Thomas Bartl

Therapeutic Effects of Lurbinectedin in PARP Inhibitor-Resistant High-Grade Serous Ovarian Cancer Using Patient-Derived Cell Lines and Organoid Models

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy which is often treated with platinum-based chemotherapy and PARP inhibitors (PARPi). However, PARPi resistance remains a major clinical challenge, necessitating alternative therapeutic strategies. In this study, we establish the first known patient-derived organoid models directly from PARPi-resistant HGSOC and demonstrate that they preserve the original tumor architecture and key biomarkers (EpCAM, CA125, PAX8, HER2, MEK1/2, Cyclin E1), thus providing unique preclinical models for drug testing. These organoids were used to evaluate lurbinectedin in comparison with standard carboplatin and paclitaxel. While lurbinectedin showed comparable apoptotic effects to paclitaxel and superior activity to carboplatin, it induced chromosomal breaks to different extents in different cell lines, suggesting a distinct mechanism of action. Importantly, this work does not advocate for lurbinectedin as a superior therapy but, rather, demonstrates the utility of organoid models in uncovering drug-specific genomic effects. Our findings underscore the critical need for expanded testing using clinically relevant models to identify more effective strategies against PARPi-resistant disease.

Novel Targeted Agents in Advanced and Recurrent Low-Grade Serous Ovarian Cancer: A Silver Lining in the Therapy of a Chemoresistant Disease?

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents.

Prognostic role of transcription factor ARID1A in patients with endometrial cancer of no specific molecular profile (NSMP) subtype

As more than 50% of newly diagnosed endometrial cancers remain classified as 'no specific molecular subtype' (NSMP) due to a lack of established biomarkers to further improve molecular subtyping, this study aims to evaluate the prognostic value of Prospectively collected molecular profiling data of all consecutive patients with endometrial cancer who underwent primary surgery at our department between August 2017 and June 2022 and for whom both molecular profiling and clinical follow-up data were available were retrospectively evaluated. Tumor specimens were evaluated by combined mismatch repair protein immunohistochemistry and targeted next-generation hotspot sequencing. A total of 127 patients with endometrial cancer were included. Among 72 patients with tumors of NSMP subtype (56.7%),

Oncologic outcome of metachronous oligometastatic recurrence in advanced cervical cancer patients after primary radio-chemotherapy

Systemic chemotherapy in recurrent cervical cancer is a palliative treatment approach with limited oncologic outcome. As emerging evidence supports favorable prognosis following radical local treatment strategies for oligometastatic recurrence in gynecologic malignancies, there is an unmet clinical need to define prognostic implications of surgical metastasectomy in recurrent cervical cancer. Data of 139 consecutive cervical cancer patients, who underwent primary external-beam radiotherapy with concomitant chemotherapy, followed by magnetic resonance image-guided adaptive brachytherapy between 2015 and 2019, was analyzed. Oncologic outcomes of recurrence patterns, defined according to the European Society for Radiotherapy and Oncology (ESTRO) and the American Society for Radiation Oncology (ASTRO) consensus, was assessed according to the type of recurrence therapy. Of 54 patients (38.8%) with metachronous disease recurrence, 21 (38.8%) classified as metastatic and 22 (40.7%) as oligometastatic. Oligometastatic recurrence was associated with improved progression-free survival after recurrence (PFS2; hazard ratio [HR]=2.95; 95% confidence interval [CI]=1.23-7.08; p=0.015) and disease-specific survival after recurrence (HR=3.28; 95% CI=1.40-7.70; p=0.006) irrespective of the type of recurrence therapy. An exploratory subgroup analysis of oligometastatic patients undergoing surgical resection ± adjuvant therapy (n=12) suggested reduced risk of second disease recurrence (odds ratio=0.15; 95% CI=0.02-0.92; p=0.020) and improved PFS2 (HR=0.24; 95% CI=0.06-0.99; p=0.048) as compared to palliative systemic treatment (n=7). A relevant number of recurrences qualifies as oligometastatic according to the ESTRO-ASTRO consensus, which associate with improved prognosis irrespective of the type of recurrence therapy. Patients experiencing oligometastatic recurrence should be carefully evaluated for potentially curative treatment approaches.

Metastasized inflammatory myofibroblastic tumor of uterine origin

Biomarkers for checkpoint inhibitor therapy in mucinous epithelial ovarian cancer

The prognosis of patients with advanced stage mucinous epithelial ovarian cancer remains poor due to a modest response to platinum-based chemotherapy and the absence of therapeutic alternatives. As targeted approaches may help to overcome these limitations, the present study evaluates biomarkers indicative of potential immune-checkpoint inhibitor therapy response. All patients who underwent primary cytoreductive surgery from January 2001 to December 2020 and for whom formalin-fixed paraffin-embedded tissue samples were available were included (n=35; 12 International Federation of Gynecology and Obstetrics (FIGO) stage ≥IIb). To define sub-groups potentially suitable for checkpoint inhibition, expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (CD3+, CD8+, CD20+, CD45+, CD68+, FoxP3+), and AT-rich interactive domain-containing protein 1A (ARID1A) immunostaining were evaluated in whole tissue sections and compared with clinicopathologic parameters and next-generation sequencing results, where available (n=11). Survival analyses were performed to assess whether identified sub-groups were associated with specific clinical outcomes. In total, 34.3% (n=12/35) of tumors were PD-L1 positive. PD-L1 expression was associated with infiltrative histotype (p=0.027) and correlated with higher CD8+ (r=0.577, p10, which was associated with increased CD8+ expression (p=0.010) and loss of ARID1A expression (p=0.034). Next-generation sequencing, which was available for all samples with a combined positive score of >10, showed A sub-group of mucinous ovarian cancers appear to demonstrate a pro-immunogenic tumor environment with high PD-L1 expression, decreased ARID1A expression, and characteristic tumor-infiltrating lymphocyte infiltration patterns. Further clinical validation of anti-PD-L1/PD-1 targeting in selected mucinous ovarian cancers appears promising.

The systemic immune-inflammation index (SII) is an independent prognostic parameter of survival in patients with invasive vulvar cancer

To assess the prognostic value of the systemic immune-inflammation index (SII) in patients with vulvar cancer. Data of 130 consecutive patients who underwent primary surgical resection for vulvar cancer at the Medical University of Vienna between 1999 and 2018 was retrospectively analyzed. The SII was defined as platelets × neutrophils/lymphocytes as previously described. Its prognostic value on disease-specific survival (DSS) and overall survival (OS) was evaluated by univariate log-rank tests and multivariable cox regression models. Prediction accuracy was assessed by receiver operating characteristics curves and Youden's J statistics. A Hosmer-Lemeshow test was performed to confirm the model's goodness of fit. A pre-therapeutic high serum SII (>866.4) was associated with advanced International Federation of Gynecology and Obstetrics (FIGO)-stage. In univariate survival analysis, a high SII was associated with both DSS (p<0.001) and OS (p=0.001). A multivariate cox regression model confirmed the prognostic value of SII regarding DSS (p<0.001) and OS (p=0.014) independently from patients' age and FIGO stage. Pretherapeutic SII may serve as a promising predictor for survival in patients with vulvar cancer. After clinical validation, the SII may be used to improve both pre-treatment patient risk stratification and patient counseling.

Indocyanine green fluorescence angiography for bowel anastomosis assessment in ovarian cancer surgery

Optimizing bowel anastomotic integrity is a key consideration in ovarian cancer cytoreductive surgery, as anastomotic complications can significantly impact postoperative recovery and delay systemic treatment. Conventional assessment techniques like visual inspection and palpation are inherently subjective and may not consistently predict the likelihood of anastomotic leakage. Due to the serious consequences of anastomotic failure and the impact of diverting ostomies, there is growing interest in fluorescence-based technologies to enhance the diagnostic accuracy of anastomoses and support more informed intraoperative decision-making. Indocyanine green fluorescence angiography (ICG-FA) has emerged as a promising tool for improving the accuracy of bowel perfusion at the time of surgery. While widely adopted in general surgery, its use in gynecologic oncology is still growing and has not yet been established as the standard of care. By allowing surgeons to assess perfusion intraoperatively, ICG-FA may help reduce anastomotic leaks and decrease the need for diverting ostomies, with the goal of improving patient outcomes and quality of life. While early evidence indicates that ICG-FA is a safe and feasible tool in ovarian cancer surgery, additional research is required to develop standardized protocols and evaluate its clinical significance and long-term benefits. This review provides a technical overview, examines the current evidence surrounding ICG-FA in gynecologic oncology, explores its potential advantages and limitations, and highlights future directions for research in fluorescence-guided bowel anastomosis assessment.

Targeting RAS–RAF–MEK–ERK signaling in mucinous ovarian cancer: a translational evidence synthesis and clinical framework

Mucinous ovarian cancer is a rare and molecularly distinct sub-type of epithelial ovarian cancer, characterized by intrinsic resistance to cytotoxic chemotherapy and poor prognosis in advanced stages, with a median overall survival of 12 to 34 months. Its low incidence (<3% of advanced epithelial ovarian cancers) limits the feasibility of large-scale clinical trials, underscoring the need for molecularly informed therapeutic strategies. Oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway (most commonly through KRAS mutations [50%-65%] and near-universal MAPK hyperactivation) constitutes a defining feature of mucinous ovarian cancer biology and a rational therapeutic target. Despite this, there are no clinical data specifically evaluating MAPK-targeted therapies to date. Insights from other KRAS-driven malignancies reveal major challenges, including adaptive resistance, activation of compensatory signaling pathways (eg, PI3K/AKT), and intratumoral heterogeneity. This review synthesizes translational evidence for MAPK pathway targeting in mucinous ovarian cancer and proposes a clinical framework for treatment selection by integrating KRAS/MAPK activation with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) signaling, PI3K pathway alterations, and tumor-immune features. As comprehensive molecular profiling advances, integrated targeting of the rat sarcoma-rapidly accelerated fibrosarcoma-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (RAS-RAF-MEK-ERK) cascade may offer promising and urgently needed therapeutic strategies for this rare malignancy.