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

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.

Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation.

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.

CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.

CD8+ T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8+ T cell dysfunction showed that interleukin-2 (IL-2)-based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2's effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (Treg) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8+ T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8+ T cells in the liver without substantially altering Treg or NK cell counts. These expanded CD8+ T cells exhibited increased interferon-γ and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen-positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8+ T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8+ T cells without affecting NK or Treg cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.

Gynecological Cancer Survivors' Experiences of Dyspareunia and Factors Influencing Care-Seeking Behavior: A Qualitative Study.

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.

Acceptability of multimodal pelvic floor physical therapy to treat dyspareunia after gynecological malignancies: a qualitative study of women's views and experiences.

INTRODUCTION AND HYPOTHESIS: Multimodal pelvic floor physical therapy (PFPT) is recommended after gynecological malignancies to treat dyspareunia. However, data to strongly support its implementation in the cancer care continuum are lacking. The aim of this study was to explore the views and experiences of gynecological cancer survivors with dyspareunia regarding the acceptability of multimodal PFPT. METHODS: This qualitative study was conducted with the participants (n = 28) of a study investigating a 12-week multimodal PFPT treatment. Individual semi-structured telephone interviews served to collect qualitative data pertaining to women's views and experiences of the treatment they received. Interviews were recorded and transcribed for analysis using the interpretative description framework. RESULTS: Our cohort described the appropriateness of the treatment in terms of modalities, physical therapist, care delivery, and intensity (Theme 1). While the intensity was reported as demanding by a few, all participants stressed that it was relevant to see significant improvements (Theme 2). In addition to the treatment characteristics and women's beliefs and attitudes, noticing the treatment effects motivated their participation (Theme 2). Women expressed being highly satisfied with the treatment based on their positive experiences and the balance between their efforts and the results they obtained (Theme 3). As a result, they all recommended this treatment (Theme 3). CONCLUSIONS: This is the first study to examine the acceptability of multimodal PFPT in the context of gynecological malignancies. This treatment was found acceptable and can be offered to gynecological cancer survivors.

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo. METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

Improvements following multimodal pelvic floor physical therapy in gynecological cancer survivors suffering from pain during sexual intercourse: Results from a one-year follow-up mixed-method study.

BACKGROUND: A large proportion of gynecological cancer survivors suffer from pain during sexual intercourse, also known as dyspareunia. Following a multimodal pelvic floor physical therapy (PFPT) treatment, a reduction in pain and improvement in psychosexual outcomes were found in the short term, but no study thus far has examined whether these changes are sustained over time. PURPOSE: To examine the improvements in pain, sexual functioning, sexual distress, body image concerns, pain anxiety, pain catastrophizing, painful intercourse self-efficacy, depressive symptoms and pelvic floor disorder symptoms in gynecological cancer survivors with dyspareunia after PFPT, and to explore women's perceptions of treatment effects at one-year follow-up. METHODS: This mixed-method study included 31 gynecological cancer survivors affected by dyspareunia. The women completed a 12-week PFPT treatment comprising education, manual therapy and pelvic floor muscle exercises. Quantitative data were collected using validated questionnaires at baseline, post-treatment and one-year follow-up. As for qualitative data, semi-structured interviews were conducted at one-year follow-up to better understand women's perception and experience of treatment effects. RESULTS: Significant improvements were found from baseline to one-year follow-up on all quantitative outcomes (P ≤ 0.028). Moreover, no changes were found from post-treatment to one-year follow-up, supporting that the improvements were sustained at follow-up. Qualitative data highlighted that reduction in pain, improvement in sexual functioning and reduction in urinary symptoms were the most meaningful effects perceived by participants. Women expressed that these effects resulted from positive biological, psychological and social changes attributable to multimodal PFPT. Adherence was also perceived to influence treatment outcomes. CONCLUSIONS: Findings suggest that the short-term improvements following multimodal PFPT are sustained and meaningful for gynecological cancer survivors with dyspareunia one year after treatment.

Changes in pelvic floor morphometry and muscle function after multimodal physiotherapy for gynaecological cancer survivors suffering from dyspareunia: a prospective interventional study.

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.

Radiation Therapy Techniques and Treatment-Related Toxicity in the PORTEC-3 Trial: Comparison of 3-Dimensional Conformal Radiation Therapy Versus Intensity-Modulated Radiation Therapy.

PURPOSE: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer. METHODS AND MATERIALS: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques. RESULTS: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences. CONCLUSIONS: IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT.

18F-4FMFES and 18F-FDG PET/CT in Estrogen Receptor-Positive Endometrial Carcinomas: Preliminary Report.

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-11ß-methoxy-16α-18F-fluoroestradiol (18F-4FMFES) and 18F-FDG PET in endometrial cancers. In parallel, noninvasive interventions were attempted to slow progression of 18F-4FMFES metabolites in the intestines to reduce abdominal background uptake. Methods: In an ongoing study, 25 patients who received prior pathologic confirmation of an ER-positive endometrial cancer or endometrial intraepithelial neoplasia agreed to participate in the ongoing clinical trial. Patients were scheduled for 18F-FDG and 18F-4FMFES PET/CT imaging in random order and within 2 wk. Patients were administered either 4 mg of loperamide orally before 18F-4FMFES tracer injection or repeated intravenous injection of 20 mg of hyoscine N-butylbromide during 18F-4FMFES PET/CT. Regions of interest covering the whole abdomen and excluding the liver, bladder, and uterus were drawn for the 18F-4FMFES PET images, and an SUV threshold of more than 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background uptake. Results: Repeated injection of hyoscine N-butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18F-4FMFES tumor SUVmax ranged from 3.0 to 14.4 (9.4 ± 3.2), whereas 18F-FDG SUVmax ranged from 0 to 22.0 (7.5 ± 5.1). Tumor-to-background ratio was significantly higher for 18F-4FMFES (16.4 ± 5.4) than for 18F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18F-4FMFES uptake and contrast, 18F-FDG uptake, and the 18F-FDG/18F-4FMFES uptake ratio. Conclusion: It is possible to improve 18F-4FMFES abdominal background using hyoscine N-butylbromide. Both 18F-FDG and 18F-4FMFES PET are suitable for detection of ER-positive endometrial cancers, although 18F-4FMFES yielded a better tumor contrast than did 18F-FDG.

A Prospective Single-Arm Study Evaluating the Effects of a Multimodal Physical Therapy Intervention on Psychosexual Outcomes in Women With Dyspareunia After Gynecologic Cancer.

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 Ë‚ 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 Ë‚ 0.001, d = 1.108), body image concerns (P Ë‚ 0.001, d = 0.829), pain anxiety (P Ë‚ 0.001, d = 0.980), pain catastrophizing (P Ë‚ 0.001, d = 0.968) and depression symptoms (P = 0.002, d = 0.636) with an increase in pain self-efficacy (P Ë‚ 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.

Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer.

BACKGROUND: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort. METHODS: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided. RESULTS: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for "other" vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, "other," and MLH1-hypermethylated MMRd-EC groups, respectively. CONCLUSIONS: The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.

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

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.

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial.

PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Feasibility, acceptability and effects of multimodal pelvic floor physical therapy for gynecological cancer survivors suffering from painful sexual intercourse: A multicenter prospective interventional study.

OBJECTIVES: Painful sexual intercourse (dyspareunia) is a distressing condition affecting a large proportion of gynecological cancer survivors, yet treatments remain limited and poorly studied. This multicenter prospective interventional study examined the feasibility, acceptability and effects of multimodal pelvic floor physical therapy in gynecological cancer survivors with dyspareunia. METHODS: Thirty-one endometrial and cervical cancer survivors with dyspareunia participated in 12 weekly 60-min physical therapy sessions combining education, manual therapy, pelvic floor muscle exercises using biofeedback and home exercises, which included the use of a dilator. The adherence rate to home exercises (≥80%), the attendance rate at physical therapy sessions (≥80% of participants attending ≥10 sessions) and the dropout rate (˂15%) served as feasibility and acceptability outcomes and benchmarks. Pain intensity, pain quality, sexual function, pelvic floor dysfunction symptoms and quality of life were measured at baseline and post-treatment. Treatment satisfaction and participants' perceived improvement were also assessed. RESULTS: The adherence rate was 88% (SD 10), 29/31 (94%) women attended ≥10 treatment sessions, and the dropout rate was 3%. Moreover, women experienced significant improvements in all outcomes after the intervention (p ≤ 0.044). They also reported being highly satisfied with the treatment (9.3/10 (SD 1.2)), and 90% of them were very much or much improved. CONCLUSIONS: Our findings support the feasibility and acceptability of multimodal pelvic floor physical therapy for gynecological cancer survivors with dyspareunia. The intervention also led to significant improvements in pain, sexual function, pelvic floor dysfunction symptoms and quality of life. A randomized controlled trial is needed to confirm these results.

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy.

PURPOSE: The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS: Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS: Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P = .019); 100% versus 97% for patients with POLEmut EC (P = .637); 68% versus 76% (P = .428) for MMRd EC; and 80% versus 68% (P = .243) for NSMP EC. CONCLUSION: Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial.

PURPOSE: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. PATIENTS AND METHODS: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation-gBRCAmut and non-gBRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. RESULTS: In the gBRCAmut and non-gBRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gBRCAmut and non-gBRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. CONCLUSION: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.

BACKGROUND: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. METHODS: In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. FINDINGS: Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. INTERPRETATION: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Ascites from ovarian cancer patients stimulates MUC16 mucin expression and secretion in human peritoneal mesothelial cells through an Akt-dependent pathway.

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.

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.

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.