Highly Sensitive Spatial Glycomics at Near-Cellular Resolution by On-Slide Derivatization and Mass Spectrometry Imaging.

Glycans on proteins and lipids play important roles in maturation and cellular interactions, contributing to a variety of biological processes. Aberrant glycosylation has been associated with various human diseases including cancer; however, elucidating the distribution and heterogeneity of glycans in complex tissue samples remains a major challenge. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is routinely used to analyze the spatial distribution of a variety of molecules including N-glycans directly from tissue surfaces. Sialic acids are nine carbon acidic sugars that often exist as the terminal sugars of glycans and are inherently difficult to analyze using MALDI-MSI due to their instability prone to in- and postsource decay. Here, we report on a rapid and robust method for stabilizing sialic acid on N-glycans in FFPE tissue sections. The established method derivatizes and identifies the spatial distribution of α2,3- and α2,6-linked sialic acids through complete methylamidation using methylamine and PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate). Our in situ approach increases the glycans detected and enhances the coverage of sialylated species. Using this streamlined, sensitive, and robust workflow, we rapidly characterize and spatially localize N-glycans in human tumor tissue sections. Additionally, we demonstrate this method's applicability in imaging mammalian cell suspensions directly on slides, achieving cellular resolution with minimal sample processing and cell numbers. This workflow reveals the cellular locations of distinct N-glycan species, shedding light on the biological and clinical significance of these biomolecules in human diseases.

Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group.

Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with CCNE1 amplification, AKT2 amplification or CDK12 alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.

Perforator versus Non-Perforator Flap-Based Vulvoperineal Reconstruction-A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with advanced vulvoperineal cancer require a multidisciplinary treatment approach to ensure oncological safety, timely recovery, and the highest possible quality of life (QoL). Reconstructions in this region often lead to complications, affecting approximately 30% of patients. Flap design has evolved towards perforator-based approaches to reduce functional deficits and (donor site) complications, since they allow for the preservation of relevant anatomical structures. Next to their greater surgical challenge in elevation, their superiority over non-perforator-based approaches is still debated. METHODS: To compare outcomes between perforator and non-perforator flaps in female vulvoperineal reconstruction, we conducted a systematic review of English-language studies published after 1980, including randomized controlled trials, cohort studies, and case series. Data on demographics and surgical outcomes were extracted and classified using the Clavien-Dindo classification. We used a random-effects meta-analysis to derive a pooled estimate of complication frequency (%) in patients who received at least one perforator flap and in patients who received non-perforator flaps. RESULTS: Among 2576 screened studies, 49 met our inclusion criteria, encompassing 1840 patients. The overall short-term surgical complication rate was comparable in patients receiving a perforator (n = 276) or a non-perforator flap (n = 1564) reconstruction (p* > 0.05). There was a tendency towards fewer complications when using perforator flaps. The assessment of patients' QoL was scarce. CONCLUSIONS: Vulvoperineal reconstruction using perforator flaps shows promising results compared with non-perforator flaps. There is a need for the assessment of its long-term outcomes and for a systematic evaluation of patient QoL to further demonstrate its benefit for affected patients.

Management of Patients with Hypersensitivity to Platinum Salts and Taxane in Gynecological Cancers: A Cross-Sectional Study by the European Network of Young Gynaecologic Oncologists (ENYGO).

Platinum and taxane chemotherapy is associated with the risk of hypersensitivity reactions (HSRs), which may require switching to less effective treatments. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen. Therefore, we aimed to investigate the current management of HSRs to platinum and/or taxane chemotherapy in patients with gynecologic cancers. We conducted an online cross-sectional survey among gynecological and medical oncologists consisting of 33 questions. A total of 144 respondents completed the survey, and 133 respondents were included in the final analysis. Most participants were gynecologic oncologists (43.6%) and medical oncologists (33.8%), and 77.4% (n = 103) were involved in chemotherapy treatment. More than 73% of participants experienced >5 HSRs to platinum and taxane per year. Premedication and a new attempt with platinum or taxane chemotherapy were used in 84.8% and 92.5% of Grade 1-2 HSRs to platinum and taxane, respectively. In contrast, desensitization was used in 49.4% and 41.8% of Grade 3-4 HSRs to platinum and taxane, respectively. Most participants strongly emphasized the need to standardize the management of platinum and taxane HSRs in gynecologic cancer. Our study showed that HSRs in gynecologic cancer are common, but management is variable and the use of desensitization is low. In addition, the need for guidance on the management of platinum- and taxane-induced HSRs in gynecologic cancer was highlighted.

Pelvic Pain of Myofascial Origin in Women: Correlation with Lower Urinary Tract Symptoms.

Introduction: Women with lower urinary tract symptoms (LUTS) and high-tone pelvic floor often experience pain and have positive trigger points upon pelvic floor examination. However, the correlation of these findings has not yet been systematically examined and sufficiently understood. The aim of this cross-sectional study is to examine the correlation of pelvic myofascial pain with LUTS and pelvic floor tone. Materials and Methods: All participants filled a standardized pelvic floor questionnaire to assess LUTS, which consists of a total of 43 questions regarding bladder, bowel, and sexual function as well as prolapse symptoms. Myofascial trigger points in different muscle groups including pubococcygeus, iliococcygeus, and obturator as well as pelvic floor muscle tone were assessed using a standardized digital examination technique. Results: 110 women were included in the study. There was a significant correlation between pain in various muscle groups and LUTS as well as high-tone pelvic floor muscle. A significant correlation could also be found between high pelvic floor muscle tone and the overall questionnaire score (p < 0.001) as well as the bladder function score (p < 0.001) and various pain scores of the different groups. Individuals with high-tone pelvic floor were more likely to have more LUTS and higher pain scores. Conclusions: The existence of myofascial pelvic floor trigger points and high pelvic floor muscle tone seem to be reflective of pelvic floor symptoms, as assessed with a standardized pelvic floor questionnaire.

De novo detection of somatic variants in long-read single-cell RNA sequencing data.

In cancer, genetic and transcriptomic variations generate clonal heterogeneity, possibly leading to treatment resistance. Long-read single-cell RNA sequencing (LR scRNA-seq) has the potential to detect genetic and transcriptomic variations simultaneously. Here, we present LongSom, a computational workflow leveraging LR scRNA-seq data to call de novo somatic single-nucleotide variants (SNVs), copy-number alterations (CNAs), and gene fusions to reconstruct the tumor clonal heterogeneity. For SNV calling, LongSom distinguishes somatic SNVs from germline polymorphisms by reannotating marker gene expression-based cell types using called variants and applying strict filters. Applying LongSom to ovarian cancer samples, we detected clinically relevant somatic SNVs that were validated against single-cell and bulk panel DNA-seq data and could not be detected with short-read (SR) scRNA-seq. Leveraging somatic SNVs and fusions, LongSom found subclones with different predicted treatment outcomes. In summary, LongSom enables de novo SNVs, CNAs, and fusions detection, thus enabling the study of cancer evolution, clonal heterogeneity, and treatment resistance.

Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer.

Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.

Comparison of different suture techniques for laparoscopic vaginal cuff closure.

Laparoscopic hysterectomy is a commonly performed procedure. However, one high-risk complication is vaginal cuff dehiscence. Currently, there is no standardization regarding thread material or suturing technique for vaginal cuff closure. Therefore, this study aimed to compare extracorporeal and intracorporeal suturing techniques for vaginal cuff closure using a pelvic trainer model. Eighteen experts in laparoscopic surgery performed vaginal cuff closures with interrupted sutures using intracorporeal knotting, extracorporeal knotting and continuous, unidirectional barbed sutures. While using an artificial tissue suturing pad in a pelvic trainer, experts performed vaginal cuff closure using each technique according to block randomization. Task completion time, tension resistance, and the number of errors were recorded. After completing the exercises, participants answered a questionnaire concerning the suturing techniques and their performance. Experts completed suturing more quickly (p < 0.001, p < 0.001, respectively) and with improved tension resistance (p < 0.001, p < 0.001) when using barbed suturing compared to intracorporeal and extracorporeal knotting. Furthermore, the intracorporeal knotting technique was performed faster (p = 0.04) and achieved greater tension resistance (p = 0.023) compared to extracorporeal knotting. The number of laparoscopic surgeries performed per year was positively correlated with vaginal cuff closure duration (p = 0.007). Barbed suturing was a time-saving technique with improved tension resistance for vaginal cuff closure.

Comparison of 2D 4K vs. 3D HD laparoscopic imaging systems in bariatric surgery: study protocol for a randomized controlled prospective trial.

BACKGROUND: Vision is an important and defining element of laparoscopy and significantly affects the outcome of surgery in terms of time, error, and precision. Several new imaging systems have become available for laparoscopic surgery, including three-dimensional (3D) high-definition (HD) and two-dimensional (2D) ultra-high-resolution (4K) monitors. 3D HD systems offer a number of potential benefits to surgeons and patients over traditional 2D systems, including reduced operating time, blood loss, and hospital stay. However, the performance of 3D systems against the new, ultra-high definition 4K systems is barely known and highly controversial. There is a paucity of studies comparing them in clinical settings. The aim of this study is to compare 2D 4K and 3D HD perspectives in gastric bypass surgery. METHODS: Forty-eight patients with an indication for gastric bypass will be randomized to receive laparoscopic gastric bypass surgery using either 2D 4K or 3D HD systems. The operations will be performed by a well-coordinated team of three senior surgeons. The primary outcome is operative time. Secondary outcomes include intraoperative complications, blood loss, operator workload as assessed by the validated Surg-TLX questionnaire, and postoperative complications according to the Clavien-Dindo classification. An interim analysis is planned after enrollment of 12 participants for each group. DISCUSSION: This prospective, randomized trial is designed to test the hypothesis that the use of a 3D HD system will result in a significant improvement in operative time compared to a 2D 4K system in bariatric surgery. The objective is to provide clinical evidence for new laparoscopic imaging systems and to evaluate potential benefits. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov under the identifier NCT05895058. Registered 30 May 2023. BASEC2023-D0014 [Registry ID Swissethics, approved 3 May 2023]. SNCTP000005489 [SNCTP study register, last updated 13 July 2023].

Intracorporeal vs. extracorporeal open and closed knot tying techniques in laparoscopy: A randomized, controlled study.

Objective: Tying knots during suturing is one of the most challenging tasks in laparoscopic surgery. Therefore, measures aimed at ensuring both the ease and speed of knot tying not only benefit the surgeon but can also reduce operating time significantly. This study compared extracorporeal and intracorporeal knot tying techniques using a Szabo pelvic trainer model from the Gynaecological Endoscopic Surgical Education and Assessment program. Design: The students tied intra- and extracorporeal knots using closed- and open-jaw knot pushers. Using an artificial tissue suturing pad in a certified Szabo pelvic trainer, students tied three knots using each technique according to block randomization. Task completion time, knot strength, knot-spread ability, and number of errors were recorded. The Wilcoxon test and mixed-effects models were used to analyze the results. After completing the exercises, participants answered a questionnaire concerning knot-tying techniques and their performance. Setting: University Hospital Basel, which provides tertiary-level clinical care. Participants: Fifty-seven medical students with no experience in laparoscopy voluntarily signed up for this study. Results: Open and closed extracorporeal knot tying was significantly faster (p < 0.001, p < 0.001, respectively), more precise (p = 0.007, p = 0.003), and associated with reduced knot-spread ability (p < 0.001, p < 0.001) compared to intracorporeal knot tying. Open- and closed-jaw knot pushers were shown to be equal in terms of speed (p = 0.563), knot-spread ability (p = 0.49), and precision (p = 0.831). The study participants rated open (30 %) and closed (49 %) extracorporeal knot tying as more intuitive than intracorporeal (21 %) knot tying. Improved concentration was significantly correlated with tighter knots (p = 0.011). Conclusions: Students achieved significantly better results using extracorporeal knot-tying techniques than intracorporeal ones, including greater speed, tighter knots, and optimized precision. These results suggest that beginners in the field of laparoscopy should be encouraged to practice extracorporeal knot-tying techniques.

Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria, Swiss AGO, BGOG, CEEGOG, GEICO, and SFOG regarding the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer.

An international joint statement about the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer was published in 2016, warning about the uncritical use of HIPEC outside controlled studies. This statement has now been updated after the most recent literature was reviewed by the participating study groups and societies. HIPEC became a treatment option in patients with advanced colon cancer after positive results of a randomized trial comparing surgery and HIPEC versus palliative treatment alone. Although this trial did not compare the added value of HIPEC to surgery alone, HIPEC for the treatment of peritoneal metastases was in the subsequent years generalized to many other cancer types associated with peritoneal carcinomatosis including epithelial ovarian cancer (EOC). In the meantime, new evidence from prospective randomized trials specifically for EOC-patients emerged, with however contradicting results and several quality aspects that made the interpretation of their findings critical. Moreover, three additional trials in colorectal cancer failed to confirm the previously presumed survival benefit through the implementation of HIPEC in peritoneally disseminated colorectal cancers. Based on a still unclear and inconsistent landscape, the authors conclude that HIPEC should remain within the remit of clinical trials for EOC-patients. Available evidence is not yet sufficient to justify its broad endorsement into the routine clinical practice.

Desensitization in patients with hypersensitivity to platinum and taxane in gynecological cancers.

BACKGROUND: Exposure to paclitaxel and carboplatin has the risk of developing hypersensitivity reactions (HSRs), which could necessitate using less effective treatments to avoid anaphylaxis. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen; therefore, this study investigated rates and benefits of successful desensitization in patients with gynecologic cancers (GC). METHODS: We collected data from 241 patients with GC who had at least one cycle of platinum or taxane chemotherapy. The rate of HSRs and successful desensitization were evaluated, and an outcome analysis was conducted. RESULTS: The rate of HSRs to platinum and taxane was 6.39% and 13.07%, respectively. We observed a 100% success rate of desensitization in our cohort. Patients with HSR were significantly younger (57.1 vs. 64.9 years, p = 0.030) in the taxane cohort. Importantly, the overall survival (OS) of patients with platinum and taxane HSRs who underwent desensitization was comparable to that of patients with no HSRs (platinum vs. controls; median OS 60.36 vs. 60.39 months, p = 0.31; taxane vs. controls; OS 80.29 vs. 60.00 months, p = 0.59). CONCLUSION: Thus, we show that desensitization for platinum and taxane HSRs is safe and effective, resulting in an outcome that is well comparable to patients without HSR. Based on these observations, desensitization procedures might be considered as standard of care before switching to less effective treatment for patients with GC.

Side Effects from Cancer Therapies and Perspective of 1044 Long-Term Ovarian Cancer Survivors-Results of Expression VI-Carolin Meets HANNA-Holistic Analysis of Long-Term Survival with Ovarian Cancer: The International NOGGO, ENGOT, and GCIG Survey.

The aim of this survey was to increase the knowledge on the characteristics and health concerns of long-term survivors (LTS; survival > 5 years) after ovarian cancer in order to tailor follow-up care. This international survey was initiated by the NOGGO and was made available to members of ENGOT and GCIG. The survey is anonymous and consists of 68 questions regarding sociodemographic, medical (cancer) history, health concerns including distress, long-term side effects, and lifestyle. For this analysis, 1044 LTS from 14 countries were recruited. In total, 58% were diagnosed with FIGO stage III/IV ovarian cancer and 43.4% developed recurrent disease, while 26.0% were receiving cancer treatment at the time of filling in the survey. LTS who survived 5-10 years self-estimated their health status as being significantly worse than LTS who survived more than 10 years (p = 0.034), whereas distress also remained high 10 years after cancer diagnosis. Almost half of the cohort (46.1%) reported still having symptoms, which were mainly lymphedema (37.7%), fatigue (23.9%), pain (21.6%), polyneuropathy (16.9%), gastrointestinal problems (16.6%), and memory problems (15.5%). Almost all patients (94.2%) regularly received follow-up care. Specialized survivorship care with a focus on long-term side effects, lifestyle, and prevention should be offered beyond the typical five years of follow-up care.

Detection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in ovarian cancer.

Understanding the complex background of cancer requires genotype-phenotype information in single-cell resolution. Here, we perform long-read single-cell RNA sequencing (scRNA-seq) on clinical samples from three ovarian cancer patients presenting with omental metastasis and increase the PacBio sequencing depth to 12,000 reads per cell. Our approach captures 152,000 isoforms, of which over 52,000 were not previously reported. Isoform-level analysis accounting for non-coding isoforms reveals 20% overestimation of protein-coding gene expression on average. We also detect cell type-specific isoform and poly-adenylation site usage in tumor and mesothelial cells, and find that mesothelial cells transition into cancer-associated fibroblasts in the metastasis, partly through the TGF-ß/miR-29/Collagen axis. Furthermore, we identify gene fusions, including an experimentally validated IGF2BP2::TESPA1 fusion, which is misclassified as high TESPA1 expression in matched short-read data, and call mutations confirmed by targeted NGS cancer gene panel results. With these findings, we envision long-read scRNA-seq to become increasingly relevant in oncology and personalized medicine.

High negative prediction for the Basel sarcoma score: Sonographic assessment of features suspicious of uterine sarcoma.

INTRODUCTION: In the management of uterine myomas, laparoscopic surgery with morcellation enables a minimal invasive procedure. Cases of unsuspected uterine sarcoma dissemination have been reported and led to regulative restrictions. To help to distinguish preoperatively myomas from sarcomas, we assessed the value of six sonographic criteria (Basel Sarcoma Score, BSS) in a prospective outpatient cohort of consecutive patients with uterine masses. MATERIAL AND METHODS: We prospectively evaluated all patients presenting with myoma-like masses planned for surgery with standardized ultrasound examination. BSS including the following criteria was investigated: rapid growth in past three months, high blood flow, atypical growth, irregular lining, central necrosis and oval solitary lesion. For each criterion, a score 0/1 was given. BSS (0-6) equals the sum of all given scores. Histological diagnosis was used as reference. RESULTS: Among 545 patients, 522 had the final diagnosis of myoma, 16 had peritoneal masses with sarcomatous components (PMSC), and seven had other malignancies. Median BSS for PMSC was 2.5 (range: 0-4) vs 0 for myomas (range: 0-3). The most common sonographic criteria leading to a false positive score in myomas were rapid growth in past three months and high blood flow. For the detection of sarcomatous masses with BSS threshold of >1, sensitivity was 93.8%, specificity 97.9%, and positive predictive value (PPV) and negative predictive value (NPV) were 57.7% and 99.8%, respectively (AUC 0.95). CONCLUSION: BSS can help distinguishing between myomas and sarcomatous masses, with high NPV. Caution is required when >1 criterion is present. As a simple tool, it could easily be integrated into routine myoma sonographic examination and help develop standardized assessment of uterine masses for better preoperative triage.

Contralateral lymph node metastasis in recurrent ipsilateral breast cancer with Lynch syndrome: a locoregional event.

INTRODUCTION: Contralateral axillary lymph node metastasis (CALNM) in breast cancer (BC) is considered a distant metastasis, marking stage 4cancer. Therefore, it is generally treated as an incurable disease. However, in clinical practice, staging and treatment remain controversial due to a paucity of data, and the St. Gallen 2021 consensus panel recommended a curative approach in patients with oligometastatic disease. Aberrant lymph node (LN) drainage following previous surgery or radiotherapy is common. Therefore, CALNM may be considered a regional event rather than systemic disease, and a re-sentinel procedure aided by lymphoscintigraphy permits adequate regional staging. CASE REPORT: Here, we report a 37-year-old patient with Lynch syndrome who presented with CALNM in an ipsilateral relapse of a moderately differentiated invasive ductal BC (ER 90%, PR 30%, HER2 negative, Ki-67 25%, microsatellite stable), 3 years after the initial diagnosis. Lymphoscintigraphy detected a positive sentinel LN in the contralateral axilla despite no sign of LN involvement or distant metastases on FDG PET/CT or MRI. The patient underwent bilateral mastectomy with sentinel node dissection, surgical reconstruction with histological confirmation of the CALNM, left axillary dissection, adjuvant chemotherapy, and anti-hormone therapy. In addition to her regular BC follow-up visits, the patient will undergo annual colonoscopy, gastroscopy, abdominal, and vaginal ultrasound screening. In January 2023, the patient was free of progression for 23 months after initiation of treatment for recurrent BC and CALNM. CONCLUSION: This case highlights the value of delayed lymphoscintigraphy and the contribution of sentinel procedure for local control in the setting of recurrent BC. Aberrant lymph node drainage following previous surgery may be the underlying cause of CALNM. We propose that CALNM without evidence of systemic metastasis should be considered a regional event in recurrent BC, and thus, a curative approach can be pursued. The next AJCC BC staging should clarify the role of CALNM in recurrent BC to allow for the development of specific treatment guidelines.

A 3D multi-cellular tissue model of the human omentum to study the formation of ovarian cancer metastasis.

Reliable and predictive experimental models are urgently needed to study metastatic mechanisms of ovarian cancer cells in the omentum. Although models for ovarian cancer cell adhesion and invasion were previously investigated, the lack of certain omental cell types, which influence the metastatic behavior of cancer cells, limits the application of these tissue models. Here, we describe a 3D multi-cellular human omentum tissue model, which considers the spatial arrangement of five omental cell types. Reproducible tissue models were fabricated combining permeable cell culture inserts and bioprinting technology to mimic metastatic processes of immortalized and patient-derived ovarian cancer cells. The implementation of an endothelial barrier further allowed studying the interaction between cancer and endothelial cells during hematogenous dissemination and the impact of chemotherapeutic drugs. This proof-of-concept study may serve as a platform for patient-specific investigations in personalized oncology in the future.

Low grade serous ovarian cancer - A rare disease with increasing therapeutic options.

High-grade serous ovarian cancers (HGSOCs) most commonly arise from the fimbrial end of the fallopian tube and harbor TP53 gene mutations. In contrast, low-grade serous ovarian cancers (LGSOCs) appear to have different pathological, epidemiological, and clinical features and should be seen as a distinct serous epithelial ovarian cancer subtype. Our current understanding of LGSOC is limited, and treatment has generally been derived from the more common HGSOCs due to a lack of separate trial data. LGSOCs are characterized by slow tumor growth and are assumed to develop from serous borderline ovarian tumors as precursors. These cancers are often estrogen-receptor positive and show an activated mitogen-activated protein kinase pathway together with KRAS and BRAF mutations and, rarely, TP53 mutations. These characteristics are now commonly used to guide therapeutical decision making and, consequently, a substantial part of treatment consists of maintenance with endocrine treatment, thus balancing disease stabilization and mild toxicity. Additionally, new trials are ongoing that examine the role of targeted therapies such as MEK inhibitors in combination with endocrine treatments. The purpose of this work is to summarize current knowledge and present ongoing trial efforts for LGSOCs.

MyCTC chip: microfluidic-based drug screen with patient-derived tumour cells from liquid biopsies.

Cancer patients with advanced disease are characterized by intrinsic challenges in predicting drug response patterns, often leading to ineffective treatment. Current clinical practice for treatment decision-making is commonly based on primary or secondary tumour biopsies, yet when disease progression accelerates, tissue biopsies are not performed on a regular basis. It is in this context that liquid biopsies may offer a unique window to uncover key vulnerabilities, providing valuable information about previously underappreciated treatment opportunities. Here, we present MyCTC chip, a novel microfluidic device enabling the isolation, culture and drug susceptibility testing of cancer cells derived from liquid biopsies. Cancer cell capture is achieved through a label-free, antigen-agnostic enrichment method, and it is followed by cultivation in dedicated conditions, allowing on-chip expansion of captured cells. Upon growth, cancer cells are then transferred to drug screen chambers located within the same device, where multiple compounds can be tested simultaneously. We demonstrate MyCTC chip performance by means of spike-in experiments with patient-derived breast circulating tumour cells, enabling >95% capture rates, as well as prospective processing of blood from breast cancer patients and ascites fluid from patients with ovarian, tubal and endometrial cancer, where sensitivity to specific chemotherapeutic agents was identified. Together, we provide evidence that MyCTC chip may be used to identify personalized drug response patterns in patients with advanced metastatic disease and with limited treatment opportunities.

Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II-IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial.