Serous Carcinoma Research Articles

Serous Ovarian Carcinoma: Detailed Analysis of Clinico-Pathological Characteristics as Prognostic Factors.

Serous ovarian carcinoma (SOC) is the most common subtype of epithelial ovarian cancer, with high-grade (HGSOC) and low-grade (LGSOC) subtypes presenting distinct clinical behaviours. This study aimed to evaluate histopathologic features in SOC, correlating these with prognostic outcomes, and explore the potential clinical implications. We analysed 51 SOC cases for lymphovascular space invasion (LVSI), tumour border configuration (TBC), microvessel density (MVD), tumour budding (TB), the tumour-stroma ratio (TSR), the stromal type, tumour-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs). A validation cohort of 54 SOC cases from The Cancer Genome Atlas (TCGA) was used for comparison. In the discovery set, significant predictors of aggressive behaviour included LVSI, high MVD, high TB, and low TILs. These findings were validated in the validation set where the absence of TLSs, lower peritumoural TILs, immature stromal type, and low TSR were associated with worse survival outcomes. The stromal type was identified as an independent prognostic predictor in SOC across both datasets. Inter-observer variability analysis demonstrated substantial to almost perfect agreement for these features, ensuring the reproducibility of the findings. The histopathological evaluation of immune and stromal features, such as TILs, TLSs, TB, TSR, and stromal type, provides critical prognostic information for SOC. Incorporating these markers into routine pathological assessments could enhance risk stratification and guide treatment, offering practical utility, particularly in low-resource settings when molecular testing is not feasible.

A Comprehensive Review of TRPS1 as a Diagnostic Immunohistochemical Marker for Primary Breast Carcinoma: Latest Insights and Diagnostic Pitfalls.

Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility.

Assessing the impact of deep-learning assistance on the histopathological diagnosis of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes.

In recent years, it has become clear that artificial intelligence (AI) models can achieve high accuracy in specific pathology-related tasks. An example is our deep-learning model, designed to automatically detect serous tubal intraepithelial carcinoma (STIC), the precursor lesion to high-grade serous ovarian carcinoma, found in the fallopian tube. However, the standalone performance of a model is insufficient to determine its value in the diagnostic setting. To evaluate the impact of the use of this model on pathologists' performance, we set up a fully crossed multireader, multicase study, in which 26 participants, from 11 countries, reviewed 100 digitalized H&E-stained slides of fallopian tubes (30 cases/70 controls) with and without AI assistance, with a washout period between the sessions. We evaluated the effect of the deep-learning model on accuracy, slide review time and (subjectively perceived) diagnostic certainty, using mixed-models analysis. With AI assistance, we found a significant increase in accuracy (p < 0.01) whereby the average sensitivity increased from 82% to 93%. Further, there was a significant 44 s (32%) reduction in slide review time (p < 0.01). The level of certainty that the participants felt versus their own assessment also significantly increased, by 0.24 on a 10-point scale (p < 0.01). In conclusion, we found that, in a diverse group of pathologists and pathology residents, AI support resulted in a significant improvement in the accuracy of STIC diagnosis and was coupled with a substantial reduction in slide review time. This model has the potential to provide meaningful support to pathologists in the diagnosis of STIC, ultimately streamlining and optimizing the overall diagnostic process.

Histology-Proven Gastrointestinal Metastasis from Nongastrointestinal Malignancies: Experience of This Rare Occurrence in a Single Center

Introduction Lymph nodes, lung, liver, bone, and brain are the commonest metastatic sites for malignancies arising in various body sites. Gastrointestinal (GI) tract is a very uncommon metastatic site and the present study describes the single-center experience of GI metastases from non-GI malignancies. Aims and Objectives To study the spectrum of metastatic tumors to GI tract and elucidate their clinicopathological characteristics. Materials and Methods This was a retrospective study done on cases diagnosed from 2015 to 2023 at our institute. All cases of non-GI malignancies metastatic to hollow GI tract were included. Cases with GI primary, hematological malignancies, cases with exclusive serosal deposits, and direct invasion of a GI organ from an adjacent primary tumor were excluded. Apart from hematoxylin &amp; eosin (H&amp;E)-stained slides, immunohistochemistry findings of these were reviewed. Results Thirty-six patients were histologically proven GI metastases from non-GI malignancies diagnosed during the study period. Most cases were seen in 5th to 7th decade with a significant female preponderance (M:F of 1:8). The commonest metastatic GI sites were small bowel (n = 11), sigmoid colon (n = 9), and rectum (n = 7), followed by stomach (n = 3), appendix (n = 3), gall bladder (n = 2), and ampulla (n = 1). Stricture, perforation, and nodular mucosa were the most common endoscopic findings. The most common primary malignancies in females were ovarian serous carcinoma (n =21) followed by squamous cell carcinoma (SCC) of cervix (n = 8). In males, there was no site preference, and the primary sites included prostate, lung, kidney, and oral mucosa. Conclusion The study highlights the rare occurrence of GI metastases from non-GI malignancies. Females are at greater risk of such metastases primarily from ovarian serous carcinoma and cervical SCCs.

Borderline tumours of the ovary: A 37-year experience at a tertiary referral centre.

Borderline ovarian tumours (BOT) are a common epithelial ovarian tumours. Typically diagnosed at an early stage with a good prognosis, many BOT are treated conservatively. Recurrence is common. This update to our last audit in 1997 represents one of the largest audits of BOT to date. All patients with BOT managed at 'the hospital' from 1984 to 2021 were included. Expert pathology review was available. There were 549 cases included. The recurrence rate was 5% (n = 29/549) with 1.4% (n = 8/549) undergoing malignant transformation. Three of the eight women who recurred as cancer died from their disease. Frozen section was predictive of histologic diagnosis in 92% (n = 55/60) of serous tumours (SBOT), but only 62% (n = 54/87) of mucinous tumours (MBOT). In MBOT where the appendix appeared normal intra-operatively, it was histologically benign in all cases (n = 63). In SBOT, the recurrence rate was 5/23 (22%), 12/52 (23%), 1/29 (3%) and 3% (P = <0.01) for unilateral cystectomy, unilateral oophorectomy ± cystectomy, bilateral oophorectomy, and bilateral oophorectomy with hysterectomy, respectively, as index procedure. In MBOT this correlated to 2/20 (10%), 3/93 (3%), 0 and 1/58 (2%), respectively. This study describes important information correlating first surgical procedure and fertility-sparing surgery to recurrence and malignant transformation. For all BOT subtypes, fertility-preserving surgery increased the risk of recurrence and hysterectomy was not superior to removal of both ovaries. In MBOT, frozen section is of limited utility and the macroscopically normal appendix is very unlikely to be anything but benign, if MBOT is the true histologic diagnosis.

MECOM Locus classical transcript isoforms affect tumor immune microenvironment and different targets in ovarian cancer

The MECOM locus is a gene frequently amplified in high-grade serous ovarian carcinoma (HGSOC). Nevertheless, the body of research examining the associations among MECOM transcripts, patient prognosis, and their role in modulating the tumor immune microenvironment (TIME) remains sparse, particularly in large cohorts. This study assessed the expression of MECOM transcripts in 352 HGSOC patients and 88 normal ovarian tissues from the combined GTEx/TCGA database. Using resources such as the UCSC Genome Browser, Ensembl, and NextProt, two transcripts corresponding to classical protein isoforms from MECOM were identified. Cox proportional hazards regression analysis, Kaplan-Meier survival curves, and a comprehensive TIME evaluation algorithm were employed to elucidate the connections between the expression levels of these transcripts and both patient prognosis and TIME status. Chromatin Immunoprecipitation sequencing (ChIP-seq) data for the two protein isoforms, as well as RNA sequencing data post-targeted silencing, were analyzed to identify potential regulatory targets of the different transcription factors. Elevated expression of the MECOM isoform transcripts was correlated with poorer survival in HGSOC patients, potentially through the modulation of cancer-associated fibroblasts (CAFs) and immunosuppressive cell populations. In contrast, higher levels of EVI1 isoform transcripts were linked to enhanced survival, possibly due to the regulation of CD8+ T cells, macrophages, and a reduction in the expression of JUN protein, or its DNA-binding activity on downstream genes. Diverse protein isoforms derived from MECOM were found to differentially affect the survival and tumor development in ovarian cancer patients through specific mechanisms. Investigating the molecular mechanisms underlying disease pathogenesis and identifying potential drug target proteins at the level of splice variant isoforms were deemed crucial.

Prognostic Significance of Chemotherapy Response Score in Patients Undergoing Interval Debulking Surgery and Attained Complete Cytoreduction for High-Grade Serous Tubal and Ovarian Carcinoma

Objectives The chemotherapy response score (CRS) has been described to assess the pathological response to chemotherapy in patients with high-grade serous tubal and ovarian carcinoma. The main aim of this study was to assess the prognostic significance of CRS in patients who underwent interval debulking surgery and attained complete cytoreduction. Materials and Methods A retrospective study was conducted on patients with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIIC and IV high-grade serous tubal and ovarian carcinomas who had undergone surgery after three to four cycles of neoadjuvant chemotherapy and attained complete cytoreduction from January 2015 to July 2018. Results A total of 125 patients were included in the study. The median age of the patients was 52 years. There were 21 patients (16.8%) with a CRS of 1, 53 patients (42.4%) with a CRS of 2, and 51 (40.8%) patients with a CRS of 3. The median follow-up period was 77 months. The CRS applied on the omental samples showed significant correlation with progression-free survival (PFS; CRS of 1 vs. 2: median PFS, 17 vs. 22 months; hazard ratio, 1.73; and CRS of 2 vs. 3: median PFS, 22 vs. 54 months; hazard ratio, 2.32) and overall survival (OS; CRS of 1 vs. 2: median OS, 19 vs. 40 months; hazard ratio, 2.13; CRS of 2 vs. 3: median OS, 40 months vs. not reached; hazard ratio, 2.19). Conclusion Our study confirms that the omental CRS is significantly associated with PFS and OS in patients who attained complete cytoreduction during interval debulking surgery.

The Diversity of Methylation Patterns in Serous Borderline Ovarian Tumors and Serous Ovarian Carcinomas.

Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa.

HIPEC as Up-Front Treatment in Locally Advanced Ovarian Cancer

Purpose: The main objective of the study is to evaluate the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of naïve ovarian cancer women undergoing complete or near-complete cytoreduction by assessing the overall survival, the disease-specific survival, and the disease-free survival. The secondary objective is the identification of prognostic indicators of survival and recurrence of these patients. Patients—Methods: Retrospective study of treatment in naïve women with locally advanced ovarian cancer treated with cytoreductive surgery (CRS) and HIPEC and compared with those who were treated with cytoreduction alone. Clinicopathologic variables were correlated to overall survival, disease-specific survival, and disease-free survival using Kaplan–Meier method, and the multivariate Cox proportional hazards regression models. Results: 5- and 10-year overall survival, disease-specific survival, and disease-free survival rates were significantly higher in patients treated with CRS and HIPEC. These patients were 67% less likely to die from any cause (adjusted hazard ratio, aHR = 0.33, p = 0.001), 75% less likely to die from cancer (aHR = 0.25, p = 0.003), and 46% less likely to develop recurrence (aHR = 0.54, p = 0.041) compared to patients treated with CRS alone. Moreover, the poor performance status (aHR = 2.96, p &lt; 0.001), the serous carcinomas (aHR = 0.14, p = 0.007), and the morbidity (aHR = 6.87, p &lt; 0.001) were identified as independent indicators of poor overall survival. The degree of differentiation (aHR = 8.64, p = 0.003) was identified as the independent indicator of disease-specific survival (aHR = 4.13, p = 0.002), while the extent of peritoneal carcinomatosis (aHR = 2.32, p &lt; 0.001) as the independent indicator of disease-free survival. Conclusions: Treatment in naïve patients with locally advanced ovarian cancer undergoing CRS plus HIPEC appears to have improved overall, disease-specific, and disease-free survival.

Real-life treatment patterns and time to next treatment among patients with ovarian cancer in the pre-PARP inhibitor era: the OCRWE-Finland Study.

As the treatment landscape for advanced ovarian cancer (OC) evolves, it is important to understand patient outcomes in real-world clinical practice. OCRWE-Finland was an observational cohort study investigating OC outcomes, including treatment patterns, time to next treatment 1 (TTNT1), overall survival and healthcare resource utilisation, in Finland during the pre-PARPi era. Patients included in OCRWE-Finland were diagnosed with OC between 2014 and 2019. Here, we report treatment patterns and TTNT1 outcomes (as a surrogate for progression-free survival) for patients in the high-grade serous ovarian carcinoma (HGSOC) cohort. In OCRWE-Finland, there were 867 patients with HGSOC. Of the 811 patients who received first-line treatment, the most common regimen was surgery and adjuvant chemotherapy (53%), and 227 patients also received first-line bevacizumab. Median TTNT1 among 623 patients with stage III/IV disease was 19 months (95% confidence interval, 18-21 months), with no difference between patients with stage III or IV disease (p = 0.24). The presence versus absence of visible residual disease post-debulking surgery was associated with shorter TTNT1 among patients with stage III tumours (p = 0.031) but showed no impact for stage IV tumours (p = 0.55). First-line versus no first-line bevacizumab was associated with shorter TTNT1 among stages I-IV (p < 0.0001) but did not affect patients with stage III/IV tumours (p = 0.45). In the pre-PARPi era, prognosis for advanced OC was poor, particularly for patients with stage III tumours and visible residual disease or stage IV tumours regardless of the presence of residual disease. The increasing use of PARPis will hopefully help address the need for effective treatments in advanced OC.

Developing a DNA Methylation Signature to Differentiate High-Grade Serous Ovarian Carcinomas from Benign Ovarian Tumors.

Epithelial ovarian cancer (EOC) represents a significant health challenge, with high-grade serous ovarian cancer (HGSOC) being the most common subtype. Early detection is hindered by nonspecific symptoms, leading to late-stage diagnoses and poor survival rates. Biomarkers are crucial for early diagnosis and personalized treatment OBJECTIVE: Our goal was to develop a robust statistical procedure to identify a set of differentially methylated probes (DMPs) that would allow differentiation between HGSOC and benign ovarian tumors. Using the Infinium EPIC Methylation array, we analyzed the methylation profiles of 48 ovarian samples diagnosed with HGSOC, borderline ovarian tumors, or benign ovarian disease. Through a multi-step statistical procedure combining univariate and multivariate logistic regression models, we aimed to identify CpG sites of interest. We discovered 21 DMPs and developed a predictive model validated in two independent cohorts. Our model, using a distance-to-centroid approach, accurately distinguished between benign and malignant disease. This model can potentially be used in other types of sample material. Moreover, the strategy of the model development and validation can also be used in other disease contexts for diagnostic purposes.

Prevalence and outcomes of germline pathogenic variants of homologous recombination repair genes in ovarian cancer.

Germline pathogenic variants (PVs) are pivotal in gynecological oncology. We focused on the prevalence, clinicopathological features, and survival impact of homologous recombination repair (HRR) PVs in patients with epithelial ovarian cancer (EOC). This was a multicenter retrospective cohort study, and 1248 patients with EOC were registered. Eligible patients (n = 1112) underwent germline DNA analysis for 26 cancer predisposition genes, including nine HRR-related genes, such as BRCA1/2, BRIP1, PALB2, RAD51C/D, and ATM. The associations between clinicopathological factors and HRR-related PVs were examined. Kaplan-Meier and Cox regression analyses were conducted. Among 1091 analyzed patients, 153 (14.0%) carried PVs and 140 (12.8%) were HRR-related. HRR-PV-positive status significantly correlated with serous carcinoma (22.9% vs. 4.8%, P < 0.0001) and advanced disease (18.5% vs. 5.9%, P < 0.0001). The HRR-PV-positive group exhibited higher prevalence of personal breast (12.9%) and familial breast/ovarian (29.2%) cancer history. HRR status independently improved overall survival in stage III/IV disease (P = 0.04) but not progression-free survival. HRR-related germline PVs exhibit distinct clinicopathological features with survival implications. Variants were significantly associated with serous carcinoma and advanced disease, underscoring the importance of genetic testing to develop individualized EOC treatment strategies. Considering the study period (2000-2019), the limited use of bevacizumab and poly (ADP-ribose) polymerase inhibitors as maintenance therapy should be recognized.

Early Genetic Divergence of High-Grade Carcinomas Originating from Low-Grade Serous Ovarian Neoplasms

The current paradigm implicates a fallopian tube precursor as the origin of most ovarian high-grade serous carcinomas (HGSCs). However, a rare subset of HGSCs develop via a distinct pathway from low-grade serous ovarian neoplasms (namely, serous borderline tumors and low-grade serous carcinoma). This alternate pathway for the development of HGSC and other poorly differentiated carcinomas of the ovary is not well understood. To elucidate the molecular pathogenesis and evolutionary trajectory of histologic transformation of low-grade serous neoplasms, we performed whole exome sequencing on microdissected low-grade and higher-grade components from 7 cases of serous borderline tumor or low-grade serous carcinoma associated with a synchronous or metachronous indeterminate/high-grade carcinoma. In most cases, there were relatively few somatic mutations shared between matched low-grade and higher-grade tumors compared with private mutations specific to each component (ie, phylogenetic trees with short trunks and long branches). Truncal mutations, present across all tumor samples from a given patient, included known drivers of low-grade serous neoplasms: KRAS (G12D, n = 4), BRAF (G469A, n = 1), NF2 (n = 1), and USP9X (n = 1). Transformation to HGSC was associated with a TP53 mutation with bi-allelic inactivation in 3 cases, all with severe nuclear atypia, and associated with genome-wide copy number alterations and allelic imbalances. TP53-wildtype tumors comprised a morphologic spectrum, which included indeterminate-grade serous carcinomas with moderate nuclear atypia and high mitotic activity, although lacking extensive chromosomal instability (n = 2) and poorly differentiated carcinomas (n = 2, including a high-grade Mullerian carcinoma and an undifferentiated carcinoma with sarcomatoid features). In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with TP53 mutations, suggests that high-grade transformation may be a relatively early molecular event.

MIR937 amplification potentiates ovarian cancer progression by attenuating FBXO16 inhibition on ULK1-mediated autophagy

High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological cancer. Genetic studies have revealed gene copy number alterations (CNAs) frequently occurred in HGSOC pathogenesis, however the function and mechanism of CNAs for microRNAs are still not fully understood. Here, we show the dependence on gene copy number amplification of MIR937 that enhances cell autophagy and dictates HGSOC proliferative activity. Data mining of TCGA database revealed MIR937 amplification is correlated with increased MIR937 expression and cell proliferation of HGSOC. Deletion of MIR937 in HGSOC cells led to impaired autophagy and retarded cell proliferation, and the extent for its inhibitory effects scaled with the degree of MIR937 copy loss. Rescue assay confirmed miR-937-5p, a mature product of MIR937, was sufficient to restore its oncogenic function. Mechanistically, MIR937 amplification raised the expression of miR-937-5p, enhanced its binding to 3′ UTR of FBXO16 transcript, and thereby restricting FBXO16 degradative effects on ULK1. Our results demonstrate that MIR937 amplification augments cell autophagy and proliferation, and suggest an alternative strategy of MIR937/FBXO16/ULK1 targeting for HGSOC treatment.

Extracellular Vesicle Characteristics in Local Fluid and Plasma Measured by Nanoparticle Tracking Analysis Can Help Differentiate High-Grade Serous Carcinoma from Benign Ovarian Pathology

Background: High-grade serous carcinoma (HGSC) is the most lethal of gynecological cancers in developed countries. It usually presents late with non-specific symptoms and most cases are diagnosed at an advanced stage, with 5-year overall survival being around 40%. Biomarkers for screening and early diagnosis of this aggressive disease are, thus, a research priority. Extracellular vesicles (EVs) that reflect the cell of origin and that can be isolated from local fluid and plasma by minimally invasive liquid biopsy are such promising biomarkers. Besides EV concentration and molecular profile, which have been the main focus of research for many years, recent studies have also called attention to EV size distribution. The aim of our study was to evaluate the potential of EV concentration and size distribution in local fluid and plasma as diagnostic biomarkers for HGSC. Methods: Paired pretreatment ascites and plasma samples from 37 patients with advanced HGSC and paired pretreatment free peritoneal fluid (FPF) and plasma samples from 40 controls with benign ovarian pathology (BOP) were analyzed using nanoparticle tracking analysis (NTA). Results: We observed a significant difference in EV concentration in local fluid, but not in plasma, between HGSC patients and the control group. We also found a significant difference in EV size distribution in both local fluid and plasma between HGSC patients and the control group. The receiver operating characteristics (ROC) curve analysis of EV characteristics showed excellent diagnostic performance for the mode, D10, and D50 in local fluid and acceptable diagnostic performance for EV concentration and mean EV size in local fluid, as well as for the mode and D10 value in plasma. Conclusions: The results of our study show that EV concentration in local fluid and more importantly EV size distribution in both local fluid and plasma are significantly changed in the presence of HGSC. Future research of size-dependent molecular profiling of EVs could help identify novel diagnostic biomarkers for HGSC.

Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.

Imaging in malignant peritoneal neoplasms.

Peritoneal malignancies encompass a diverse range of tumors originating within the peritoneum, including primary tumors such as mesothelioma and primary serous peritoneal carcinoma or secondary tumors resulting from the spread of cancers from gastrointestinal, gynecological, and extra-abdominal sources. The traditional approach of palliative care for these malignancies is being replaced by a multimodal strategies that integrates surgery with systemic or intraperitoneal chemotherapy. Notably, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy has shown significant improvements in survival rates. Imaging is crucial in the multidisciplinary management of these tumors, aiding in diagnosis, staging, restaging, and monitoring therapy response. It is also vital for appropriate patient selection, using the acronym "PAUSE", which involves assessing tumor burden via the peritoneal carcinomatosis index, evaluating patients pre- and post-therapy, detecting complications following therapy, and predicting treatment outcomes. This review explores the imaging manifestations of peritoneal malignancies, distinguishing them from various mimics, and underscores the importance of imaging modalities such as CT, MRI, PET/CT, and PET/MRI in effective decision-making and management.

Uterine carcinosarcomas: A case series of 9 cases from a low-income country.

Uterine carcinosarcomas (UCS) are rare aggressive biphasic tumors classified as a subtype of high-grade uterine carcinomas. However, these tumors have particular histopathological features and clinical behavior with worse prognosis than high-grade uterine carcinomas. The incidence of UCS is increasing and more studies are required to elucidate their clinical and histopathological characteristics. Herein, we report clinicopathological features of 9 cases of UCS in a low-income country. We retrospectively collected all cases of UCS at our Pathology Department over a period of 4 years. The diagnosis was performed on formalin-fixed, paraffin-embedded and hematoxylin and eosin-stained surgical specimens. Nine surgically treated cases of UCS have been registered, representing 12.67% of all uterine malignancies with a mean age of 58.88 years (range: 50-65 years). Abdominal pain and metrorrhagia were the main clinical presentations. The epithelial component of UCS was often a serous carcinoma (66.66%) and patients presented with large tumors (mean size of 9.24 cm, range of 5-19 cm), with advanced FIGO stages (stages III-IV) in 5/9 patients (55.55%). Follow-up data were available in 5/9 patients among which only 2 were alive 2 and 25 months after the surgical treatment (overall survival of 40%). UCS are rare and aggressive uterine tumors with very poor prognosis especially in low-income countries.

Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma

ObjectiveTargeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart. MethodsUsing a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration. ResultsCompared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed. ConclusionsThough less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.

Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones

Intratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in patient cells. Here, we describe a machine learning approach, scTherapy, which leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors. Patient-specific treatments reveal a wide spectrum of co-inhibitors of multiple biological pathways predicted for primary cells from heterogenous cohorts of patients with acute myeloid leukemia and high-grade serous ovarian carcinoma, each with unique resistance patterns and synergy mechanisms. Experimental validations confirm that 96% of the multi-targeting treatments exhibit selective efficacy or synergy, and 83% demonstrate low toxicity to normal cells, highlighting their potential for therapeutic efficacy and safety. In a pan-cancer analysis across five cancer types, 25% of the predicted treatments are shared among the patients of the same tumor type, while 19% of the treatments are patient-specific. Our approach provides a widely-applicable strategy to identify personalized treatment regimens that selectively co-inhibit malignant cells and avoid inhibition of non-cancerous cells, thereby increasing their likelihood for clinical success.