Endometrioma surgery: Hit with your best shot (But know when to stop).

Ovarian endometriomas (OEs) are commonly detected by ultrasound in individuals affected by endometriosis. Although surgery was widely regarded in the past as the gold standard for treating OEs, especially in the case of large cysts, the surgical management of OEs remains debated. Firstly, OEs often represent the "tip of the iceberg" of underlying deep endometriosis, and this should be considered when treating OEs to ameliorate patients' pain for focusing on the surgical objectives and providing better patient counseling. In the context of fertility care, OEs may have a detrimental effect on ovarian reserve through structural alterations, inflammatory responses, and oocyte reserve depletion. Conversely, the surgical approach may exacerbate the decline within the same ovarian reserve. While evidence suggests no improvement in in-vitro fertilization (IVF) outcomes following OE surgery, further studies are needed to understand the impact of OE surgery on spontaneous fertility. Therefore, optimal management of OEs is based on individual patient and fertility characteristics such as the woman's age, length of infertility, results of ovarian reserve tests, and surgical background. Among the available surgical approaches, cystectomy appears advantageous in terms of reduced recurrence rates, and traditionally, bipolar coagulation has been used to achieve hemostasis following this approach. Driven by concerns about the negative impact on ovarian reserve, alternative methods to obtain hemostasis include suturing the cyst bed, and novel methodologies such as CO2 laser and plasma energy have emerged as viable surgical options for OEs. In instances where sonographic OE features are non-reassuring, surgery should be contemplated to obtain tissue for histological diagnosis and rule out eventual ovarian malignancy.

Real life clinical outcomes of relapsed/refractory diffuse large B cell lymphoma in the rituximab era: The STRIDER study.

BACKGROUND: Relapse and refractory (R/R) rates after first-line R-CHOP in diffuse large B cell lymphomas (DLBCL) are ~40% and ~15% respectively. AIMS: We conducted a retrospective real-world analysis aimed at evaluating clinical outcomes of R/R DLBCL patients. MATERIAL AND METHODS: Overall, 403 consecutive DLBCL patients treated in two large hematological centers in Torino, Italy were reviewed. RESULTS: At a median follow up of 50 months, 5-year overall survival from diagnosis (OS-1) was 66.5%, and 2-year progression free survival (PFS-1) was 68%. 134 (34.4%) patients relapsed (n = 46, 11.8%) or were refractory (n = 88, 22.6%) to R-CHOP. Most employed salvage treatments included platinum salt-based regimens in 38/134 (28.4%), lenalidomide in 14 (10.4%). Median OS and PFS after disease relapse or progression (OS-2 and PFS-2) were 6.7 and 5.1 months respectively. No significant difference in overall response rate, OS-2 or PFS-2 in patients treated with platinum-based regimens versus other regimens was observed. By multivariate analysis, age between 60 and 80 years, germinal center B cell type cell of origin and extranodal involvement of <2 sites were associated with better OS-2. DISCUSSION: Our findings confirm very poor outcomes of R/R DLBCL in the rituximab era. Widespread approval by national Medicine Agencies of novel treatments such as CAR-T cells and bispecific antibodies as second-line is eagerly awaited to improve these outcomes.

Stem cell collection and hematological recovery in the Fondazione Italiana Linfomi (FIL) MCL0208 clinical trial.

In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity. We therefore focused on the role played by CD34 + hematopoietic stem cells (PBSC) harvesting and reinfusion on toxicity and outcome. Overall, 90% (n = 245) of enrolled patients who underwent the first leukapheresis collected ≥ 4 × 106 PBSC/kg, 2.6% (n = 7) mobilized < 4 × 106 PBSC/kg and 7.7% (n = 21) failed the collection. Similar results were obtained for the planned second leukapheresis, with only one patient failing both attempts. Median count of reinfused PBSC was 5 × 106/kg and median time to recovery from neutropenia G4 was 10 days from ASCT. No impact of mobilizing subtype or number of reinfused PBSC on hematological recovery and LEN dose reduction was noted. At a median follow-up of 75 months from ASCT, PFS and OS of transplanted patients were 50% and 73%, respectively. A long lasting G4 neutropenia after ASCT (> 10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial.

BACKGROUND: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Perception about benefits and risks related to combined hormonal contraceptives use in women with Lynch syndrome.

OBJECTIVE: Lynch syndrome (LS) is a hereditary condition associated with an increased risk of colorectal and endometrial cancer. This study aimed to assess the knowledge, attitudes, and beliefs of women with LS regarding combined hormonal contraceptive (CHC) use compared to a control group of healthy women. METHODS: Pre-menopausal women with LS (n = 43) and an age-matched control group of healthy women (n = 128) participated in this prospective, cross-sectional study (NCT05909410). Participants completed an electronic questionnaire evaluating perceptions of CHC use and its impact on various cancers, medical conditions, and symptoms. Statistical analysis compared responses between the two groups, with reported p-values. RESULTS: Women with LS were less likely to use CHCs compared to the control group (p = 0.03) and had a more negative perception of CHCs' impact on colorectal cancer (p = 0.023) and endometrial cancer (p = 0.028). Limited knowledge was observed in both groups regarding the protective effects of CHCs against colorectal and ovarian cancer. Perceptions of CHC use and its impact on symptoms and chronic diseases did not significantly differ between the groups (p > 0.05). CHC use was not associated with greater awareness of the protective effect against colorectal (p = 0.89) and endometrial cancer (p = 0.47), but it was associated with a desire for contraception (OR 21.25; 95% CI 1.16 to 388.21; p = 0.039). CONCLUSION: This study highlights contrasting perceptions of CHCs and their implications in oncology between women with LS and healthy women. Tailored counselling and support strategies are crucial for empowering women with LS to make informed decisions about their gynaecologic health.

This study illuminates divergent perceptions of combined hormonal contraceptives and their oncological implications between women with Lynch syndrome and healthy women.Tailored counseling and supportive strategies are essential for empowering women with Lynch syndrome to make informed decisions regarding their gynecologic health.

Frozen Section of Placental Membranes and Umbilical Cord: A Valid Diagnostic Tool for Early-Onset Neonatal Sepsis Management.

Early-onset neonatal sepsis (EONS), a serious infection in newborns within 3 days, is challenging to diagnose. The current methods often lack accuracy, leading to unnecessary antibiotics or delayed treatment. This study investigates the role of the frozen section examination of placental membranes and umbilical cord (FSMU) to improve EONS diagnosis in the daily lab practice. This retrospective study reviewed data from 59 neonates with EONS risk factors who underwent FSMU according to our institutional protocol. Concordance between the FSMU and the Final Pathological Report (FPR) was assessed. The FSMU demonstrated a high concordance (Kappa = 0.88) for funisitis diagnosis, with excellent accuracy (98.3%). A moderate concordance was observed for chorioamnionitis stage and grade. The FSMU shows promise as a rapid and accurate tool for diagnosing EONS, particularly for funisitis. This study suggests that the FSMU could be a valuable tool for EONS diagnosis, enabling a more judicious antibiotic use and potentially improving outcomes for newborns.

Fertility preservation in women with endometriosis: Oocyte cryopreservation and other techniques.

In recent years, advancements in cryopreservation techniques for oocytes, embryos, and ovarian tissue have enabled offering fertility preservation (FP) options to women with endometriosis. It is recommended to always conduct specialized counselling on FP, especially before considering surgical interventions for endometriosis. The decision regarding the methods of FP, the timing, and to which women affected by endometriosis these techniques should be offered are still subjects of discussion. However, several studies suggest that it can be proposed before surgical interventions for endometriosis, particularly if the patient is undergoing mono or bilateral endometrioma surgery. The most recommended technique is ovarian stimulation, followed by oocyte cryopreservation. Nevertheless, the literature contains various studies describing FP through embryo cryopreservation or the retrieval and cryopreservation of ovarian tissue.

Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment.

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.

Experimental and new investigational drugs for the treatment of uterine fibroids.

INTRODUCTION: Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations. AREAS COVERED: This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids. EXPERT OPINION: Despite ulipristal acetate's well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

"From the tip to the deep of the iceberg": Parametrial involvement in endometriosis.

Deep endometriosis (DE) can be localized in the parametrium, a complex bilateral anatomical structure, sometimes necessitating intricate surgical intervention due to the potential involvement of autonomic nerves, uterine artery, and ureter. If endometriotic ovarian cysts have been considered metaphorically representative of "the tip of the iceberg" concerning concealed DE lesions, it is reasonable to assert that parametrial lesions should be construed as the most profound region of this iceberg. Also, based on a subdual clinical presentation, a comprehensive diagnostic parametrial evaluation becomes imperative to strategize optimal management for patients with suspected DE. Recently, the ULTRAPARAMETRENDO studies aimed to evaluate the role of transvaginal ultrasound for parametrial endometriosis, showing distinctive features, such as a mild hypoechoic appearance, starry morphology, irregular margins, and limited vascularization. The impact of medical therapy on parametrial lesions has not been described in the current literature, primarily due to the lack of adequate detection at imaging. The extension of DE into the parametrium poses significant challenges during the surgical approach, thereby increasing the risk of intra- and postoperative complications, mainly if performed by centers with low expertise and following multiple surgical procedures where parametrial involvement has gone unrecognized. Over time, the principles of nerve-sparing surgery have been incorporated into the surgical DE treatment to minimize iatrogenic damage and potentially reduce the risk of functional complications.

Impact of surgery for endometriosis on the outcomes of in vitro fertilization.

This narrative review aims to summarize available evidence on the IVF-associated outcomes after surgery for endometriosis. Only one retrospective study investigated if surgical treatment of superficial/peritoneal endometriosis may modify the outcomes of IVF; therefore, more data are needed to confirm the benefit of surgery for this type of disease for improving ART outcomes, and to be able to support it in routine practice. Solid evidence from several meta-analyses demonstrates that surgical treatment of endometriomas does not enhance the outcomes of IVF. In contrast, surgical treatment of ovarian endometriosis may lead to a reduction in ovarian reserve, especially in cases involving bilateral endometriomas or repeated surgical procedures. Some non-randomized studies have examined if surgical treatment on deep endometriosis may influence IVF outcomes. A systematic review with meta-analysis revealed that patients who underwent surgery before IVF exhibited significantly higher pregnancy rates per patient, pregnancy rates per cycle, and live birth rates per patient compared to those without prior surgery. However, the available data are insufficient to recommend surgical excision of deep endometriosis as the first-line treatment for asymptomatic patients to enhance IVF outcomes.

Endometriosis-associated ovarian cancer: a different clinical entity.

OBJECTIVE: To compare survival outcomes and patterns of recurrence between endometriosis-associated ovarian cancer patients and non-endometriosis-associated ovarian cancer patients. METHODS: This retrospective study included data of consecutive patients with endometrioid or clear cell ovarian cancer treated at the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano between January 2010 and June 2021. Patients were assigned to one of two groups according to the absence or presence of endometriosis together with ovarian cancer at final histological examination. Survival outcomes were assessed using Kaplan-Meier and Cox hazard models. Proportions in recurrence rate and pattern of recurrence were evaluated using the Fisher exact test. RESULTS: Overall, 83 women were included in the endometriosis-associated ovarian cancer group and 144 in the non-endometriosis-associated ovarian cancer group, respectively. Patients included in the non- endometriosis-associated ovarian cancer group had a shorter disease-free survival than those in the endometriosis-associated ovarian cancer group (23.4 (range 2.0-168.9) vs 60.9 (range 4.0-287.8) months; p<0.001). Univariable and multivariable analyses showed that the association with endometriosis, previous hormonal treatment, early stage at presentation, and endometrioid histology were related to better disease-free survival in the entire study population. Similarly, patients in the non-endometriosis-associated ovarian cancer group had a shorter median (range) overall survival than those in the endometriosis-associated ovarian cancer group (54.4 (range 0.7-190.6) vs 77.6 (range 4.5-317.8) months; p<0.001). Univariable and multivariable analyses showed that younger age at diagnosis, association with endometriosis, and early stage at presentation were related to better overall survival. The recurrence rate was higher in the non-endometriosis-associated ovarian cancer group (63/144 women, 43.8%) than in the endometriosis-associated ovarian cancer group (17/83 women, 20.5%; p<0.001). CONCLUSIONS: Endometriosis-associated ovarian cancer patients had significantly longer disease-free survival and overall survival than non-endometriosis-associated ovarian cancer patients, while the recurrence rate was higher in non-endometriosis-associated ovarian cancer patients.

Ultrasonographic characterization of parametrial endometriosis: a prospective study.

OBJECTIVE: To study the ultrasonographic diagnostic accuracy and characteristics of parametrial endometriosis comprehensively. DESIGN: This prospective study enrolled patients with suspected deep endometriosis (DE) scheduled for laparoscopic surgical treatment. Preoperative ultrasonographic examinations were performed following the International Deep Endometriosis Analysis criteria. This study aimed to evaluate the presence of parametrial endometriosis and its ultrasonographic characteristics, using surgical diagnosis as the reference standard. Additionally, indirect signs of DE and concomitant DE nodules associated with parametrial involvement were identified, assessing their predictive significance in the anterior, lateral, and posterior parametrial areas. SETTING: Referral institution for endometriosis. PATIENTS: Patients with suspected DE scheduled for surgical treatment. INTERVENTIONS: Standardized preoperative ultrasonographic examination. MAIN OUTCOME MEASURES: The diagnostic accuracy of transvaginal ultrasound in identifying parametrial endometriosis, including sensitivity and specificity, and the ultrasonographic characteristics of parametrial nodules, prevalence in distinct parametrial areas, and associations with indirect DE signs and concomitant DE nodules. RESULTS: Surgical confirmation of parametrial nodules was observed in 105 of 545 patients (left, 18.5; right, 17.0%). Transvaginal ultrasound demonstrated a sensitivity of 77.1% (95% confidence interval, 68.0%-84.8%) and specificity of 99.1% (95% confidence interval, 67.7%-99.8%). Parametrial nodules typically exhibited characteristics such as a mild hypoechoic appearance (83.6%), starry morphology (74.7%), irregular margins (70.2%), and low vascularization. The posterior parametrial region was the most common location (52.2%), followed by the lateral (41.0%) and anterior (6.8%) parametrial regions. Concomitant DE nodules in the rectum (63.5%) and infiltrating the rectovaginal septum (56.5%) were significantly more prevalent in patients with parametrial involvement. Indirect DE signs, such as the ovaries fixed to the uterine wall (71.8%) and the absence of a posterior sliding sign (51.8%), were also more common in women with parametrial nodules. Hydronephrosis, although relatively uncommon in patients with parametrial involvement (8.2%), was largely detected in lateral parametrial nodules (70.0%). CONCLUSIONS: This study represents a systematic ultrasonographic characterization of parametrial endometriosis. Specifically, it comprehensively assesses the diagnostic accuracy of transvaginal ultrasound in identifying parametrial involvement within a sizable cohort of patients with preoperative suspicion of DE. CLINICAL TRIAL REGISTRATION NUMBER: NCT06017531.

Endometrial receptivity in women with endometriosis.

As endometriosis is recognized as a contributing factor to infertility, prompting couples to embark on Assisted Reproductive Technology (ART) treatments, it becomes crucial to comprehend the extent and way this condition can affect success rates. Natural conception data reveal lower success rates for women with endometriosis, yet the same cannot be extrapolated to the outcomes of in vitro fertilization (IVF). In recent years, advancements in the ART process, particularly the distinct stages of the IVF pathway and investigations into embryo quality have shown a comparable rate of embryonic quality and chromosomal normalcy (euploidy) between embryos obtained from individuals with or without endometriosis. Thus, the primary question that lingers relates to the functionality of the endometrium. This review addresses whether endometriosis can influence endometrial receptivity and implantation rates.

Epidemiology of infertility in women with endometriosis.

Endometriosis is a benign, chronic, inflammatory condition affecting up to 10 % of women and characterised by the presence of glands and stroma tissue outside the uterus. Epidemiological and clinical studies demonstrate a consistent association between endometriosis and infertility. However, this relationship is far to be clearly understood and several mechanisms are involved. Available data show that patients with endometriosis have an increased estimated risk of infertility between two and four times compared with the general population. On the other hand, the probability of patients with infertility to have endometriosis is reported up to about 50 % of the cases. Future studies should aim to better elucidate the mechanisms behind endometriosis-associated infertility in order to offer the more appropriate and tailored management for the patients.

A review of phase II and III drugs for the treatment and management of endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy. AREAS COVERED: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis. EXPERT OPINION: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.