Search Results (419)

Background: Neoadjuvant systemic therapy is the preferred treatment approach for stage II–III HER2-positive breast cancer (BC). Real-life data comparing regimens with or without anthracyclines combined with two HER2 drugs is lacking. We compared the efficacy and toxicity of two commonly used regimens. Methods: Retrospective data were collected on patients newly diagnosed with clinical stage II–III HER2-positive BC and treated at Sheba Medical Center, Israel, between September 2017 and June 2022 with either neoadjuvant DCbHP (docetaxel, carboplatin, trastuzumab, pertuzumab) or ACTHP (doxorubicin, cyclophosphamide, paclitaxel trastuzumab pertuzumab). PCR (pathological complete response) (ypT0/isN0) was evaluated in both cohorts and according to HER2 immunohistochemistry (IHC) staining (3+ or 2+ and fluorescence in situ hybridization [FISH] positive), estrogen receptor (ER), tumor size and nodal status. The toxicity indices evaluated were reductions in left ventricle ejection fraction (LVEF), dose reductions, hospitalizations and febrile neutropenia. Results: Here, 106 received ACTHP and 73 received DCbHP. Median age at diagnosis, ER status, HER2 IHC (2+/FISH pos or 3+) and nodal status were balanced. PCR occurred in 63.1% of patients, 67.0% and 57.5% in the ACTHP and DCbHP groups, respectively (p = 0.129). In patients with HER2 3+ IHC, pCR rates were significantly better with the ACTHP regimen than with DCbHP (83% vs. 62.9%, p < 0.039). No difference was observed among patients with HER2 +2 IHC FISH pos. Symptomatic LVEF decrease was observed in seven patients (6.6%) receiving ACTHP vs. none (0%) receiving DCbHP (p < 0.001). Conclusions: PCR rates were similar overall between ACTHP and DCbHP; however, in the HER2 3+ subgroup, ACTHP demonstrated increased efficacy. DCbHP was significantly less cardiotoxic. Full article

Electricity markets are transitioning to zonal and nodal pricing to maximize social welfare, improve price signals, and enhance congestion management. South Korea, traditionally reliant on uniform pricing, is evaluating this transition but lacks a detailed impact analysis. This study assessed the impacts of various zonal and nodal pricing schemes on power systems and provided policy implications for this transition. We (1) modeled the power system at various levels of granularity, obtaining a detailed 4579-node representation; (2) constructed a set of zonal and nodal pricing schemes reflecting changes in market-clearing models and pricing mechanisms; and (3) performed quantitative analyses through simulations for each scheme. Under the current system marginal price (SMP)-based uniform pricing, the schemes with the least market impact are SMP-based zonal pricing with two bidding zones and extended locational marginal pricing. These results can guide the development of an appropriate pricing transition pathway, although a market price reduction of 4.8–7.0% appears inevitable. Within the Korean electricity market, wherein a Transco is a monopoly retailer, we identified potential conflicts of interest for the Transco in zonal and nodal pricing. By focusing on South Korea, this study offers valuable insights into any electricity market considering the transition to zonal and nodal pricing. Full article

Growing global concerns over reducing carbon emissions in the electricity market have accelerated the integration of renewable energy sources and electric vehicles, increasing variabilities and uncertainties across various nodes of power networks. System planners and operators recognize the importance of probabilistic bulk system reliability assessment methods capable of capturing the real-time behavior of components in the emerging systems. In this regard, the paper proposes a methodology for conducting bulk system reliability assessments of power system networks characterized by variable supply and demand profiles at different bulk power points. This paper implements a nodal negative load modeling method to integrate wind power generation in reliability assessment, capturing the cross-correlation between demand–supply variabilities at any node of the network. The multi-state load model employs the load cut-off strategy to reduce the number of demand scenarios, enhancing the computational efficiency. Moreover, the multi-state wind modeling approach considers the penetration levels, ensuring the impact of increasing penetration is appropriately captured. The methodology determines a list of a reduced set of scenarios for which consequence assessment needs to be conducted. The proposed framework and methods can readily be applied by power utilities, as these methods can be incorporated into most commercial software that uses an analytical approach for CSR assessment. The methodology is illustrated using the Roy Billinton Test System (RBTS) and can be effectively applied to other networks. Full article

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for patients with locally advanced cervical cancer (LACC), nodal failure remains a major challenge to cure. To optimize treatment outcomes for node-positive LACC and reduce the incidence of nodal failure, various treatment approaches have been explored, including methods of surgical nodal staging or dissection, RT dose escalation strategies, such as intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to involved nodes, and elective treatment of subclinical para-aortic (PAO) disease. Additionally, there is growing interest in emerging precision RT techniques, such as magnetic resonance-guided radiotherapy (MRgRT) and proton therapy, which may allow for further improvement in the therapeutic ratio. This review outlines the various methods of detection of nodal metastasis, treatment options for node-positive LACC, techniques of nodal radiotherapy and their clinical evidence in efficacy and toxicity profiles. Furthermore, recent advances in systemic therapy and promising novel therapeutic directions that may shape the management of node-positive LACC are discussed. Full article

Today, topological structural optimisation is a valuable computational technique for designing mechanical components with optimal mass-to-stiffness ratios. Thus, this work aims to assess the performance of the Radial Point Interpolation Method (RPIM) when compared with the well-established Finite Element Method (FEM) within the context of a vehicle suspension control arm’s structural optimisation process. Additionally, another objective of this work is to propose an optimised design for the suspension control arm. Being a meshless method, RPIM allows one to discretise the problem’s domain with an unstructured nodal distribution. Since RPIM relies on a weak form equation to establish the system of equations, it is necessary to additionally discretise the problem domain with a set of background integration points. Then, using the influence domain concept, nodal connectivity is established for each integration point. RPIM shape functions are constructed using polynomial and radial basis functions with interpolating properties. The RPIM linear elastic formulation is then coupled with a bi-evolutionary bone remodelling algorithm, allowing for non-linear structural optimisation analyses and achieving solutions with optimal stiffness/mass ratios. In this work, a vehicle suspension control arm is analysed. The obtained solutions were evaluated, revealing that RPIM allows better solutions with enhanced truss connections and a higher number of intermediate densities. Assuming the obtained optimised solutions, four models are investigated, incorporating established design principles for material removal commonly used in vehicle suspension control arms. The proposed models showed a significant mass reduction, between 18.3% and 31.5%, without losing their stiffness in the same amount. It was found that the models presented a stiffness reduction between 5.4% and 9.8%. The obtained results show that RPIM is capable of delivering solutions similar to FEM, confirming it as an alternative numerical technique. Full article

The spontaneous firing of the sinoatrial (SA) node, the physiological pacemaker of the heart, is generated within sinoatrial nodal cells (SANCs) and is regulated by a “coupled-clock” pacemaker system, which integrates a “membrane clock”, the ensemble of ion channel currents, and an intracellular “Ca²⁺ clock”, sarcoplasmic reticulum-generated local submembrane Ca²⁺ releases via ryanodine receptors. The interactions within a “coupled-clock” system are modulated by phosphorylation of surface membrane and sarcoplasmic reticulum proteins. Though the essential role of a high basal cAMP level and PKA-dependent phosphorylation for basal spontaneous SANC firing is well recognized, the role of basal CaMKII-dependent phosphorylation remains uncertain. This is a critical issue with respect to how cardiac pacemaker cells fire spontaneous action potentials. This review aspires to explain and unite apparently contradictory results of pharmacological studies in the literature that have demonstrated a fundamental role of basal CaMKII activation for basal cardiac pacemaker function, as well as studies in mice with genetic CaMKII inhibition which have been interpreted to indicate that basal spontaneous SANC firing is independent of CaMKII activation. The assessment of supporting and opposing data regarding CaMKII effects on phosphorylation of Ca²⁺-cycling proteins and spontaneous firing of SANC in the basal state leads to the necessary conclusion that CaMKII activity and CaMKII-dependent phosphorylation do regulate basal cardiac pacemaker function. Full article

Background: The incidence of melanoma is increasing globally. The estimated worldwide incidence is projected to increase from 324,635 cases in 2020 to 510,000 in 2040. In the UK, melanoma accounts for 4% of all new cases of cancer. Melanomas occurring in the skin of the head and neck represent 13% and 23% of cases in women and men, respectively. Prognostic indicators include presence of nodal or distant metastasis, ulceration, and Breslow thickness, where >4 mm thickness predicts poorest overall survival rates. Giant melanomas, a term generally applied to melanomas larger than 5–10 cm, are rare and often have a very poor prognosis. Clinical case: An 82-year-old female presented acutely with a 2–3-day history of delirium and urinary retention in February 2022. In addition, she was noted to have a large fungating growth on her forehead that obscured the bridge of the nose and had been slowly increasing in size for the past year prior to admission. She had initially presented in primary care with a small growth on her forehead but declined further investigations for fear of contracting COVID-19. She consented to having further assessment and management of the forehead mass. A shave biopsy revealed giant nodular melanoma, specifically, the largest melanoma of the face reported in the literature. Remarkably, our patient underwent a successful complete excision and skin grafting, with no evidence of recurrence or distal metastasis after 2 years of follow up. Conclusions: This case highlights the anxieties people felt about contracting COVID-19 when national guidelines recommended shielding that had resulted in further morbidity. Despite poor prognostic factors, clinically and histologically, our patient did not need any systemic anticancer therapy nor radiotherapy. She was well after 2 years follow up without any signs of recurrence. Full article

Purpose: Bladder cancer is one of the most common malignancies worldwide with over 614,000 new cases and 220,000 deaths annually. Five percent of newly diagnosed patients have metastatic disease. Metastatic urothelial carcinoma (mUC) is primarily treated with cisplatin-based chemotherapy, immunotherapy, targeted therapy, or combinations. Cure from disease is rarely achieved, with the overall survival being between 12 and 15 months, and the 5-year survival in the range of 5–15%. Historically, mUC has been deemed surgically incurable. There are limited data available to assess survival benefit with surgical extirpation of the primary site or metastases. In this review, we summarize findings from previous studies regarding the role of surgery in patients with clinically node-positive bladder cancer or metastatic urothelial carcinoma, focusing on cytoreductive radical cystectomy (RC) and distant metastasectomy. Materials and Methods: A literature search was conducted on The Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica dataBASE (Embase), preprints, and ClinicalTrials.gov for studies that discussed the role of surgery in patients with clinically node-positive bladder cancer or mUC, focusing on cytoreductive radical cystectomy (RC) and distant metastasectomy. The keywords used included transitional cell carcinoma, urothelial carcinoma, bladder cancer, bladder carcinoma, bladder metastasis, bladder tumor, lymph node metastasis, metastasis, and muscle-invasive bladder cancer. Results: The final analysis included 21 studies, including 17 retrospective reviews, 2 prospective phase II trials, and 2 meta-analyses. Of the studies that assessed patients with urothelial carcinoma (UC) with nodal involvement, 15 of 17 showed improved survival with chemotherapy followed by radical cystectomy (RC). To our knowledge, few studies have solely assessed surgery in patients with distant metastases. Most studies include patients with both UC with local LN involvement and patients with distant sites of metastasis. Of these studies, 12 of 13 indicated improved survival with metastasectomy. Conclusions: While it remains to be seen whether metastasectomy will have a role in patients with mUC, patient selection is an important factor when assessing the survival benefits. Patient characteristics correlated with improved survival include good performance status, good response to chemotherapy, and single site of metastasis. Further studies of mUC patients are required to clearly assess the survival impact of cytoreductive surgery. Full article

In architectural engineering, triangular tessellation using polygon mesh topology is one of the commonly used computational geometric approaches to simplify a free curved building façade into flat triangular facets and their subsequent straight edges. In such a façade system, exterior panels are supported by a network of profiles that correspond to their edges hidden behind the panels at an offset distance. A group of profiles, derived from the edges common to a node point of tessellated panels (i.e., the outermost panels enveloping the building), may dislocate from each other when offset from their original locations due to non-coplanar alignment and unique offset directions and distances. This dislocation problem gives rise to geometric complications in nodal connector design in addition to varying in the connected profile count and orientations. Design considerations regarding the effects of ’offset vertex dislocation’ (i.e., the dislocation of the edges when it offsets from the original topology due to incoherent normal direction) should incorporate proper variables in the correct sequence based on a fundamental understanding that causes the dislocation problem. However, it is very often these topological problems pertaining to offset that are neglected, leading to subsequent design flaws. Such oversights diminish the inherent strengths of DfMA (design for manufacture and assembly) and design automation. This study develops a computational mathematical approach aimed at addressing the geometric complexities in nodal connector design. It focuses on two main areas: the precise positioning of substructure profiles essential for the design and a design automation approach that minimizes the length of the nodal connector arms to enhance 3D printing productivity. A life-scale proof-of-concept structure based on an automated parametric design process that implements the research findings demonstrates the application, incorporating 3D-printed PA12 (Polyamide-12) nodal connectors. Full article

Adjuvant radiation therapy (ART) for macroscopic regional nodal cutaneous melanoma has evolved. A significant step was the discovery of targeted therapies, particularly towards V600E-mutated melanoma, and immunotherapy under its different kinds. Prior to this, the defining trial was the Australia and New Zealand Melanoma Trials Group (ANZMTG) 01.02/Trans-Tasman Radiation Oncology Group (TROG) 02.01 phase III trial that showed that ART using three-dimensional conformal radiotherapy (3DCRT) decreased in-field recurrence by 50% (48 Gray (Gy) in 20 fractions). After the advent of systemic therapies, a trial of the combination targeted therapy of dabrafenib plus trametinib toward BRAF V600-mutant nodal cutaneous melanoma showed that all 35 patients achieved a pathological response. Radiotherapy (RT) was found to be safe to give with concurrent combination therapy. A retrospective immunotherapy study found that in 71 patients that received ART after a first recurrence, further in-field recurrence significantly decreased (p = 0.01). For those tumours that do recur in-field, there are now competing therapies like Talimogene laherparepvec or T-VEC. Generally, ART is now used at the first recurrence. The challenge now is to find which melanomas are truly radiosensitive if ART is to have any future role in this scenario. Full article

Desmoplastic melanoma (DM) is an uncommon subtype of cutaneous melanoma that presents distinct diagnostic and treatment challenges. This review aims to explore the role of adjuvant radiation therapy (RT) in managing DM. To evaluate this question, we reviewed relevant published reports on DM and its treatment and synthesized these findings. It was found that the clinical behavior of DM varies significantly based on its classification as either “pure” DM (pDM, ≥90% desmoplastic features) or mixed DM (mDM, ≤90% desmoplastic features). Patients with pDM have a uniquely high risk of local recurrence but a relatively lower likelihood of nodal disease. Recent studies question the necessity of sentinel lymph node biopsy for pDM patients while illustrating impressive response rates to immune checkpoint inhibition. Most data supporting adjuvant RT predate these changes in surgical management and systemic therapy, yet consistently demonstrate that adjuvant RT reduces the absolute risk of local recurrence by >50%, without significant long-term toxicity. Thus, the existing literature continues to support the conclusion that adjuvant RT effectively reduces the likelihood of local recurrence in pDM patients. Although evolving surgical and systemic therapies are reshaping treatment approaches, adjuvant RT should remain a standard of care. Full article

Water distribution systems (WDSs) are crucial for providing clean drinking water, requiring an efficient design to minimize costs and energy usage. This study introduces an enhanced life cycle energy analysis (LCEA) model for an optimal WDS design, incorporating novel criteria for pipe maintenance and a new resilience index based on nodal pressure. The improved LCEA model features a revised unit energy formula and sets standards for pipe rehabilitation and replacement based on regional regulations. Applied to South Korea’s Goyang network, the model reduces energy expenditure by approximately 35% compared to the cost-based design. Unlike the cost-based design, the energy-based design achieves results that can relatively reduce energy when designing water distribution networks by considering recovered energy. This allows designers to propose designs that consume relatively less energy. Analysis using the new resilience index shows that the energy-based design outperforms the cost-based design in terms of pressure and service under most pipe failure scenarios. The implementation of the improved LCEA in real-world pipe networks, including Goyang, promises a practical life cycle-based optimal design. Full article

In this study, a thorough experimental investigation of the synchronous blade vibrations of a radial turbine is performed for different IGV configurations. First, the blade modes are measured experimentally and calculated numerically. Subsequently, the vibrations are recorded with two redundant measurement systems during real operation. Strain gauges were applied on certain blades, while a commercial blade-tip-timing system is used for the measurement of blade deflections. The experimentally determined vibration properties are compared with numerical estimations. Initially, the vibrations recorded with the “nominal” IGV were presented. This IGV primarily generates nodal diameter (ND) 0 vibrations. Subsequently, the impact of two different IGV configurations is examined. First, a mistuned IGV, which has the same number of vanes as the “nominal” IGV is examined. By intentionally varying the distance between the vanes, additional low engine order excitations are generated. Moreover, an IGV with a higher number of vanes is employed to induce excitations at higher frequency modes and ND6 vibrations. Certain vibrations are consistently measured across all IGV configurations, which cannot be attributed to the spiral turbine casing. In addition, a turbine–compressor interaction has been observed. Full article

While South Africa is deemed one of the countries with the highest irradiation levels, it still utilises coal as its primary energy source due to its abundance. Due to the world-wide drive towards carbon neutrality, residential, commercial, agricultural, and industrial consumers are considering small-scale embedded generation systems. The National Rationalised Specifications 097-2-3 document specifies the scale of the embedded generation capacity a consumer is allowed to install. However, specifications do not yet make the required provisions for the addition of energy storage. The effective collective management of the grouped small-scale embedded generation systems could provide a high level of energy security and increase the percentage of renewable energy generation in the total energy mix. Potential challenges come into play when considering the stochastic nature of photovoltaic generation and its effect on the storage capacity and the dispersion in load profiles of the residential units typically present on a low-voltage network. This paper contributes by investigating the utilisation of photovoltaic generation in conjunction with storage as the basis for virtual power plant control, with the aim to safely increase renewable energy penetration and improve energy security, all while remaining within the South African low-voltage regulatory limits. A two-level virtual power plant controller is proposed with the dispersed energy storage units as the primary controllable resources and the dispersed photovoltaic generation as the secondary controllable resources. The objective of the controller is to achieve nodal energy management, energy sharing, and ancillary service provision and finally to increase renewable energy penetration. A representative single-feeder low-voltage network is simulated, and test cases of 50% and 75% renewable energy penetration are investigated as the basis for evaluation. The proposed controller architecture proved to maintain network integrity for both test cases. The adaptability of the controller architecture was also confirmed for a changed feeder topology; in this case, it was a multi-feeder topology. Future work is warranted to inform policy on the allowed levels of renewable energy penetration to be based not only on demand but also on the level of energy storage present in a network. Full article

Background/Objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient’s quality of life is of paramount importance. Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024. Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1–2] (97%) and typically occurred after 10 weeks of treatment. Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center. Full article