Nodal staging in high and high-intermediate risk endometrial cancer surgery: Which role in the molecular classification era?

OBJECTIVES: Nodal staging contributes to risk group definition and the indication to adjuvant treatment in endometrial cancer (EC) patients. However, the role of nodal assessment evolved and requires redefinition. Primary outcome of the study was to assess the impact of surgical nodal staging in defining high-risk (HR) EC. Secondary outcome was to evaluate the contribution of nodal assessment to the decision for adjuvant treatment in both high-risk and high-intermediate risk (HIR) patients submitted to surgery. METHODS: Clinical stage I-II EC patients with postoperative diagnosis of HR and HIR disease were included. The contribution of nodal staging in prognostic groups allocation was assessed by reviewing HR patients to identify those without any other feature of such class (non-endometrioid histology, p53abn immunohistochemistry, post-operative T3-T4 disease) and HIR cases to assess how nodal staging affected adjuvant treatment indication. Descriptive statistics were conducted to describe the two populations. RESULTS: Fifty-seven patients were included, 46 with HR and 11 with HIR disease. Chemotherapy and external-beam radiotherapy (EBRT) were proposed in 40 HR patients. Considering histology, immunohistochemical profile and FIGO stage, high risk classification was exclusively relied on nodal involvement in 2/46 cases (4.3 %). Omitting retroperitoneal staging, one of them would have been classified in the intermediate risk group and the other as HIR: without nodal staging, chemotherapy and EBRT would have been omitted in 1/40 (2.5 %) case. Among HIR patients, chemotherapy was proposed in 7/11 cases and EBRT in all cases. Adjuvant chemotherapy was indicated in 5/6 (83.3 %) and omitted in 1/6 (16.7 %) pN0 patient (stage Ib G2, substantial LVSI). In HIRpN0 patients, omitting nodal staging could have changed adjuvant treatment indication in 1/6 (16.7 %) case. In HIRpNx patients, adjuvant chemotherapy was omitted in one patient (stage II, grade 2 and LVSI negative): nodal staging unavailability might have changed indication to chemotherapy in 1/5 (20 %) case, without changing indication to EBRT. Unavailable nodal staging could globally be related to omission of chemotherapy in 2/57 (3.5 %) patients and of EBRT in 1/57 (1.8 %) patient. CONCLUSIONS: In this series, nodal staging had limited impact on definition of HR class and on the choice of adjuvant treatment in HR and HIR EC patients.

Impact of different follow-up regimens on health-related quality of life and costs in endometrial cancer patients: Results from the TOTEM randomized trial.

PURPOSE: To investigate whether intensive follow-up (INT) after surgery for endometrial cancer impact health-related quality of life (HRQoL) and healthcare costs compared to minimalist follow-up (MIN), in the absence of evidence supporting any benefit on 5-year overall survival. METHODS: In the TOTEM trial, HRQoL was assessed using the SF-12 and the Psychological General Well-Being (PGWB) questionnaires at baseline, after 6 and 12 months and then annually up to 5 years of follow-up. Costs were analyzed after 4 years of follow-up from a National Health Service perspective, stratified by risk level. The probability of missing data was analyzed for both endpoints. RESULTS: 1847 patients were included in the analyses. The probability of missing data was not influenced by the study arms (MIN vs INT OR: 0.97 95%CI: 0.87-1.08). Longitudinal changes in HRQoL scores did not differ between the two follow-up regimens (MIN vs INT SF-12 PCS: -0.573, CI95%: -1.31; 0.16; SF-12 MCS: -0.243, CI95%: -1.08; 0.59; PGWB: -0.057, CI95%: -0,88; 0,77). The mean cost difference between the intensive and minimalist arm was €531 for low-risk patients and €683 for high-risk patients. CONCLUSION: In the follow-up of endometrial cancer after surgery, a minimalist treatment regimen did not affect quality of life and was cost-saving in both low-risk and high-risk recurrence patients. As previous results showed no survival benefit, a minimalist approach is justified. The relevant proportion of missing data on secondary outcomes of interest could be a critical point that deserves special attention.

Factors associated with adherence to BRCA1/2 mutation testing after oncogenetic counseling in long-surviving patients with a previous diagnosis of breast or ovarian cancer.

BRCA1/2 mutations account for 5 to 10% of breast and 15% of ovarian cancers. Various guidelines on BRCA1/2 genetic counseling and testing have been issued, and the criteria have evolved over the years. Oncogenetic counseling aims to inform patients about the possibility and implications of undergoing predictive testing and risk management programs. We analyzed a cohort of 50 subjects with a previous personal history of breast or ovarian cancer who had not been tested for BRCA1/2 mutations at the time of diagnosis but were found eligible according to the most recent guidelines. All patients were offered pre-test oncogenetic counseling and BRCA1/2 genetic testing. The mean time from cancer diagnosis to genetic counseling was over 10 years. We analyzed socio-demographic and psychological parameters associated with the decision to undergo BRCA1/2 genetic testing or the reasons behind the withdrawal. Thirty-nine patients underwent BRCA1/2 genetic testing. Patients who accept the genetic test communicate more easily with family members than those who refuse. Factors associated with test refusal are having a long-term partner and having a negative perception of life. There is a trend, although not statistically significant, toward younger age at cancer diagnosis, more likely to participate in cancer screening programs (71.8% vs. 45.5%), and more likely to have daughters (63.3% vs. 37.5%) in the group that accepted the test. The offer of BRCA testing was well accepted by our study population, despite the many years since the cancer diagnosis. With the perspective of further broadening the access criteria to genetic testing, it is important to understand how to best approach pre-test counseling in long-surviving patients with a previous diagnosis of cancer.

Retrospective Analysis of the Correlation of MSI-h/dMMR Status and Response to Therapy for Endometrial Cancer: RAME Study, a Multicenter Experience.

BACKGROUND: There is poor evidence regarding sensitivity to chemotherapy in endometrial cancer (EC) based on microsatellite instability (MSI)/mismatch repair (MMR) status. METHODOLOGY: The RAME study is a retrospective analysis aiming to assess response to chemotherapy in MSI-high (h)/deficient (d) MMR and MSI-low (l)/proficient (p) MMR EC patients. Primary endpoints were recurrence-free survival (RFS) for patients with localized disease and progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent disease. RESULTS: A total of 312 patients treated between 2010 and 2022 in four high-volume Multicenter Italian Trial in Ovarian cancer and gynecological malignancies (MITO) centers were selected. In total, 239 patients had endometrioid EC (76.6%), 151 had FIGO stage I at diagnosis (48.9%) and 71 were MSI-h/dMMR (22.8%). Median age was 65 (range 31-91) years. Among patients with localized disease, median RFS was 100.0 months (95% CI 59.4-140.7) for MSI-l/pMMR and 120.9 months (60.0-181.8) for MSI-h/dMMR (p = 0.39). Seventy-seven patients received first-line chemotherapy for advanced/recurrent disease. Patients with MSI-h/dMMR ECs had a significantly worse OS (p = 0.039). In patients receiving platinum-based chemotherapy, no statistically significant differences in PFS (p = 0.21) or OS (p = 0.057) were detected, although PFS and OS were numerically longer in the MSI-l/pMMR population. CONCLUSIONS: Patients with metastatic MSI-h/dMMR EC receiving first-line chemotherapy had a significantly worse OS.

Clinical, Sonographic, and Hysteroscopic Features of Endometrial Carcinoma Diagnosed after Hysterectomy in Patients with a Preoperative Diagnosis of Atypical Hyperplasia: A Single-Center Retrospective Study.

BACKGROUND: atypical endometrial hyperplasia (AEH) is a precancerous condition implying a high risk of concurrent endometrial cancer (EC), which might be occult and only diagnosed at postoperative histopathological examination after hysterectomy. Our study aimed to investigate potential differences in preoperative clinical, sonographic, and hysteroscopic characteristics in patients with AEH and postoperative diagnosis of EC. METHODS: a retrospective single-center study was carried out on a case series of 80 women with AEH undergoing diagnostic workup, including ultrasonography and hysteroscopy, with subsequent hysterectomy. Women with AEH confirmed at the histopathological examination were compared with patients with a postoperative diagnosis of EC. RESULTS: in our population, EC was diagnosed in 53 women, whereas the preoperative diagnosis of AEH was confirmed in 27 cases. At ultrasonography, women with occult EC showed greater endometrial thickness (20.3 mm vs. 10.3 mm, p 0.001) and size of the endocavitary lesion (maximum diameter 25.2 mm vs. 10.6 mm, p 0.001), and a higher prevalence of irregular endometrial-myometrial junction (40.5% vs. 6.7%, p 0.022) and endouterine vascularization at color Doppler (64.2% vs. 34.6%, p 0.017). At hysteroscopy, patients with occult EC showed a higher prevalence of necrosis (44.2% vs. 4.2%, p 0.001) and atypical vessels (70.6% vs. 33.3%, p 0.003), whereas true AEH mainly presented as a protruding intracavitary lesion (77.8% vs. 50.9%, p 0.029). In EC, subjective assessment by the operator was more frequently indicative of cancer (80.0% vs. 12.5%). No difference was found for clinical variables. CONCLUSIONS: occult EC in AEH may exhibit some differences in ultrasonographic and hysteroscopic patterns of presentation compared with real AEH, which could prompt a more significant suspect for the possible presence of concurrent EC at preoperative diagnostic workup.

The "Sandwich" Schedule: A Well-Tolerated Adjuvant Treatment Both in Intermediate-High- and High-Risk Endometrial Cancer.

(1) Background: In intermediate-high- and high-risk endometrial cancer (EC), radiotherapy (RT) and chemotherapy (CT) play a basic role. However, there is controversy regarding the optimal timing of their combination. The "sandwich" schedule involves adjuvant CT followed by RT and subsequent CT. The aim of this study is to assess the tolerability and efficacy of the "sandwich" schedule. (2) Methods: A retrospective study was conducted in two gynecological oncology units in Torino, Italy, from 1 January 2003 until 31 December 2021. Intermediate-high- and high-risk patients with available clinical data were included. Compliance with treatment, CT and RT toxicities, disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were analyzed. (3) Results: A total of 118 patients were selected: 27.1% FIGO I-II stages and 72.9% III-IV. Most of the patients (75.4%) received a carboplatin-paclitaxel combination, and as much as 94.9% of CT cycles were completed. Chemotherapy-related G3-4 toxicities were detected in 5.3% of the patients, almost half of which were hematological. Grade 2 gastrointestinal and genitourinary toxicities were reported in 8.4% and 4.2% of cases, respectively. With a median follow-up of 46 months, DFS was 77.6%, CSS was 70% and 5-year OS was 54%. (4) Conclusions: The "sandwich" schedule for CT and RT combination is an effective adjuvant treatment with low toxicity both in intermediate-high- and high-risk EC.

Low-Grade Uterine Endometrial Stromal Sarcoma: Prognostic Analysis of Clinico-Pathological Characteristics, Surgical Management, and Adjuvant Treatments. Experience From Two Referral Centers.

Objective: Low-grade uterine endometrial stromal sarcoma (LG-ESS) is a rare tumor characterized by an overall good survival but showing a indolent behavior and a variable risk of recurrence. There is no clear consensus on the optimal management of these tumors and no prognostic or predictive factors have been established. With this study, we evaluated the prognostic relevance of several clinical, surgical, and pathological features in patients affected by LG-ESS to identify risk factors associated with recurrence. Methods: We retrospectively analyzed 52 LG-ESS cases, treated from January 1st, 1994, to May 31st, 2020, in two referral centers. The relationship between recurrence and clinicopathological characteristics as well as surgical treatment was investigated. Risk of recurrence and disease-free survival (DFS) were estimated by Cox regression and the Kaplan-Meier analysis, respectively. Results: Of 52 patients with LG-ESS, 8 experienced recurrence (15%). The median follow-up was 100 months (SD ± 96, range: 15-336). By univariate analysis, fragmentation/morcellation, tumor size, FIGO stage, higher mitotic count, presence of necrosis, and lymphovascular space invasion (LSVI) resulted associated with a poorer outcome. Conversely, the surgical modality (laparotomic vs laparoscopic and hysterectomy with bilateral salpingo-oophorectomy vs local excision) and pelvic lymphadenectomy were not. Even the different modalities of adjuvant therapy (hormonal therapy, radiotherapy, and chemotherapy) showed no prognostic significance. Tumor fragmentation/morcellation and higher mitotic count resulted independent prognostic variables at multivariate analysis. Conclusions: This data supports the avoidance of any type of morcellation if LG-ESS is suspected preoperatively. Higher mitotic count and, possibly, tumor size, advanced FIGO stage, necrosis, and LVSI could be exploited to tailor the adjuvant therapy, but these results need to be confirmed in larger prospective studies.

Evaluation of the Impact of Cognitive Training on Quality of Life in Patients with Multiple Sclerosis.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of cognitive rehabilitation in a group of multiple sclerosis (MS) patients. METHODS: Thirty-four patients were included in this study and randomly allocated either to treatment with multidisciplinary rehabilitation plus cognitive training or to treatment with multidisciplinary rehabilitation alone. RESULTS: After 3 months of cognitive treatment, the patients assigned to the rehabilitation plus cognitive training group displayed an improvement in the cognitive test of executive function and a marked improvement in quality of life (QoL). The patients treated with multidisciplinary rehabilitation without cognitive training improved in the physical composite score alone. Both groups of patients displayed an improvement in depression, though the improvement was confirmed at the 6-month follow-up examination (p = 0.036) only in patients treated with multidisciplinary rehabilitation plus cognitive training. CONCLUSIONS: Our results indicate that the multidisciplinary rehabilitation treatment is the best approach to treat MS. The specific effect of each treatment needs to be assessed to be able to determine its role within a multidisciplinary approach. Cognitive rehabilitation is an important aspect of this multidisciplinary approach insofar as it may improve the QoL of MS people.

Does robot-assisted gait training improve ambulation in highly disabled multiple sclerosis people? A pilot randomized control trial.

BACKGROUND: Robotic training is commonly used to assist walking training in patients affected by multiple sclerosis (MS) with non-conclusive results. OBJECTIVE: To compare the effect of robot-assisted gait training (RAGT) with that of conventional walking training (CWT) on gait competencies, global ability, fatigue and spasticity in a group of severely affected patients with MS. METHODS: A pilot, single-blind randomized controlled trial was conducted in 43 severe (Expanded Disability Status Scale (EDSS) score of 6-7.5) and non-autonomous ambulant in-patients with MS. Experimental group performed 12 sessions of RAGT, whereas control group performed the same amount of CWT. Primary outcome measures were gait ability assessed by 2 minutes walking test and Functional Ambulatory Category; secondary outcomes were global ability (modified Barthel Index), global mobility (Rivermead Mobility Index), severity of disease (EDSS) and subjectively perceived fatigue (Fatigue Severity Scale). RESULTS: The number of subjects who achieved a clinical significant improvement was significantly higher in RAGT than in CWT ( p < 0.05 for both primary outcome measures). RAGT also led to an improvement in all the other clinical parameters (global ability: p < 0.001, global mobility: p < 0.001, EDSS: p = 0.014 and fatigue: p = 0.001). CONCLUSIONS: RAGT improved the walking competencies in non-autonomous ambulant patients with MS, with benefits in terms of perceived fatigue.

Chronic Pain in Multiple Sclerosis Patients: Utility of Sensory Quantitative Testing in Patients with Fibromyalgia Comorbidity.

BACKGROUND: Lower thermal and discomfort thresholds may predispose multiple sclerosis (MS) patients to chronic pain, but a possible effect of fibromyalgia (FM) comorbidity has never been investigated. Aims were to investigate the thermal and discomfort thresholds in the evaluation of pain intensity between MS patients with FM (PFM+) and MS patients with pain not associated to FM (PFM-). METHODS: One hundred thirty three MS patients were investigated for chronic pain. FM was assessed according to the 1990 ACR diagnostic criteria. An algometer was used to measure the thresholds in the patients and 60 matched healthy subjects. RESULTS: Chronic pain was present in 88 (66.2%) patients; 12 (13.6%) had neuropathic pain, 22 (17.3%) were PFM+ and 65 (48.9%) PFM-. PFM+ were predominantly female (p = 0.03) and had a greater EDSS (p = 0.01) than NoP; no other significant differences emerged than PFM-. The thresholds were lower in MS patients than controls (p < 0.01), mainly in the PFM+. FM severity influenced the thermal threshold (p < 0.001), while the female gender influenced the discomfort threshold (p < 0.001). CONCLUSION: Thermal and discomfort thresholds were lower in patients than controls and were the lowest in PFM+. Their more severely impaired thermal threshold supports a neurophysiological basis of such association.

Chronic pain in multiple sclerosis: is there also fibromyalgia? An observational study.

BACKGROUND: Chronic pain is common in persons with multiple sclerosis (MS), but the co-morbidity of fibromyalgia (FM) has yet to be investigated in MS. Objectives of the study were to evaluate, among the various types of chronic pain, the frequency of FM in MS and its impact on MS patients' health-related quality of life (HRQoL). MATERIAL AND METHODS: 133 MS patients were investigated for the presence and characterization of chronic pain within 1 month of assessment. A rheumatologist assessed the presence FM according to the 1990 ACR diagnostic criteria. Depression, fatigue, and HRQoL were also assessed by means of specific scales. RESULTS: Chronic pain was present in 66.2% of patients (musculoskeletal in 86.3%; neuropathic in 13.7%; absent in 33.8% [called NoP]). Pain was diagnosed with FM (PFM+) in 17.3% of our MS patients, while 48.9% of them had chronic pain not FM type (PFM-); the prevalence of neuropathic pain in these 2 sub-groups was the same. PFM+ patients were prevalently females and had a higher EDSS than NoP. The PFM+ patients had a more pronounced depression than in the NoP group, and scored the worst in both physical and mental QoL. CONCLUSIONS: In our sample of MS patients we found a high prevalence of chronic pain, with those patients displaying a higher disability and a more severe depression. Moreover, FM frequency, significantly higher than that observed in the general population, was detected among the MS patients with chronic pain. FM occurrence was associated with a stronger impact on patients' QoL.

Enhanced-MRI and ultrasound evaluation of painful shoulder in patients after stroke: a pilot study.

BACKGROUND: Epidemiological and radiological studies have previously been performed to identify the possible causes of hemiplegic shoulder pain (HSP). Many different etiologies have been postulated, though no clear correlations have emerged, and a multifactorial pathogenesis of HSP has been proposed. Recently, two MRI-based studies have described different shoulder findings as possible causes of pain in chronic stroke survivors. PURPOSE: The aim of this study was to describe the structural abnormalities of the painful shoulder in the first months after stroke by ultrasound and enhanced MRI. The secondary aims were to identify possible predisposing factors for HSP and to evaluate its impact on motor recovery. METHODS: One hundred and fifty-three first-time stroke patients, admitted to the Santa Lucia Foundation for rehabilitation, were investigated for HSP. Twenty-five stroke patients with HSP and 16 stroke patients without shoulder pain were included. An ultrasound evaluation and enhanced shoulder MRI were performed for all the patients. RESULTS: Among the shoulder abnormalities detected by both imaging studies, only capsulitis, which was detected by enhanced shoulder MRI in 88% of the HSP patients, was independently associated with pain (p < 0.001) and proven to be predictive of pain intensity as expressed by the VAS score (p < 0.003). HSP correlated with a worse global recovery (p < 0.05) as well as with male sex (p = 0.006), neglect (p = 0.02) and subluxation (p = 0.03), although none of these features were found to be independent predictors of pain. CONCLUSION: Adhesive capsulitis was found to be a possible cause of HSP. However, MRI, which is more expensive than other diagnostic tools, may be considered the gold standard tool for understanding the etiology of HSP.