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Article: Serum CA125 and ascites leptin level ratio predicts baseline clinical resistance to first-line platinum-based treatment and poor prognosis in patients with high grade serous ovarian cancer.

Matte, Isabelle / Garde-Granger, Perrine / Bessette, Paul / Piché, Alain

2019 Volume 9, Issue 1, Page(s) 160–170

Abstract: About 20% of patients with high grade serous epithelial ovarian carcinoma (HGSOC) are intrinsically resistant to standard first-line platinum-based combination therapy. There is no marker yet available to identify these patients. In that context, all ... ...

Abstract	About 20% of patients with high grade serous epithelial ovarian carcinoma (HGSOC) are intrinsically resistant to standard first-line platinum-based combination therapy. There is no marker yet available to identify these patients. In that context, all patients with HGSOC initially receive the same standard first-line platinum-based therapy, and those with intrinsically resistant diseases can only be identified retrospectively after they experienced early relapse to therapy. The aim of this study was to evaluate serum or ascites CA125 and ascites leptin in patients with intrinsic resistance and to compare them with those of sensitive patients. To this end, we enrolled 80 women with HGSOC who underwent cytoreductive surgery. Thirty seven were considered to have baseline clinical resistance to first-line therapy with progression-free survival < 6 months despite treatment. Serum were collected preoperatively and ascites samples were collected at the time of the surgery. The levels of CA125 and leptin were measured by ELISA. Patients with baseline clinical resistance to first-line therapy had a significantly poorer outcome compared to patients with sensitive HGSOC with an OS of 21 months versus 43 months. Median levels of serum CA125, ascites CA125 and ascites leptin were not significantly different between patients with sensitive and resistant HGSOC. Serum CA125/ascites leptin ratio was found to be significantly elevated in resistant patients compared to patients with drug-sensitive diseases. In ROC analysis, the AUC for serum CA125/ascites leptin ratio was higher than CA125 or leptin alone to differentiate patients with resistance from those with sensitive HGSOC. Elevated serum CA125/ascites leptin ratio was a predictor of poor OS in HGSOC patients. Thus, serum CA125/ascites leptin is a potential novel biomarker to predict baseline clinical resistance to first-line treatment and poor outcome in patients with HGSOC.
Language	English
Publishing date	2019-01-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2589522-9
ISSN	2156-6976
ISSN	2156-6976
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Article ; Online: Ascites from ovarian cancer patients stimulates MUC16 mucin expression and secretion in human peritoneal mesothelial cells through an Akt-dependent pathway.

Matte, Isabelle / Garde-Granger, Perrine / Bessette, Paul / Piché, Alain

BMC cancer

2019 Volume 19, Issue 1, Page(s) 406

Abstract: Background: CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 ... ...

Abstract	Background: CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 is released from the cell surface into malignant ascites and blood vessels. Previous studies have shown that both tumor and surrounding mesothelial cells may express MUC16. Although little is known about the regulation of MUC16 expression in these cells, recent evidence suggest that inflammatory cytokines may stimulate MUC16 expression. Because malignant ascites is a pro-inflammatory environment, we investigated whether OC ascites stimulate the expression and release of MUC16 by human peritoneal mesothelial cells (HPMCs). Methods: HPMCs were isolated from peritoneal lavages of women operated for conditions other than cancer. MUC16 protein expression was determined by immunoblot, immunofluorescence or immunohistochemistry depending on the experiments. The release of MUC16 from the cell surface was measured using EIA and MUC16 mRNA expression by ddPCR. Results: We show that high-grade serous ascites from patients with OC (n = 5) enhance MUC16 expression in HPMCs. Malignant ascites, but not benign peritoneal fluids, stimulate the release of MUC16 in HPMCs in a dose-dependent manner, which is abrogated by heat inactivation. Moreover, we establish that ascites-induced MUC16 expression occurs at the post-transcriptional level and demonstrate that ascites-induced MUC16 expression is mediated, at least partially, through an Akt-dependent pathway. A cytokine array identified upregulation of several cytokines and chemokines in ascites that mediate MUC16 upregulation versus those that do not, including CCL7, CCL8, CCL16, CCL20, CXCL1, IL-6, IL-10, HGF and IL-1 R4. However, when individually tested, none of these factors affected MUC16 expression or secretion. Concentrations of CA125 in the serum of a given patient did not correlate with the ability of its corresponding ascites to stimulate MUC16 release in HPMCs. Conclusions: Collectively, these data indicate that mesothelial cells are an important source of MUC16 in the context of ovarian cancer and malignant ascites is a strong modulator of MUC16 expression in HPMCs and uncover the Akt pathway as a driving factor for upregulation of MUC16. Factors in ascites associated with enhanced MUC16 expression and release remains to be identified.
MeSH term(s)	Ascites/genetics ; Ascites/metabolism ; Ascites/pathology ; CA-125 Antigen/genetics ; CA-125 Antigen/metabolism ; Cell Line, Tumor ; Cytokines/genetics ; Epithelial Cells/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Neoplasm Grading ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Peritoneum/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Up-Regulation
Chemical Substances	CA-125 Antigen ; Cytokines ; MUC16 protein, human ; Membrane Proteins ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2019-04-30
Publishing country	England
Document type	Journal Article
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-019-5611-7
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Article ; Online: CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.

Andreata, Francesco / Moynihan, Kelly D / Fumagalli, Valeria / Di Lucia, Pietro / Pappas, Danielle C / Kawashima, Keigo / Ni, Irene / Bessette, Paul H / Perucchini, Chiara / Bono, Elisa / Giustini, Leonardo / Nguyen, Henry C / Chin, S Michael / Yeung, Yik Andy / Gibbs, Craig S / Djuretic, Ivana / Iannacone, Matteo

Science translational medicine

2024 Volume 16, Issue 729, Page(s) eadi1572

Abstract: ... ...

Abstract	CD8
MeSH term(s)	Humans ; Animals ; Mice ; Interleukin-2 ; Hepatitis B virus ; CD8-Positive T-Lymphocytes ; Hepatitis B, Chronic/drug therapy ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use
Chemical Substances	Interleukin-2 ; Antiviral Agents
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adi1572
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Article ; Online: Gynecological Cancer Survivors' Experiences of Dyspareunia and Factors Influencing Care-Seeking Behavior: A Qualitative Study.

Cyr, Marie-Pierre / Camden, Chantal / Dumoulin, Chantale / Dostie, Rosalie / Bessette, Paul / Pina, Annick / Gotlieb, Walter Henry / Lapointe-Milot, Korine / Mayrand, Marie-Hélène / Morin, Mélanie

Archives of sexual behavior

2023 Volume 52, Issue 6, Page(s) 2669–2681

Abstract: Pain during sexual intercourse, also called dyspareunia, affects most women after treatment for gynecological cancer. Previous work adopted a biomedical approach to depict dyspareunia in this population, which provided a narrow perspective of this ... ...

Abstract	Pain during sexual intercourse, also called dyspareunia, affects most women after treatment for gynecological cancer. Previous work adopted a biomedical approach to depict dyspareunia in this population, which provided a narrow perspective of this condition. Taking into account women's experiences of dyspareunia and the factors influencing their care-seeking behaviors would provide insight to improve care in the context of gynecological cancer. The aim of this study was to describe gynecological cancer survivors' experiences of dyspareunia and factors influencing care-seeking behavior. A qualitative study was performed with 28 gynecological cancer survivors with dyspareunia. Individual telephone interviews were conducted based on the Common-Sense Model of Self-Regulation. Interviews were recorded and transcribed for analysis using the interpretative description framework. Concerning their experience, participants reported the oncological treatments as the primary cause of dyspareunia. Loss of libido, lower vaginal lubrication, and smaller vaginal cavity were described as being linked with dyspareunia. Women explained how dyspareunia and these changes had led them to engage less in, and even interrupt, sexual activity. They expressed that they were distressed, felt less of a woman, and experienced low control and/or self-efficacy. Regarding the factors influencing women's care-seeking behaviors, participants emphasized that they were provided with insufficient information and support. Balancing priorities, denial or reluctance, misbeliefs, resignation and acceptance, and negative emotions were reported as barriers, whereas acknowledgement of sexual dysfunction, desire for improvement, awareness of treatment possibilities, willingness to undertake treatment and treatment acceptability were reported as facilitators to seeking care. Findings suggest that dyspareunia is a complex and impactful condition after gynecological cancer. While this study highlights the importance of alleviating the burden of sexual dysfunction in cancer survivors, it identified factors that should be considered in the provision of services to improve care.
MeSH term(s)	Female ; Humans ; Dyspareunia/therapy ; Dyspareunia/psychology ; Cancer Survivors ; Sexual Behavior/psychology ; Coitus ; Patient Acceptance of Health Care/psychology ; Sexual Dysfunction, Physiological/etiology ; Sexual Dysfunction, Physiological/therapy ; Neoplasms
Language	English
Publishing date	2023-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184221-3
ISSN	1573-2800 ; 0004-0002
ISSN (online)	1573-2800
ISSN	0004-0002
DOI	10.1007/s10508-023-02589-4
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Zs.A 1106: Show issues

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Article ; Online: 18

Paquette, Michel / Espinosa-Bentancourt, Esteban / Lavallée, Éric / Phoenix, Serge / Lapointe-Milot, Korine / Bessette, Paul / Guérin, Brigitte / Turcotte, Éric E

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

2021 Volume 63, Issue 5, Page(s) 702–707

Abstract: This article reports the preliminary results of a phase II clinical trial investigating the use of the estrogen receptor (ER)-targeting PET tracer 4-fluoro-11β-methoxy-16α- ...

Abstract	This article reports the preliminary results of a phase II clinical trial investigating the use of the estrogen receptor (ER)-targeting PET tracer 4-fluoro-11β-methoxy-16α-
MeSH term(s)	Butylscopolammonium Bromide ; Endometrial Neoplasms/diagnostic imaging ; Estradiol/analogs & derivatives ; Female ; Fluorodeoxyglucose F18 ; Humans ; Loperamide ; Positron Emission Tomography Computed Tomography ; Receptors, Estrogen/metabolism
Chemical Substances	11-methoxy-4,16-difluoroestradiol ; Receptors, Estrogen ; Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Butylscopolammonium Bromide (2Z3E1OF81V) ; Estradiol (4TI98Z838E) ; Loperamide (6X9OC3H4II)
Language	English
Publishing date	2021-08-19
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article
ZDB-ID	80272-4
ISSN	1535-5667 ; 0097-9058 ; 0161-5505 ; 0022-3123
ISSN (online)	1535-5667
ISSN	0097-9058 ; 0161-5505 ; 0022-3123
DOI	10.2967/jnumed.121.262617
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Zs.A 114: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Changes in pelvic floor morphometry and muscle function after multimodal physiotherapy for gynaecological cancer survivors suffering from dyspareunia: a prospective interventional study.

Cyr, Marie-Pierre / Dumoulin, Chantale / Bessette, Paul / Pina, Annick / Gotlieb, Walter Henry / Lapointe-Milot, Korine / Mayrand, Marie-Hélène / Morin, Mélanie

Physiotherapy

2021 Volume 114, Page(s) 54–62

Abstract: Objective: To investigate the changes in pelvic floor morphometry and muscle function after multimodal pelvic floor physiotherapy treatment in gynaecological cancer survivors suffering from painful intercourse (dyspareunia).: Design: Prospective ... ...

Abstract	Objective: To investigate the changes in pelvic floor morphometry and muscle function after multimodal pelvic floor physiotherapy treatment in gynaecological cancer survivors suffering from painful intercourse (dyspareunia). Design: Prospective interventional study. Setting: Three university hospitals. Participants: Thirty-one gynaecological cancer survivors with dyspareunia. Intervention: The treatment consisted of 12 weekly sessions of physiotherapy combining education, pelvic floor muscle exercises with biofeedback, manual therapy and home exercises. Main outcome measures: Women were assessed at baseline and post-treatment. Pelvic floor morphometry was evaluated at rest and on maximal contraction by measuring bladder neck position, anorectal and levator plate angles as well as levator hiatal dimensions with three-dimensional/four-dimensional transperineal ultrasound imaging. Pelvic floor muscle function was evaluated by measuring passive forces (muscle tone measure), flexibility, stiffness, strength, coordination and endurance with an intra-vaginal dynamometric speculum. Results: Significant changes in pelvic floor morphometry and muscle function were found post-treatment. The parameters assessing the changes from rest to maximal contraction significantly improved (e.g., mean change of levator hiatal area narrowing 14%, 95% CI 11-18, Cohen's d effect size 1.48)), supporting the hypothesis of decreased muscle tone and improved muscle contractility following treatment. Women also presented with a significant decrease in tone (mean change -0.4N, 95% CI -0.7 to -0.1, Cohen's d effect size 0.57) and stiffness (mean change -0.1N/mm, 95% CI -0.2 to -0.1, Cohen's d effect size 0.59), as well as significant improvements in flexibility (mean change 9.0mm, 95% CI 5.8-12.2, Cohen's d effect size 1.08), coordination (mean change 3 rapid contractions, 95% CI 2-4, Cohen's d effect size 0.85) and endurance (mean change 683%s, 95% CI 388-978, Cohen's d effect size 0.90). Conclusion:* Our findings suggest significant improvements in pelvic floor morphometry and muscle function after a multimodal physiotherapy treatment in gynaecological cancer survivors with dyspareunia. These effects may represent key treatment mechanisms to reduce dyspareunia, supporting the rationale for multimodal physiotherapy in this population. CLINICAL TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT03935698.
MeSH term(s)	Cancer Survivors ; Dyspareunia/therapy ; Female ; Humans ; Muscle Contraction/physiology ; Neoplasms ; Pelvic Floor/diagnostic imaging ; Physical Therapy Modalities ; Prospective Studies ; Ultrasonography/methods
Language	English
Publishing date	2021-09-30
Publishing country	England
Document type	Clinical Study ; Journal Article
ZDB-ID	391109-3
ISSN	1873-1465 ; 0031-9406
ISSN (online)	1873-1465
ISSN	0031-9406
DOI	10.1016/j.physio.2021.09.003
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Zs.B 383: Show issues

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Article ; Online: Characterizing Pelvic Floor Muscle Function and Morphometry in Survivors of Gynecological Cancer Who Have Dyspareunia: A Comparative Cross-Sectional Study.

Cyr, Marie-Pierre / Dumoulin, Chantale / Bessette, Paul / Pina, Annick / Gotlieb, Walter H / Lapointe-Milot, Korine / Morin, Mélanie

Physical therapy

2021 Volume 101, Issue 4

Abstract: Objective: More than one-half of gynecological cancer survivors are affected by pain during sexual intercourse, also known as dyspareunia. Oncological treatments may result in pelvic floor muscle (PFM) alterations, which are suspected to play a key role ...

Abstract	Objective: More than one-half of gynecological cancer survivors are affected by pain during sexual intercourse, also known as dyspareunia. Oncological treatments may result in pelvic floor muscle (PFM) alterations, which are suspected to play a key role in dyspareunia. However, to our knowledge, no study has investigated PFM function and morphometry in this population. The aim of the study was to characterize and compare PFM function and morphometry between gynecological cancer survivors with dyspareunia and asymptomatic women. Methods: Twenty-four gynecological cancer survivors with dyspareunia and 32 women with a history of total hysterectomy but without pelvic pain (asymptomatic women) participated in this comparative cross-sectional study. PFM passive forces (tone), flexibility, stiffness, maximal strength, coordination, and endurance were assessed with an intra-vaginal dynamometric speculum. Bladder neck position, levator plate angle, anorectal angle, and levator hiatal dimensions were measured at rest and on maximal contraction with 3D/4D transperineal ultrasound imaging. Results: Compared with asymptomatic women, gynecological cancer survivors showed heightened PFM tone, lower flexibility, higher stiffness, and lower coordination and endurance. At rest, they had a smaller anorectal angle and smaller levator hiatal dimensions, indicating heightened PFM tone. They also presented fewer changes from rest to maximal contraction for anorectal angle and levator hiatal dimensions, suggesting an elevated tone or altered contractile properties. Conclusions: Gynecological cancer survivors with dyspareunia present with altered PFM function and morphometry. This research therefore provides a better understanding of the underlying mechanisms of dyspareunia in cancer survivors. Impact: Our study confirms alterations in PFM function and morphometry in gynecological cancer survivors with dyspareunia. These findings support the rationale for developing and assessing the efficacy of physical therapy targeting PFM alterations in this population.
MeSH term(s)	Aged ; Cancer Survivors ; Cross-Sectional Studies ; Dyspareunia/diagnostic imaging ; Dyspareunia/etiology ; Dyspareunia/physiopathology ; Female ; Genital Neoplasms, Female/complications ; Genital Neoplasms, Female/therapy ; Humans ; Middle Aged ; Pelvic Floor Disorders/diagnostic imaging ; Pelvic Floor Disorders/etiology ; Pelvic Floor Disorders/physiopathology ; Surveys and Questionnaires ; Ultrasonography
Language	English
Publishing date	2021-01-31
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	415886-6
ISSN	1538-6724 ; 0031-9023
ISSN (online)	1538-6724
ISSN	0031-9023
DOI	10.1093/ptj/pzab042
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Article ; Online: A Prospective Single-Arm Study Evaluating the Effects of a Multimodal Physical Therapy Intervention on Psychosexual Outcomes in Women With Dyspareunia After Gynecologic Cancer.

Cyr, Marie-Pierre / Dumoulin, Chantale / Bessette, Paul / Pina, Annick / Gotlieb, Walter Henry / Lapointe-Milot, Korine / Mayrand, Marie-Hélène / Morin, Mélanie

The journal of sexual medicine

2021 Volume 18, Issue 5, Page(s) 946–954

Abstract: Background: Dyspareunia affects most women after treatment for gynecologic malignancies. However, to date, evidence-based interventions remain limited and no study has examined the effects of multimodal physical therapy on psychosexual outcomes in these ...

Abstract	Background: Dyspareunia affects most women after treatment for gynecologic malignancies. However, to date, evidence-based interventions remain limited and no study has examined the effects of multimodal physical therapy on psychosexual outcomes in these patients. Aim: To assess the effects of multimodal physical therapy on psychosexual outcomes including sexual distress, body image concerns, pain anxiety, pain catastrophizing, pain self-efficacy and depressive symptoms in women with dyspareunia after treatment for gynecologic malignancies. Methods: Thirty-one gynecologic cancer survivors with dyspareunia enrolled in this prospective single-arm interventional study. The participants undertook 12 weekly sessions of physical therapy incorporating education, pelvic floor muscle exercises with biofeedback, manual therapy and home exercises. Outcome measures were evaluated pre- and post-treatment. Paired t-tests were conducted to investigate the changes from pre-treatment (P-value ˂ 0.05) while effect sizes (Cohen's d) were calculated to measure the magnitude of the change. Main outcome measures: Sexual distress (Female Sexual Distress Scale-Revised), body image concerns (Body Image Scale), pain anxiety (Pain Anxiety Symptoms Scale), pain catastrophizing (Pain Catastrophizing Scale), pain self-efficacy (Painful Intercourse Self-Efficacy Scale) and depressive symptoms (Beck Depression Inventory-II). Results: Significant changes were found from pre- to post-treatment for all psychosexual outcomes. Women reported reductions in sexual distress (P ˂ 0.001, d = 1.108), body image concerns (P ˂ 0.001, d = 0.829), pain anxiety (P ˂ 0.001, d = 0.980), pain catastrophizing (P ˂ 0.001, d = 0.968) and depression symptoms (P = 0.002, d = 0.636) with an increase in pain self-efficacy (P ˂ 0.001, d ≥ 0.938) following the intervention. Clinical implications: The results suggest that multimodal physical therapy significantly improves sexual distress, body image concerns, pain anxiety, pain catastrophizing, pain self-efficacy and depressive symptoms in our sample of women with dyspareunia after treatment for gynecologic malignancies. The medium to large effect sizes obtained with the high proportion of women presenting meaningful changes according to the known minimal clinically important difference or clinical cut-off underlines the significance of these effects. Strengths & limitations: The current study used validated questionnaires to assess the psychosexual outcomes of a well-designed physical therapy intervention using multiple modalities to address the multifaceted aspect of dyspareunia in cancer survivors. This study did not include a control group, which may limit drawing definitive conclusions. Conclusion: Findings showed that multimodal physical therapy yielded significant improvements in psychosexual outcomes in gynecologic cancer survivors with dyspareunia. A randomized controlled trial is indicated to confirm these results. Cyr M-P, Dumoulin C, Bessette P, et al. A Prospective Single-Arm Study Evaluating the Effects of a Multimodal Physical Therapy Intervention on Psychosexual Outcomes in Women With Dyspareunia After Gynecologic Cancer. J Sex Med 2021;18:946-954.
MeSH term(s)	Dyspareunia/therapy ; Female ; Genital Neoplasms, Female/complications ; Humans ; Physical Therapy Modalities ; Prospective Studies ; Sexual Behavior ; Surveys and Questionnaires
Language	English
Publishing date	2021-04-28
Publishing country	Netherlands
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2251959-2
ISSN	1743-6109 ; 1743-6095
ISSN (online)	1743-6109
ISSN	1743-6095
DOI	10.1016/j.jsxm.2021.02.014
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Zs.A 6417: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 505: Show issues

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Article ; Online: IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity.

Moynihan, Kelly D / Kumar, Manu P / Sultan, Hussein / Pappas, Danielle C / Park, Terrence / Chin, S Michael / Bessette, Paul / Lan, Ruth Y / Nguyen, Henry C / Mathewson, Nathan D / Ni, Irene / Chen, Wei / Lee, Yonghee / Liao-Chan, Sindy / Chen, Jessie / Schumacher, Ton N M / Schreiber, Robert D / Yeung, Yik A / Djuretic, Ivana M

Cancer discovery

2024

Abstract: IL-2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, while others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL-2 to CD8+ T ... ...

Abstract	IL-2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, while others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL-2 to CD8+ T cells, which are key anti-tumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, CD8 cis-targeted IL-2 that demonstrates over 500-fold preference for CD8+ T cells over NK and Treg cells, which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL-2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+ T cells in primates. In mice, an AB248 surrogate demonstrated superior anti-tumor activity and enhanced tolerability as compared to an untargeted IL-2RBy agonist. Efficacy was associated with expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings.
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-23-1266
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Article ; Online: Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2024 Volume 37, Issue 3, Page(s) 100423

Abstract: Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed ... ...

Abstract	Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.
MeSH term(s)	Female ; Humans ; DNA Mismatch Repair/genetics ; MutL Protein Homolog 1/genetics ; MutL Protein Homolog 1/metabolism ; Endometrial Neoplasms/pathology ; Germ-Line Mutation ; Mismatch Repair Endonuclease PMS2/genetics ; Microsatellite Instability ; DNA Methylation
Chemical Substances	MutL Protein Homolog 1 (EC 3.6.1.3) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; MLH1 protein, human
Language	English
Publishing date	2024-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1016/j.modpat.2024.100423
Database	MEDical Literature Analysis and Retrieval System OnLINE

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