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In a double-blind, randomized trial involving nearly 1000 patients followed for a median of 2 years, pembrolizumab injections for 1 year after surgery led to improved disease-free survival at 24 months as compared with placebo (77% vs. 68%). Almost one third of patients in the pembrolizumab group had a grade 3 adverse event, but no deaths were due to pembrolizumab.

Gestational trophoblastic disease represents a spectrum of pregnancy related disorders, ranging from pre-malignant hydatidiform mole to malignant tumours, collectively referred to as gestational trophoblastic neoplasia. Gestational trophoblastic neoplasia includes malignant invasive mole, choriocarcinoma, and rare placental site trophoblastic and epithelioid trophoblastic tumours.1

Background Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors. Methods The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976–2006) were compared to our new modern cohort (2007–2014), when intensified treatments were introduced. Results Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8–87.6%) and 75% (95% CI 66.3–84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61–23.81, p  = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17–50.96, p  < 0.001) were most significant on multivariable analysis. No significant differences in prognostic factors were seen between the old and new patient cohort. However, the new cohort received significantly more cisplatin-based and high-dose chemotherapy, and patients with an interval ≥48 months demonstrated an improved median overall survival (8.3 years, 95% CI 1.53–15.1, versus 2.6 years, 95% CI 0.73–4.44, p  = 0.·005). Conclusion PSTT/ETT with advanced FIGO stage or an interval ≥48 months from their last known pregnancy have poorer outcomes. Platinum-based and high-dose chemotherapy may help to improve survival in poor-prognosis patients.

Background In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. Patients and Methods In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. Results No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (–2.5; 95% CI –5.2 to 0.1), EORTC QLQ-C30 physical functioning (–0.87; 95% CI –2.7 to 1.0), and FKSI-DRS (–0.7; 95% CI –1.2 to –0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). Conclusions Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. Trial Registration Clinicaltrials.gov Identifier: NCT03142334 Patient-reported outcomes provide an important measure of health-related quality of life and can complement efficacy and safety results. This article presents analyses of health-related quality of life in patients enrolled in the KEYNOTE-564 trial.

Patients with gestational trophoblastic neoplasia who have an International Federation of Gynaecology and Obstetrics (FIGO) risk score of 5 or 6 usually receive non-toxic single-agent chemotherapy as a first-line treatment. Previous studies suggest that only a third of patients have complete remission, with the remaining patients requiring toxic multiagent chemotherapy to attain remission. As stratification factors are unknown, some centres offer multiagent therapy upfront, resulting in overtreatment of many patients. We aimed to identify predictive factors for resistance to single-agent therapy to inform clinicians on which patients presenting with a FIGO score of 5 or 6 are likely to benefit from upfront multiagent chemotherapy. We did a multicentre, retrospective, cohort study of patients with gestational trophoblastic neoplasia presenting with a FIGO score of 5 or 6, who received treatment at three gestational trophoblastic neoplasia reference centres in the UK, Brazil, and the USA between Jan 1, 1964, and Dec 31, 2018. All patients who had been followed up for at least 12 months after remission were included. Patients were excluded if they had received a non-standard single-agent treatment (eg, etoposide); had been given a previously established first-line multiagent chemotherapy regimen; or had incomplete data for our analyses. Patient data were retrieved from medical records. The primary outcome was the incidence of chemoresistance after first-line or second-line single-agent chemotherapy. Variables associated with chemoresistance to single-agent therapies were identified by logistic regression analysis. In patient subgroups defined by choriocarcinoma histology and metastatic disease status, we did bootstrap modelling to define thresholds of pretreatment human chorionic gonadotropin concentrations and identify groups of patients with a greater than 80% risk (ie, a positive predictive value [PPV] of 0·8) of resistance to single-agent chemotherapy. Of 5025 patients with low-risk gestational trophoblastic neoplasia, we identified 431 patients with gestational trophoblastic neoplasia presenting with a FIGO risk score of 5 or 6. All patients were followed up for a minimum of 2 years. 141 (40%) of 351 patients developed resistance to single-agent treatments and required multiagent chemotherapy to achieve remission. Univariable and multivariable logistic regression revealed metastatic disease status (multivariable logistic regression analysis, odds ratio [OR] 1·9 [95% CI 1·1–3·2], p=0·018), choriocarcinoma histology (3·7 [1·9–7·4], p=0·0002), and pretreatment human chorionic gonadotropin concentration (2·8 [1·9–4·1], p<0·0001) as significant predictors of resistance to single-agent therapies. In patients with no metastatic disease and without choriocarcinoma, a pretreatment human chorionic gonadotropin concentration of 411 000 IU/L or higher yielded a PPV of 0·8, whereas in patients with either metastases or choriocarcinoma, a pretreatment human chorionic gonadotropin concentration of 149 000 IU/L or higher yielded the same PPV for resistance to single-agent therapy. Approximately 60% of women with gestational trophoblastic neoplasia presenting with a FIGO risk score of 5 or 6 achieve remission with single-agent therapy; almost all remaining patients have complete remission with subsequent multiagent chemotherapy. Primary multiagent chemotherapy should only be given to patients with metastatic disease and choriocarcinoma, regardless of pretreatment human chorionic gonadotropin concentration, or to those defined by our new predictors. None. For the Portuguese translation of the abstract see Supplementary Materials section.

Acute kidney injury is widely recognized in acute urate nephropathy, but hyperuricemia is now considered as a threat for acute kidney injury and its mortality. The objective of the study was to observe the effect of uric acid levels in patients with acute kidney injury as a predictor of mortality. A cross-sectional study was conducted at inpatients nephrology department of Pakistan Institute of Medical Sciences, Islamabad from May 2019 to May 2020. The outcome of the study was measured in terms of normal and elevated uric acid levels in acute kidney injury patients. 196 patients with acute kidney injury, who were followed up through history, examination and serum markers included in this study. The association of the outcome with serum uric acid levels was analyzed using the chi-square test.The mean age of the patients was 46.54 ± 19.06 years. It included 115 (58.7%) males and 81 (41.3%) females. The average level of uric acid was 7.29 ± 2.35 mg/dL. 158 (80.6%) patients were discharged and 38 (19.4%) expired. Serum uric acid is positively interrelated with renal function test levels. The correlation was significant with a p-value ≤ 0.05. The mean uric acid of individuals who expired was significantly more than the mean uric acid of discharged patients (p = 0.0001). Out of 158 discharged patients 56 (35.44%) had hyperuricemia and out of 38 expired patients 32 (84.2%) had hyperuricemia. As a result, it was seen that among the patients who had expired increased levels of uric acid were seen (p>0.0001). The study concluded that high uric acid is a predictor of the outcome of patients with acute kidney injury.

With the ongoing urbanization and densification of cities worldwide, the planning and utilization of urban underground space (UUS) have become crucial for developing urban underground infrastructure. Given the limited construction space within dense urban areas and the influence of declining groundwater levels, technologies such as open caissons and various vertical shaft methods have been introduced for UUS development. However, the dissemination of these technologies remains fragmented across different domains, lacking systematic summarization. A comprehensive, up-to-date overview of open caisson and vertical shaft technologies is essential for their effective application. In the manuscript, a systematic analysis of vertical shaft technologies, specifically focusing on their use in soft ground conditions, is conducted. The analysis is based on an extensive literature review and case study evaluation. It addresses the unique challenges posed by high compressibility, low bearing capacity, and groundwater sensitivity. Conventional shaft technologies and mechanized systems, including open caissons, drilled shafts, and the novel pressed-in ultra-deep assembled shafts (PIAUS), are evaluated systematically. Key aspects such as design principles, construction techniques, and stability in soft soils are discussed. The limitations of conventional methods in soft UUS are highlighted, while the advantages of advanced mechanized systems—such as rapid construction, reduced environmental impact, and improved safety—are emphasized. A detailed comparison of case studies demonstrates that PIAUS construction technology is particularly efficient in urban areas with confined spaces, dense building conditions, and ground conditions up to 200 MPa, with shaft diameters up to 12.8 m and depths of 115.2 m. Additionally, its suitability for rapid construction in soft and medium ground conditions is supported by undrained excavation with parallel excavation and liner sinking techniques. The PIAUS technology shows considerable potential for future projects, including shield construction shafts, ventilation shafts for tunnels, underground parking garages, and stormwater storage wells. This manuscript also highlights emerging mechanized methods in underground space development, their advantages, limitations, and areas for future research and improvement.

Research on the multi-field coupling effects in rocks has been ongoing for several decades, encompassing studies on single physical fields as well as two-field (TH, TM, HM) and three-field (THM) couplings. However, the environmental conditions of rock masses in deep resource extraction and underground space development are highly complex. In such settings, rocks are put through thermal-hydrological-mechanical-chemical (THMC) coupling effects under peak temperatures, strong osmotic pressures, extreme stress, and chemically reactive environments. The interaction between these fields is not a simple additive process but rather a dynamic interplay where each field influences the others. This paper provides a comprehensive analysis of fragmentation evolution, deformation mechanics, mechanical constitutive models, and the construction of coupling models under multi-field interactions. Based on rock strength theory, the constitutive models for both multi-field coupling and creep behavior in rocks are developed. The research focus on multi-field coupling varies across industries, reflecting the diverse needs of sectors such as mineral resource extraction, oil and gas production, geothermal energy, water conservancy, hydropower engineering, permafrost engineering, subsurface construction, nuclear waste disposal, and deep energy storage. The coupling of intense stress, fluid flow, temperature, and chemical factors not only triggers interactions between these fields but also alters the physical and mechanical properties of the rocks themselves. Investigating the mechanical behavior of rocks under these conditions is essential for averting accidents and assuring the soundness of engineering projects. Eventually, we discuss vital challenges and future directions in multi-field coupling research, providing valuable insights for engineering applications and addressing allied issues.

Background Etoposide (E) at 100 mg/m 2 combined with Cisplatin (P) at 20 mg/m 2 represents an induction 2-day regimen embedded in our clinical practice for patients with advanced GCT or TN at high risk of early death. We evaluated 24/7 Em-EP administration to a combined GCT-TN cohort at our Emergency Cancer Treatment Centre (ECTC) to determine its efficacy within the acute setting. Methods Patients who received Em-EP during a five-year interval were identified from electronic databases at Imperial College Healthcare NHS Trust. Data collected included demographics, treatment details and clinical outcome. Results Em-EP was administered in the emergency setting to 104 patients, predominantly young adults (median age 35, range 17–71). Half the cases were GCT ( n  = 52): 22 male (6 seminomas, 13 non-seminomas); 30 female (2 dysgerminomas, 28 non-dysgerminomas). The other 50% were treated for TN ( n  = 52): 45 gestational (GTN) and 7 non-gestational. Most patients received Em-EP for a new cancer diagnosis ( n  = 100, 96%), within 24 h ( n  = 93, 89%) and out-of-hours ( n  = 74, 70%). Indications for Em-EP included symptomatic disease ( n =  66, 63%), high-burden disease, ( n =  51, 49%) and organ failure requiring Intensive Care Unit support ( n =  9, 9%). Neutropenic sepsis was observed in 5%. Four-week overall survival after Em-EP administration was 98%. Conclusions Despite the potentially fatal complications encountered in the acute setting, early mortality with Em-EP is low at our ECTC. Specialist units that treat unwell patients with advanced GCT or TN should consider making Em-EP available 24/7 for emergency administration. Its efficacy within a prospective cohort and in other platinum-sensitive malignancies requires evaluation.

The rapid advancement of modern megapolises has led to a dearth of surface space, and, in response, engineers have begun to trial substitutes below ground level. Shafts are generally used to provide temporary access and permanent work to the subsurface for tunnelling, as well as for lifts or ventilation purposes. In urban areas, one important design issue is the prediction of the excavation-induced displacements by open caisson shaft construction. Settlements and ground movements associated with open caisson shafts are influenced by the choice of construction method, soil composition, and excavation geometry. Compared with other geotechnical construction events, for instance, tunnelling, the literature relating to the ground deformations induced from open caisson shafts are comparatively limited. This review offers an evaluation of several case studies that utilize experimental and computational modeling techniques to provide clearer insights into earth pressure distribution and induced surface and subsurface soil displacements, as well as the associated ground deformations during open caisson shaft construction. The modeling test results are compared to the state of the practice ground deformation prediction theories and measured results from field monitoring data. Findings indicate that the lateral earth pressure distribution aligns closely with the theoretical predictions based on Terzaghi’s and Berezantzev’s models, and lateral earth pressure diminishes gradually until the onset of active wall displacement. Current modeling techniques generally fail to properly represent in situ stress states and large-scale complexities, emphasizing the need for hybrid approaches that combine physical and numerical methodologies. In future studies, modern approaches, including artificial intelligence (AI) monitoring (e.g., PINNs, ACPP), multi-field coupling models (e.g., THMC), and transparent soil testing, hold profound potential for real-time prediction, optimization, and visualization of soil deformation. Numerical–physical coupling tests will integrate theory and practice. Improving prediction reliability in complicated soil conditions such as composite and heterogenous strata using different modeling techniques is still unclear, and further investigation is therefore needed.