Background The role of adjuvant treatment in the intermediate-risk group of patients with early-stage cervical cancer is controversial and is supported by a single randomized Gynecologic Oncology Group (GOG) 92 study performed more than 20 years ago. Recent retrospective studies have shown excellent local control in this group of patients after radical surgery with no additional adjuvant treatment. Primary Objective To evaluate if adjuvant (chemo)radiation is associated with a survival benefit after radical surgery in patients with intermediate-risk cervical cancer. Study Hypothesis Radical surgery alone is non-inferior to the combined treatment of radical surgery followed by adjuvant (chemo)radiation in disease-free survival in patients with intermediate-risk cervical cancer. Trial Design This is a phase III, international, multicenter, randomized, non-inferiority trial in which patients with intermediate-risk cervical cancer will be randomized 1:1 into arm A, with no additional treatment after radical surgery, and arm B, receiving adjuvant external beam radiotherapy±brachytherapy ± concomitant chemotherapy. Patient data will be collected over 3 years post-randomization of the last enrolled patient for primary endpoint analysis or for 6 years for the overall survival analysis. Major Inclusion/Exclusion Criteria Patients with intermediate-risk early-stage cervical cancer (IB1–IIA), defined as lymph node-negative patients with a combination of negative prognostic factors (tumor size >4 cm; tumor size >2 cm and lymphovascular space invasion; deep stromal invasion >2/3; or tumor-free distance <3 mm) with squamous cell carcinoma or human papillomavirus (HPV)-related adenocarcinoma, are eligible for the trial. Primary Endpoint Disease-free survival defined as time from randomization to recurrence diagnosis. Sample Size 514 patients from up to 90 sites will be randomized. Estimated Dates for Completing Accrual and Presenting Results It is estimated that the accrual will be completed by 2027 (with 3 additional years of follow-up) and primary endpoint results will be published by 2031. Estimated trial completion is by 2034. Trial Registration NCT04989647.

Background: To prospectively assess LLL incidence among cervical cancer patients treated by uterine surgery complemented by SLN biopsy, without PLND. Methods: A prospective study in 150 patients with stage IA1–IB2 cervical cancer treated by uterine surgery with bilateral SLN biopsy. Objective LLL assessments, based on limb volume increase (LVI) between pre- and postoperative measurements, and subjective patient-perceived swelling were conducted in six-month periods over 24-months post-surgery. Results: The cumulative incidence of LLL at 24 months was 17.3% for mild LLL (LVI 10–19%), 9.2% for moderate LLL (LVI 20–39%), while only one patient (0.7%) developed severe LLL (LVI > 40%). The median interval to LLL onset was nine months. Transient edema resolving without intervention within six months was reported in an additional 22% of patients. Subjective LLL was reported by 10.7% of patients, though only a weak and partial correlation between subjective-report and objective-LVI was found. No risk factor directly related to LLL development was identified. Conclusions: The replacement of standard PLND by bilateral SLN biopsy in the surgical treatment of cervical cancer does not eliminate the risk of mild to moderate LLL, which develops irrespective of the number of SLN removed.

Do the perinatal outcomes of patients following hysteroscopic treatment for Asherman syndrome (AS) differ from that of a control population? Perinatal complications including placental issues, high blood loss, and prematurity in women after treatment for AS should be considered as moderate to high risk, especially in patients who have undergone more than one hysteroscopy (HS) or repeated postpartum instrumental revisions of the uterine cavity (Dilation and Curettage; D&C). The detrimental impact of AS on obstetrics outcomes is commonly recognized. However, prospective studies evaluating perinatal/neonatal outcomes in women with AS history are sparse, and the characteristics accounting for the respective morbidity of AS patients remain to be elucidated. We conducted a prospective cohort study utilizing data from patients who underwent HS treatment for moderate to severe AS in a single tertiary University-affiliated hospital (enrolled between 01 January 2009 and March 2021), and who consequently conceived and progressed to at least 22nd gestational week of pregnancy. Perinatal outcomes were compared to a control population without an AS history, retrospectively enrolled concomitantly at the time of delivery for each patient with AS. Maternal and neonatal morbidity was assessed as well as the characteristics-related risk factors of AS patients. Our analytic cohort included a total of 198 patients, 66 prospectively enrolled patients with moderate to severe AS and 132 controls. We used multivariable logistic regression to calculate a propensity score to match 1–1 women with and without AS history based on demographic and clinical factors. After matching, 60 pairs of patients were analysed. Chi-square test was used to compare perinatal outcomes between the pairs. Spearman’s correlation analysis was utilized to investigate the correlation between perinatal/neonatal morbidity and the characteristics-related factors of AS patients. The odds ratio (OR) for the associations was calculated by logistic regression. Among the 60 propensity matched pairs, the AS group more frequently experienced overall perinatal morbidity, including abnormally invasive placenta (41.7% vs 0%; P < 0.001), retained placenta requiring manual or surgical removal (46.7% vs 6.7%; P < 0.001), and peripartum haemorrhage occurrence (31.7% vs 3.3%; P < 0.001). Premature delivery (<37 gestational weeks) was reported more frequently also for patients with AS (28.3% vs 5.0%; P < 0.001). However, no increased frequency of intra-uterine growth restriction or worsened neonatal outcomes were observed in AS group. Univariable analysis of risk factors for AS group morbidity outcomes revealed that the main factor related to abnormally invasive placenta was two or more HS procedures (OR 11.0; 95% CI: 1.33–91.23), followed by two or more D&Cs preceding AS treatment (OR 5.11; 95% CI: 1.69–15.45), and D&C performed postpartum as compared to post abortion (OR 3.0; 95% CI: 1.03–8.71). Similarly, two or more HS procedures were observed as the most important factor for retained placenta (OR 13.75; 95% CI: 1.66–114.14), followed by two or more preceding D&Cs (OR 5.16; 95% CI: 1.67–15.9). Premature birth was significantly associated with the number of preceding D&Cs (OR for two or more, 4.29; 95% CI: 1.12–14.91). Although the cohort of patients with AS was enrolled prospectively, a baseline imbalance was intrinsically involved in the retrospective enrolment of the control group. However, to reduce the risk of bias, confounding factors were adjusted for using propensity score matching. The limitation to the generalization of our reported results is the single institution design in which all patients were treated for AS in one tertiary medical centre. Within our search scope, our study represents one of the first and largest prospective studies of perinatal and neonatal outcomes in moderate to severe AS patients with a prospectively analysis of the risks factors of characteristics significantly influencing reported morbidities among patients with AS. The study was supported by the Charles University in Prague [UNCE 204065] and by the institutional grant of The General Faculty Hospital in Prague [00064165]. No competing interests were declared. N/A.

Background In addition to the diagnostic accuracy of imaging methods, patient-reported satisfaction with imaging methods is important. Objective To report a secondary outcome of the prospective international multicenter Imaging Study in Advanced ovArian Cancer (ISAAC Study), detailing patients’ experience with abdomino-pelvic ultrasound, whole-body contrast-enhanced computed tomography (CT), and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for pre-operative ovarian cancer work-up. Methods In total, 144 patients with suspected ovarian cancer at four institutions in two countries (Italy, Czech Republic) underwent ultrasound, CT, and WB-DWI/MRI for pre-operative work-up between January 2020 and November 2022. After having undergone all three examinations, the patients filled in a questionnaire evaluating their overall experience and experience in five domains: preparation before the examination, duration of examination, noise during the procedure, radiation load of CT, and surrounding space. Pain perception, examination-related patient-perceived unexpected, unpleasant, or dangerous events (‘adverse events’), and preferred method were also noted. Results Ultrasound was the preferred method by 49% (70/144) of responders, followed by CT (38%, 55/144), and WB-DWI/MRI (13%, 19/144) (p<0.001). The poorest experience in all domains was reported for WB-DWI/MRI, which was also associated with the largest number of patients who reported adverse events (eg, dyspnea). Patients reported higher levels of pain during the ultrasound examination than during CT and WB-DWI/MRI (p7 of 10) during the ultrasound examination. We did not identify any factors related to patients' preferred method. Conclusion Ultrasound was the imaging method preferred by most patients despite being associated with more pain during the examination in comparison with CT and WB-DWI/MRI. Trial registration number NCT03808792.

This is a case report of a rare finding of an extragonadal yolk sac tumor in a 37-year-old patient who presented with shortness of breath and abdominal bloating. During imaging and staging surgery, the findings were strongly suggestive of an extragonadal advanced tumor presenting with peritoneal dissemination, predominantly affecting omentum, with no clear primary origin. Histology revealed an extragonadal yolk sac tumor in a pure form outside the ovaries. Lacking an obvious origin elsewhere, the tumor was highly suspected to have truly originated from the omentum. The patient underwent surgery and four cycles of chemotherapy consisting of cisplatin, etoposide, and bleomycin. One-year outpatient follow-up thereafter showed no relapse. We herein discuss a possible site of the tumor origin and its development, as well as diagnostic challenges and disease prognosis.

To take full advantage of recombinant Pichia pastoris (Komagataella phaffii) as a production system for heterologous proteins, the complex protein secretory process should be understood and optimised by circumventing bottlenecks. Typically, little or no attention has been paid to the fate of newly synthesised protein inside the cell, or its passage through the secretory pathway, and only the secreted product is measured. However, the system’s productivity (i.e. specific production rate q_p), includes productivity of secreted (q_p,extra) plus intracellularly accumulated (q_p,intra) protein. In bioreactor cultivations with P. pastoris producing penicillin G acylase, we studied the dynamics of product formation, i.e. both the specific product secretion (q_p,extra) and product retention (q_p,intra) as functions of time, as well as the kinetics, i.e. productivity in relation to specific growth rate (μ). Within the time course, we distinguished (I) an initial phase with constant productivities, where the majority of product accumulated inside the cells, and q_p,extra, which depended on μ in a bell-shaped manner; (II) a transition phase, in which intracellular product accumulation reached a maximum and productivities (intracellular, extracellular, overall) were changing; (III) a new phase with constant productivities, where secretion prevailed over intracellular accumulation, q_p,extra was linearly related to μ and was up to three times higher than in initial phase (I), while q_p,intra decreased 4–6-fold. We show that stress caused by heterologous protein production induces cellular imbalance leading to a secretory bottleneck that ultimately reaches equilibrium. This understanding may help to develop cultivation strategies for improving protein secretion from P. pastoris. Key Points• A novel concept for industrial bioprocess development.• A Relationship between biomass growth and product formation in P. pastoris.• A Three (3) phases of protein production/secretion controlled by the AOX1-promoter.• A Proof of concept in production of industrially relevant penicillin G acylase.