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Article: Non-gestational choriocarcinoma with hyperprogression on pembrolizumab: A case report and review of the literature.

Kazemi, Nazanin Yeganeh / Langstraat, Carrie / John Weroha, S

2022 Volume 39, Page(s) 100923

Abstract: Non-gestational choriocarcinoma is a rare and aggressive germ cell tumor. Here we present the case of a post-menopausal 49-year-old woman who presented with metastatic disease and initially achieved a complete radiographic and biomarker response with ... ...

Abstract	Non-gestational choriocarcinoma is a rare and aggressive germ cell tumor. Here we present the case of a post-menopausal 49-year-old woman who presented with metastatic disease and initially achieved a complete radiographic and biomarker response with seven cycles of EMA-CO chemotherapy. Upon recurrence, she received two separate courses of chemotherapy, initially with paclitaxel/cisplatin/etoposide and later FOLFOX. Tumor analysis revealed 22% PD-L1 positivity (tumor proportion score) and she was treated with pembrolizumab. However, βhCG levels rose abruptly and uncharacteristically through all three cycles of anti-PD1 therapy. The patient developed dyspnea on exertion, cough, and right flank pain. CT imaging demonstrated marked progression of liver metastases and innumerable new pulmonary metastases and the patient died 10 weeks after starting pembrolizumab. Here we describe the clinical presentation and management of this patient, along with analysis of molecular aberrations which could potentially explain hyperprogression in response to pembrolizumab.
Language	English
Publishing date	2022-01-17
Publishing country	Netherlands
Document type	Case Reports
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2022.100923
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Article: High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas.

Kurnit, Katherine C / Steiner, Meghan / Lastra, Ricardo R / Weroha, S John / Cursio, John / Lengyel, Ernst / Fleming, Gini F / Conzen, Suzanne D

Gynecologic oncology reports

2022 Volume 41, Page(s) 100987

Abstract: Glucocorticoid receptor can be associated with poor prognosis among a variety of solid tumors in the absence of other nuclear hormone receptors. Our objective was to characterize differences in glucocorticoid receptor (GR), estrogen receptor (ER), ... ...

Abstract	Glucocorticoid receptor can be associated with poor prognosis among a variety of solid tumors in the absence of other nuclear hormone receptors. Our objective was to characterize differences in glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor expression in the sarcomatous versus carcinomatous components of ovarian and uterine carcinosarcomas. Eighteen patients diagnosed with Mullerian carcinosarcoma between May 2009 and August 2014 were included. Nuclear receptor expression was evaluated by immunohistochemistry using whole tissue specimens. Receptor expression was quantified using the H-score. Mean H-scores were compared between the sarcomatous and carcinomatous components of tumors using Wilcoxon signed-rank tests. We found that GR expression was significantly higher in the sarcomatous components than in the carcinomatous components of the cancers (mean H score 144.4 vs 38.9, p = 0.002). Conversely, ER (3.1 vs 63.1, p = 0.002) and PR (1.7 vs 47.2, p < 0.0001) expression were significantly decreased in the sarcomatous component compared to the carcinomatous component. Androgen receptor expression was low overall (0 versus 2.8, p = 0.04). We hypothesize that GR-high, ER/PR-low expression is associated with epithelial to mesenchymal transition in the sarcomatous cells and may serve as a potential therapeutic target.
Language	English
Publishing date	2022-04-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2022.100987
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Article: Prognostic stratification of endometrial cancers with high microsatellite instability or no specific molecular profile.

Gonzalez-Bosquet, Jesus / Weroha, S John / Bakkum-Gamez, Jamie N / Weaver, Amy L / McGree, Michaela E / Dowdy, Sean C / Famuyide, Abimbola O / Kipp, Benjamin R / Halling, Kevin C / Yadav, Siddhartha / Couch, Fergus J / Podratz, Karl C

Frontiers in oncology

2023 Volume 13, Page(s) 1105504

Abstract: Objective: To identify high-risk disease in clinicopathologic low-risk endometrial cancer (EC) with high microsatellite instability (MSI-H) or no specific molecular profile (NSMP) and therapeutic insensitivity in clinicopathologic high-risk MSI-H/NSMP ... ...

Abstract	Objective: To identify high-risk disease in clinicopathologic low-risk endometrial cancer (EC) with high microsatellite instability (MSI-H) or no specific molecular profile (NSMP) and therapeutic insensitivity in clinicopathologic high-risk MSI-H/NSMP EC. Methods: We searched The Cancer Genome Atlas for DNA sequencing, RNA expression, and surveillance data regarding MSI-H/NSMP EC. We used a molecular classification system of Results: Data were available for 239 patients with EC, which included 58 MSI-H and 89 NSMP cases. ECPPF effectively stratified MSI-H/NSMP EC into distinct molecular groups with prognostic implications: molecular low risk (MLR), with low Conclusion: ECPPF may resolve prognostic challenges for MSI-H/NSMP EC by identifying occult high-risk disease in EC with clinicopathologic low-risk indicators and therapeutic insensitivity in EC with clinicopathologic high-risk indicators.
Language	English
Publishing date	2023-05-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1105504
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Article ; Online: Incidence of venous thromboembolism in patients with advanced stage ovarian cancer undergoing neoadjuvant chemotherapy: Is it time for thromboprophylaxis?

Shafa, Anousheh / Watkins, A Brooke / McGree, Michaela E / Weroha, S John / Wahner Hendrickson, Andrea E / Block, Matthew S / Langstraat, Carrie L / McBane, Robert D / Bakkum-Gamez, Jamie N / Kumar, Amanika

Gynecologic oncology

2023 Volume 176, Page(s) 36–42

Abstract: Objectives: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the ... ...

Abstract	Objectives: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment. Methods: This retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution. Risk factors were compared between patients with versus without VTE between EOC diagnosis and 180 days after ICS. Bleeding complications were compared between patient who received a DOAC versus non-DOAC. Results: VTE cases occurred amongst 33 of the 154 (21.4%) patients with 4 (2.6%) concurrent with EOC diagnosis, 9 (5.8%) between EOC diagnosis and NACT start, 13 (8.4%) between NACT start and ICS, and 7 (4.5%) within 180 days after ICS. There were no statistically significant differences in risk factors assessed (age, body mass index, functional status, histology, Khorana score, and smoking history) between patients with versus without VTE. Eleven patients (33.3%) received a DOAC for VTE treatment. There were no significant differences in number of intraoperative blood transfusions (p = 0.38), blood loss (p = 0.95), or bleeding complications (p = 0.53) between patients treated with a DOAC versus a non-DOAC. Conclusion: There is a high incidence of VTE events (21.4%) in patients with advanced stage EOC undergoing NACT. Two-thirds of the VTEs may have been prevented with thromboprophylaxis as they occurred between EOC diagnosis and ICS. These data support consideration of thromboprophylaxis in all patients with advanced stage EOC undergoing NACT.
MeSH term(s)	Humans ; Female ; Carcinoma, Ovarian Epithelial/drug therapy ; Carcinoma, Ovarian Epithelial/surgery ; Carcinoma, Ovarian Epithelial/complications ; Neoadjuvant Therapy/adverse effects ; Anticoagulants/adverse effects ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/surgery ; Ovarian Neoplasms/pathology ; Venous Thromboembolism/epidemiology ; Venous Thromboembolism/etiology ; Venous Thromboembolism/prevention & control ; Incidence ; Retrospective Studies
Chemical Substances	Anticoagulants
Language	English
Publishing date	2023-07-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2023.06.577
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Article ; Online: Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

2024 Volume 74, Page(s) 101085

Abstract: Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged ... ...

Abstract	Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.
Language	English
Publishing date	2024-04-16
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	1474513-6
ISSN	1532-2084 ; 1368-7646
ISSN (online)	1532-2084
ISSN	1368-7646
DOI	10.1016/j.drup.2024.101085
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Zs.A 5099: Show issues

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Article ; Online: Frequent POLE-driven hypermutation in ovarian endometrioid cancer revealed by mutational signatures in RNA sequencing.

Davila, Jaime I / Chanana, Pritha / Sarangi, Vivekananda / Fogarty, Zachary C / Weroha, S John / Guo, Ruifeng / Goode, Ellen L / Huang, Yajue / Wang, Chen

BMC medical genomics

2021 Volume 14, Issue 1, Page(s) 165

Abstract: Background: DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly ... ...

Abstract	Background: DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. POLE-driven cases possess an abundance of TCT > TAT and TCG > TTG somatic mutations characterized by mutational signature 10 from the Catalog of Somatic Mutations in Cancer (COSMIC). By quantifying the contribution of COSMIC mutational signature 10 in RNA sequencing (RNA-seq) we set out to identify POLE-driven tumors in a set of unselected Mayo Clinic OC. Methods: Mutational profiles were calculated using expressed single-nucleotide variants (eSNV) in the Mayo Clinic OC tumors (n = 195), The Cancer Genome Atlas (TCGA) OC tumors (n = 419), and the Genotype-Tissue Expression (GTEx) normal ovarian tissues (n = 84). Non-negative Matrix Factorization (NMF) of the mutational profiles inferred the contribution per sample of four distinct mutational signatures, one of which corresponds to COSMIC mutational signature 10. Results: In the Mayo Clinic OC cohort we identified six tumors with a predicted contribution from COSMIC mutational signature 10 of over five mutations per megabase. These six cases harbored known POLE hotspot mutations (P286R, S297F, V411L, and A456P) and were of endometrioid histotype (P = 5e-04). These six tumors had an early onset (average age of patients at onset, 48.33 years) when compared to non-POLE endometrioid OC cohort (average age at onset, 60.13 years; P = .008). Samples from TCGA and GTEx had a low COSMIC signature 10 contribution (median 0.16 mutations per megabase; maximum 1.78 mutations per megabase) and carried no POLE hotspot mutations. Conclusions: From the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials.
MeSH term(s)	Carcinoma, Endometrioid
Language	English
Publishing date	2021-06-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-021-01017-7
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Article ; Online: Characterization and Optimization of Multiomic Single-Cell Epigenomic Profiling.

Sandoval, Leticia / Mohammed Ismail, Wazim / Mazzone, Amelia / Dumbrava, Mihai / Fernandez, Jenna / Munankarmy, Amik / Lasho, Terra / Binder, Moritz / Simon, Vernadette / Kim, Kwan Hyun / Chia, Nicholas / Lee, Jeong-Heon / Weroha, S John / Patnaik, Mrinal / Gaspar-Maia, Alexandre

Genes

2023 Volume 14, Issue 6

Abstract: The snATAC + snRNA platform allows epigenomic profiling of open chromatin and gene expression with single-cell resolution. The most critical assay step is to isolate high-quality nuclei to proceed with droplet-base single nuclei isolation and barcoding. ... ...

Abstract	The snATAC + snRNA platform allows epigenomic profiling of open chromatin and gene expression with single-cell resolution. The most critical assay step is to isolate high-quality nuclei to proceed with droplet-base single nuclei isolation and barcoding. With the increasing popularity of multiomic profiling in various fields, there is a need for optimized and reliable nuclei isolation methods, mainly for human tissue samples. Herein we compared different nuclei isolation methods for cell suspensions, such as peripheral blood mononuclear cells (PBMC,
MeSH term(s)	Humans ; Leukocytes, Mononuclear ; Epigenomics ; Multiomics ; Reproducibility of Results ; RNA, Small Nuclear/genetics
Chemical Substances	RNA, Small Nuclear
Language	English
Publishing date	2023-06-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14061245
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Article ; Online: Not all stage I and II endometrial cancers are created equal: Recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy alone in all subgroups of early-stage high-intermediate and high-risk endometrial cancer.

Garzon, Simone / Grassi, Tommaso / Mariani, Andrea / Kollikonda, Swapna / Weaver, Amy L / McGree, Michaela E / Petersen, Ivy A / Weroha, S John / Glaser, Gretchen E / Langstraat, Carrie L / Amarnath, Sudha R / AlHilli, Mariam M

Gynecologic oncology

2022 Volume 167, Issue 3, Page(s) 444–451

Abstract: Objective: To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC).: Methods: We ... ...

Abstract	Objective: To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC). Methods: We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors. Results: Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology. Conclusions: Observation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.
Language	English
Publishing date	2022-10-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2022.10.004
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Article ; Online: DNA barcoded competitive clone-initiating cell analysis reveals novel features of metastatic growth in a cancer xenograft model.

Aalam, Syed Mohammed Musheer / Tang, Xiaojia / Song, Jianning / Ray, Upasana / Russell, Stephen J / Weroha, S John / Bakkum-Gamez, Jamie / Shridhar, Viji / Sherman, Mark E / Eaves, Connie J / Knapp, David J H F / Kalari, Krishna R / Kannan, Nagarajan

NAR cancer

2022 Volume 4, Issue 3, Page(s) zcac022

Abstract: A problematic feature of many human cancers is a lack of understanding of mechanisms controlling organ-specific patterns of metastasis, despite recent progress in identifying many mutations and transcriptional programs shown to confer this potential. To ... ...

Abstract	A problematic feature of many human cancers is a lack of understanding of mechanisms controlling organ-specific patterns of metastasis, despite recent progress in identifying many mutations and transcriptional programs shown to confer this potential. To address this gap, we developed a methodology that enables different aspects of the metastatic process to be comprehensively characterized at a clonal resolution. Our approach exploits the application of a computational pipeline to analyze and visualize clonal data obtained from transplant experiments in which a cellular DNA barcoding strategy is used to distinguish the separate clonal contributions of two or more competing cell populations. To illustrate the power of this methodology, we demonstrate its ability to discriminate the metastatic behavior in immunodeficient mice of a well-established human metastatic cancer cell line and its co-transplanted
Language	English
Publishing date	2022-07-22
Publishing country	England
Document type	Journal Article
ISSN	2632-8674
ISSN (online)	2632-8674
DOI	10.1093/narcan/zcac022
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Article ; Online: GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.

Clemente, Valentino / Hoshino, Asumi / Shetty, Mihir / Nelson, Andrew / Erickson, Britt K / Baker, Ruth / Rubin, Nathan / Khalifa, Mahmoud / Weroha, S John / Lou, Emil / Bazzaro, Martina

Cancer research communications

2022 Volume 2, Issue 8, Page(s) 784–794

Abstract: Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine ... ...

Abstract	Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming.
MeSH term(s)	Animals ; Female ; Humans ; Mice ; Adenocarcinoma, Clear Cell/genetics ; DNA-Binding Proteins/genetics ; Glutaminase/genetics ; Glutamine/metabolism ; Ovarian Neoplasms/genetics ; Protective Factors ; Transcription Factors/genetics
Chemical Substances	ARID1A protein, human ; DNA-Binding Proteins ; GLS1 protein, mouse (EC 3.5.1.2) ; Glutaminase (EC 3.5.1.2) ; Glutamine (0RH81L854J) ; Transcription Factors ; Arid1a protein, mouse
Language	English
Publishing date	2022-08-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.crc-22-0122
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