage. Results: Hystologically the removed left-sided mass was a tuboovarian abscess with actinomycotic colonies. On microbiologic examination Enterococcus faecium, Bacteroides capillosus and Anaerobic gram negative bacilli were isolated, sensitive to Metronidazol, Clindamycin, Imipenem and Amoksicilin with Clavulonic Acid. The definite diagnosis was tuboovarian abscess caused by actinomyces complicated with etiologically undeterminated cerebritis. Conclusions: Tuboovarian abscess in a postmenopausal woman as a cause for brain inflammation or abscess is an absolute rarity. Actinomyces species are not generally considered as a part of the normal vaginal flora but rather are associated with the presence of a foreign body, most often an IUD. It is a chronic supurative infection, with a tendency to form abscess. Pelvic actinomycosis is a rare bacterial disease in women (3). It is difficult to diagnose because of the non specific clinical symptoms and imaging findings. Treatment is not standardized and depends on the clinical form. Medical therapy is based on long-term Penicillin G (4). The prognosis of correctly treated pelvic actinomycosis is generally good (3, 4). Experiences with the infection of the CNS by Actinomyces showed that it is potentially fatal (5) and should be considered in those patients with cerebral abscesses or cerebral infection as evident from our case.

The C-reactive protein-albumin-lymphocyte (CALLY) index is a novel immunonutritional marker reflecting systemic inflammation and host immune status. This study aimed to evaluate the diagnostic and prognostic value of the CALLY index and compare its performance with other systemic inflammatory indices in hospitalized patients with pelvic inflammatory disease (PID) and tubo-ovarian abscess (TOA). This retrospective observational study included 124 patients hospitalized with PID and/or TOA between January 2020 and November 2025. Patients were classified into TOA and non-TOA groups based on clinical and radiological findings. Demographic data, laboratory parameters, and length of hospital stay were recorded. Inflammatory and immunonutritional indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), C-reactive protein-to-albumin ratio (CAR), hemoglobin-albumin-lymphocyte-platelet (HALP) score, neutrophil percentage-to-albumin ratio (NPAR), and CALLY index, were calculated using admission laboratory values. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance. Patients with TOA had significantly higher C-reactive protein (CRP), procalcitonin, C-reactive protein-to-albumin ratio (CAR), hemoglobin-albumin-lymphocyte-platelet (HALP) score, systemic inflammatory response index (SIRI), and neutrophil percentage, and significantly lower CALLY index compared to non-TOA PID patients (p<0.05). The CALLY index showed a significant negative correlation with length of hospital stay (r = -0.283, p = 0.001), whereas CRP, CAR, HALP, and neutrophil percentage-to-albumin ratio (NPAR) demonstrated positive correlations. ROC analysis revealed moderate diagnostic accuracy of the CALLY index for predicting TOA (AUC = 0.671, p = 0.001). The HALP score demonstrated the highest diagnostic performance among evaluated parameters. The CALLY index is a promising immunonutritional biomarker associated with disease severity and hospitalization burden in patients with TOA. Its integration into routine clinical evaluation may improve early risk stratification and clinical decision-making in PID management.

Tubo-ovarian abscess (TOA) is a rare but serious condition that carries with it a high rate of morbidity and even mortality. This review highlights the pearls and pitfalls of TOA, including diagnosis, initial resuscitation, and management in the emergency department (ED) based on current evidence. TOA is associated with pelvic inflammatory disease (PID) as well as intrauterine devices, uterine procedures, multiple sexual partners, diabetes mellitus, and immunocompromised states. While usually arising from a gynecologic infection, TOA can be associated with a gastrointestinal source. History and physical examination are limited, demonstrating predominantly lower abdominal pain, but a minority of patients will present with vaginal symptoms. Half of patients will exhibit systemic illness to include fever, nausea, and vomiting. Laboratory evaluation may reveal elevations in white blood cell count and other inflammatory markers. Transvaginal ultrasound and computed tomography (CT) may be utilized for diagnosis, though CT has higher sensitivity and can differentiate this disease from similarly presenting gastrointestinal pathology. Initial medical management includes antibiotics. Surgical intervention is indicated in those who fail initial medical therapy, which is more likely in those with bilateral abscesses, large abscesses, and older patients. An understanding of TOA can assist emergency clinicians in diagnosing and managing this potentially deadly disease.