The role of surgery for invasive pulmonary aspergillosis in paediatric hemato-oncology patients-Can we better define it?

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a serious condition with high morbidity and mortality in paediatric patients with cancer, haematological diseases or immunodeficiencies with or without allogeneic haematopoietic stem cell transplantation (HSCT). The role of surgical intervention for the management of IPA has scarcely been investigated. OBJECTIVES: The aim of this study was to present a single center experience of management of IPA in paediatric patients of an oncological ward, to determine the short and long-term outcomes after thoracic surgical interventions, and to outline the indications of surgical interventions in selected patients. PATIENTS/METHODS: We conducted a retrospective study of 44 paediatric patients with proven and probable IPA treated in our institution between January 2003 and December 2021. The primary endpoint was the overall survival after surgical interventions. Secondary endpoints included post-operative morbidity and mortality. RESULTS: The median age at diagnosis of IPA in our cohort was 11.79 years (range 0.11-19.6). The underlying conditions were malignancies in 34 (77%) patients and haematological or immunological disorders with allogeneic HSCT in 9 (23%) patients. We performed thoracic surgical interventions in 10 (22.7%) patients. Most patients received a video assisted thoracic surgery. Only one patient died within 90 days after surgery with a median follow-up time of 50 months. No other major post-operative complications occurred. The calculated 5-year survival rate from IPA for patients after surgical intervention with curative intention was 57% and 56% for patients without (p = .8216). CONCLUSIONS: IPA resulted in relevant morbidity and mortality in our paediatric patient cohort. Thoracic surgical interventions are feasible and may be associated with prolonged survival as a part of multidisciplinary approach in selected paediatric patients with IPA. Larger scale studies are necessary to investigate the variables associated with the necessity of surgery.

Hybrid (Digital/Water Seal) Chest Drainage System - An Innovative Device for Patients with Anticipated Air Leaks.

BACKGROUND: To date, several chest drainage systems are available, such as digital drainage systems (DDS) and traditional systems with continuous suction or water seal. However, none of these systems were yet shown to be favorable in the treatment of complex situations such as persistent air leaks or residual spaces. We present in-vitro as well as clinical data of a novel hybrid drainage system consisting of an optimized digital drainage system (ODDS) and an underwater seal drainage system (UWSD). METHODS: For in-vitro analysis, a DDS and an ODDS were connected to a pleural cavity simulator. Different air leaks were produced and data on intrapleural pressure and air flow were analyzed. Furthermore, we tested the hybrid drainage system in 10 patients with potential air leaks after pulmonary surgery. RESULTS: In in-vitro analysis, we could show, that with advanced pump technology, pressure fluctuations caused by the drainage system when trying to maintain a set pressure level in patients with airleaks were much smaller when using an ODDS and could even be eliminated when using a fluid collection canister with sufficient buffer capacity. This minimized air leak boosts caused by the drainage system. Optimizing the auto-pressure regulation algorithms also led to a reduced airflow through the fistula and promoted rest. Switching to a passive UWSD also reduced the amount of airflow. Clinical application of the hybrid drainage system yielded promising results. CONCLUSION: The novel hybrid drainage system shows promising results in the treatment of patients with complex clinical situations such as persistent air leaks.

Psychiatrists and general practitioners perspectives on sexual wellbeing: Why it matters?

OBJECTIVE: Sexual wellbeing is a fundamental component of overall wellbeing and is often impacted by common psychiatric disorders such as depression. Despite this, research suggests it is underexplored in clinical practice. This preliminary study aimed to examine whether this is the case in both psychiatrists and general practitioners (GPs). METHOD: GPs and psychiatrists completed a survey examining the exploration of various sexual wellbeing domains with patients. It included open-ended questions regarding factors that influence this exploration, whether clinicians felt this was their responsibility, and their level of training in this area. RESULTS: Clinicians who felt it was their responsibility to enquire about sexual wellbeing reported exploring it in more patients than those who did not endorse this perspective. Overall, clinicians from both specialties demonstrated a reluctance to explore most sexual wellbeing topics, and this appeared to be due to many factors including views held by clinicians themselves. Most clinicians felt they had not received adequate training in this area. CONCLUSIONS: Domains of sexual wellbeing are largely underexplored by clinicians from both specialties. Educational materials and training for clinicians are needed to facilitate the exploration of this important area with patients, specifically in the context of mental health.

[Surgical and Percutaneous Dilatational Tracheostomy - Technique and Pitfalls]. / Plastische und dilatative Tracheostomie ­ Technik und Fallstricke.

A tracheostomy is usually necessary for long-term mechanical ventilation or complicated weaning. Other indications include swallowing disorders with recurrent aspiration in neuromuscular disease and high-grade subglottic stenosis. The tracheostomy can be performed as a percutaneous dilatational tracheostomy or as a surgical tracheostomy. The complication rate is low, and intraoperative complications are differentiated from early and late postoperative complications. This article aims to present the indications, the techniques and complications of percutaneous dilatational and surgical tracheostomy, and highlights the long-term complications of tracheal stenosis and tracheomalacia.

[Perioperative Immunotherapy for Resectable Non-Small Cell Lung Cancer: Current Evidence and New Standard of Care]. / Perioperative Immuntherapie beim operablen Lungenkarzinom: aktuelle Studienlage und neue Therapiestandards.

Immunotherapy has drastically changed the treatment of lung cancer not only in systemic disease but also in the perioperative setting in locally advanced non-small cell lung cancer. In particular, the neoadjuvant and perioperative therapy regimes of the CheckMate 816 and KEYNOTE-671 studies as well as the adjuvant therapy according to the IMPower010 and the PEARLS/KEYNOTE-091 protocols have already been approved by the European Medicines Agency (EMA) for the treatment of selected cases. Other therapy protocols and combination therapies with varying drug classes and therapy modalities are currently being examined for their effectiveness and tolerance. The new treatment landscape creates new opportunities but also challenges for the treating disciplines. This article will focus on the current evidence for perioperative immunotherapy for resectable lung cancer and the resulting therapy standards, especially with regard to patient selection for both neoadjuvant and adjuvant immunotherapy, as well as current research efforts.

Impact of chemical modifications on the antimicrobial and hemolytic activity of helical amphipathic peptide Lasioglossin LL-III.

Insect venom is abundant in potential antimicrobial peptides (AMPs), which can serve as novel alternatives to conventional antibiotics. Among them, Lasioglossin III LL-III) is a promising candidate with a broad spectrum against many fungi strains and both types of bacteria, whereas almost non-toxic to red blood cells. Many chemical approaches have been recently applied to improve its pharmacological properties and provide useful information regarding structure-activity relationships. Hence, this review focused on highlighting the lesson learned from each modification and supporting the future design of potent, selective, and metabolically stable AMPs.

Robotic diaphragm plication: functional and surgical outcomes of a single-center experience.

BACKGROUND: Diaphragm plication remains the only effective treatment for diaphragm paralysis. Robot-assisted thoracoscopic (RATS) diaphragm plication combines advantages of open and thoracoscopic techniques. We present our experiences focussing on lung-function improvement and surgical outcome. METHODS: In this single-center retrospective study with comparative analysis, perioperative data of all patients who underwent RATS or thoracoscopic (VATS) diaphragm plication between 2015 and 2022 at our institution were assessed. Functional outcome was analysed with pre- and postoperative pulmonary function tests in sitting and supine position. RESULTS: We included 43 diaphragm plications, of which 31 were performed via RATS. Morbidity in the RATS- and VATS-cohort were 13 and 8%, respectively (p = 0.64), without any major complication (Clavien-Dindo ≥ III, 0%). Surgical time for RATS diaphragm plication was reduced drastically with a median operating time for the first 16 patients of 136 min (range 84-185) and 84 min (range 56-122) for the most recent 15 patients (p < 0.0001). Pulmonary function testing after RATS-plication showed a mean increase in vital capacity (VC) of 9% (SD 8, p < 0.0001) and of 7% (SD 9, p = 0.0009) in forced expiratory volume in 1 s (FEV1) when sitting and 9% (SD 8, p < 0.0001) for VC as well as 10% (SD 8, p = 0.0001) for FEV1 when in supine position. CONCLUSION: RATS diaphragm plication is a very safe and feasible approach, yielding good results in improving patients' pulmonary function. Further studies are required to elucidate possible advantages over VATS or open approaches.

Outcome of Repeated Resection of Pulmonary Metastases for Renal Cell Cancer.

BACKGROUND: To date, many studies investigated results and prognostic factors of pulmonary metastasectomy (PM) in renal cell cancer (RCC). However, reports concerning repeated resection for patients with recurrent pulmonary metastases (RPM) are limited. In this study, we analyzed safety, efficacy, and prognostic factors for survival after PM focusing on RPM for RCC. PATIENTS AND METHODS: Clinical, operative, and follow-up data of patients who underwent PM or RPM for RCC in our institution were retrospectively collected and correlated with each other from January 2005 to December 2019. RESULTS: Altogether 154 oncological pulmonary resections in curative intention as PM or RPM were performed in 82 and 26 patients. Postoperative complications were similar in both groups (n = 22 [26.8%] vs. 4 [15.4%], p = 0.2). Zero mortality was documented up to the 30th postoperative day. RPM was not associated with decreased 5-year-survival compared with PM (66.2 vs. 57,9%, p = 0.5). Patients who underwent RPM for recurrent lung metastases had a better overall survival in comparison with the other treatments including chemotherapy, radiotherapy, immunotherapy, and best supportive care (p = 0.04). In the multivariate analysis, disease-free survival was identified as an independent prognostic factor for survival (hazard ratio: 0.969, 0.941-0.999, p = 0.04). CONCLUSION: RPM is a safe and feasible procedure. The resection of recurrent lung metastases shows to prolong survival in comparison with the other therapeutic options for selected patients with RCC.

The study of predictive factors for the evolution of vestibular schwannomas.

PURPOSE: The primary objective was to determine whether the analysis of textural heterogeneity of vestibular schwannomas on MRI at diagnosis was predictive of their radiological evolutivity. The secondary objective was to determine whether some clinical or radiological factors could also be predictive of growth. METHODS: We conducted a pilot, observational and retrospective study of patients with a vestibular schwannoma, initially monitored, between April 2001 and November 2019 within the Oto-Neurosurgical Institute of Champagne Ardenne, Texture analysis was performed on gadolinium injected T1 and CISS T2 MRI sequences and six parameters were extracted: mean greyscale intensity, standard deviation of the greyscale histogram distribution, entropy, mean positive pixels, skewness and kurtosis, which were analysed by the Lasso method, using statistically penalised Cox models. Extrameatal location, tumour necrosis, perceived hearing loss < 2 years with objectified tone audiometry asymmetry, tinnitus at diagnosis, were investigated by the Log-Rank test to obtain univariate survival analyses. RESULTS: 78 patients were included and divided into 2 groups: group A comprising 39 "stable patients", and B comprising the remaining 39 "progressive patients". Independent analysis of the texture factors did not predict the growth potential of vestibular schwannomas. Among the clinical or radiological signs of interest, hearing loss < 2 years was identified as a prognostic factor for tumour progression with a significant trend (p = 0.05). CONCLUSIONS: This study did not identify an association between texture analysis and vestibular schwannomas growth. Decreased hearing in the 2 years prior to diagnosis appears to predict potential radiological progression.

[Resection of Solitary Lung Metastasis of Urinary Tract Transitional Cell Cancer Can Prolong Survival in Selected Patients]. / Die Resektion solitärer Lungenmetastasen des Urothelkarzinom kann das Überleben bei selektionierten Patienten verlängern.

There are only a few small published studies on pulmonary metastasectomy for urinary tract transitional cell carcinoma (TCC). In this study, we examined the long-term outcome and the prognostic survival factors associated with pulmonary metastasectomy of urinary tract TCC, as based on our centre's 20-year experience. Between 2000 and 2020, curative pulmonary metastasectomy was performed in 18 patients (14 males and 4 females). Clinical, demographical and surgical data were retrospectively analysed. The disease-free interval between treatment of the primary tumour and pulmonary metastasectomy ranged from one to 48 months. Survival analysis was conducted with the Kaplan-Meier method and log-rank test. The 3- and 5-year survival rates were 84.7% and 52.9%, respectively. Resection of solitary metastases was a positive and independent factor for survival (p = 0.04). Pulmonary metastasectomy of urinary tract TCC is associated with a favourable outcome and solitary metastasis is associated with long-term survival. Surgical resection of solitary pulmonary metastasis and repeated lung metastasectomy by pulmonary recurrence from a urinary tract TCC is feasible in selected patients.

[Robotic Diaphragm Plication]. / Roboterassistierte thorakoskopische Zwerchfellraffung.

Acquired unilateral hemidiaphragm elevation is characterised by dyspnoea, which is typically aggravated when lying down, bending over or during swimming. The most common causes are idiopathic or due to injury to the phrenic nerve during cervical or cardio-thoracic surgery. To date, surgical diaphragm plication remains the only effective treatment. The aim of the procedure is to plicate the diaphragm to restore its tension and thus improve breathing mechanics, increase the available space for the lung and reduce compression from abdominal organs. In the past, various techniques using open and minimally invasive approaches have been described. Robot-assisted thoracoscopic diaphragm plication combines the advantages of a minimally invasive approach with excellent visualisation and freedom of movement. It was shown to be a safe technique which is easy to establish and can significantly improve pulmonary function.

Options of Therapeutics and Novel Delivery Systems of Drugs for the Treatment of Melanoma.

Melanoma is one of the most severe cancerous diseases. The cells employ multiple signaling pathways, such as ERK, HGF/c-MET, WNT, and COX-2 to cause the cell proliferation, survival, and metastasis. Treatment of melanoma, including surgery, chemotherapy, immunotherapy, radiation, and targeted therapy, is based on 4 major or 11 substages of the disease. Fourteen drugs, including dacarbazine, interferon α-2b, interleukin-12, ipilimumab, peginterferon α-2b, vemurafenib, trametinib, talimogene laherparepvec, cobimetinib, pembrolizumab, dabrafenib, binimetinib, encorafenib, and nivolumab, have been approved by the FDA for the treatment of melanoma. All of them are in conventional dosage forms of injection solutions, suspensions, oral tablets, or capsules. Major drawbacks of the treatment are side effects of the drugs and patients' incompliance to them. These are consequences of high doses and long-term treatments for the diseases. Currently more than 350 NCI-registered clinical trials are being carried out to treat advanced and/or metastatic melanoma using novel treatment methods, such as immune cell therapy, cancer vaccines, and new therapeutic targets. In addition, novel delivery systems using biomaterials of the approved drugs have been developed attempting to increase the drug delivery, targeting, stability, bioavailability, thus potentially reducing the toxicity and increasing the treatment effectiveness. Nanoparticles and liposomes have been emerging as advanced delivery systems which can improve drug stability and systemic circulation time. In this review, the most recent findings in the options for treatment and development of novel drug delivery systems for the treatment of melanoma are comprehensively discussed.

Single-Cell Transcriptome of Wet AMD Patient-Derived Endothelial Cells in Angiogenic Sprouting.

Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. 'Wet' AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our 'activated' BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research.

Degradation of Diuron by a Bacterial Mixture and Shifts in the Bacterial Community During Bioremediation of Contaminated Soil.

Diuron, a phenylurea herbicide, has been extensively applied in controlling a wide range of weeds in several crops. In the current study, a mixed culture of three bacterial strains, i.e., Bacillus subtilis DU1, Acinetobacter baumannii DU, and Pseudomonas sp. DUK, isolated from sugarcane soil, completely degraded diuron and 3,4-DCA in liquid media at 20 mg L-1 within 48 h. During diuron degradation, a few metabolites (DCPMU, DCPU, and 3,4-DCA) were produced. Further determination of ring-cleavage pathways demonstrated that Acinetobacter baumannii DU and Pseudomonas fluorescens DUK degraded diuron and 3,4-DCA via ortho-cleavage. In contrast, Bacillus subtilis DU transformed these compounds via meta-cleavage pathways. Moreover, diuron caused a significant shift in the bacterial community in soil without diuron history. The augmentation of mountain soil with the isolated bacteria resulted in nearly three times higher degradation rate of diuron than the degradation by indigenous microorganisms. This study provides important information on in situ diuron bioremediation from contaminated sites by bioaugmentation with a mixed bacterial culture.

[Surgery for Thoracic Malignancies during the COVID-19 Pandemic: a Case-control Study Investigating the Risk for Postoperative Complications]. / Onkologische Thoraxchirurgie während der COVID-19-Pandemie: eine Fallkontrollstudie zum Risiko für postoperative Komplikationen.

BACKGROUND: The COVID-19 pandemic led to a major disturbance in the health care system. Many elective operations were postponed, including surgical oncology cases. Besides the need to contain hospital resources, this was also due to concerns about the safety to perform surgery during the pandemic and the impact of perioperative infections on postoperative outcomes. In this study we investigate the safety of surgery for thoracic malignancies during the COVID-19 pandemic. METHODS: We retrospectively analysed the outcome of surgery for thoracic malignancies during the first, second and third waves of the COVID-19 pandemic (from 01.01. to 30.04.2020 and from 01.01. to 30.04.2021). As a control group we included the patients who received thoracic oncology surgeries during the same period in the last 2 years before the onset of the pandemic. The primary outcome was the rate of postoperative complications. RESULTS: 236 operations were included in the pandemic group and 227 operations in the control group. There was no statistically significant difference in the rate of postoperative minor complications (16.1% vs. 18.5%, p = 0.5395) or major complications (12.2% vs. 10.13 %, p = 0.5563). The risk to develop postoperative pulmonary complications was not higher in the pandemic group (odds ratio 1.193, 95% CI 0.6515-2.203, p = 0.8232). There were 5 cases with COVID-19 infection after the operation in the pandemic group. There was no difference in the rate of postoperative mortalities (2 (0.85%) vs. 1 (0.44%), p > 0.9999) There was no COVID-19 related mortality. CONCLUSION: Maintaining oncologic thoracic surgery during the COVID-19 pandemic is safe, feasible and not associated with increased risks of postoperative complications or mortalities.

Rapid evolution of BRCA1 and BRCA2 in humans and other primates.

BACKGROUND: The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers. RESULTS: To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection. CONCLUSIONS: While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.

Impact of high-stakes exams, incentives, and preparation on student performance: Insights from the pharmacy curriculum outcomes assessment.

INTRODUCTION: Efforts to ensure success of pharmacy students in passing pharmacy standardized exams require substantial investments. Engaging students effectively can be a challenge when there are no consequences for non-participation or poor performance. This study examined how engagement reinforcement, including high-stake exam requirements, instructional strategies, and incentives, impacted student performance on the Pharmacy Curriculum Outcomes Assessment (PCOA). METHODS: PCOA scores, milestone exams, grade point averages (GPAs), and PCOA preparedness assessments for cohorts (Co) that received high-stakes exams, incentives, and preparation (Co2019, Co2020, and Co2021) was compared with those that did not receive these interventions (Co2017 and Co2018). Students' perceptions regarding reinforcement, incentive, and preparedness were evaluated using an anonymous survey. RESULTS: Analyzing data from 545 students over five years, mandated PCOA preparedness, high-stakes PCOA requirements, and incentives for Co2019, Co2020, and Co2021 improved scores by 11% to 18% compared to Co2017 and Co2018. This corresponded to a rise in performance from the 12th to 27th percentile for Co2017 and Co2018 to the 39th to 49th percentile for Co2019, Co2020, and Co2021. In these later cohorts, PCOA scores consistently correlated with the school's milestone exams and students' cumulative GPAs (correlation coefficients 0.47-0.70, P < .001), while no such correlation was observed in Co2017 and Co2018. Faculty-led PCOA preparation yielded better results (48.2% in Co2020, 45.8% in Co2021) than self-learning (42% in Co2019). Students using faculty-prepared assessments reported increased confidence in biomedical and pharmaceutical sciences. CONCLUSIONS: This study highlights the importance of high-stakes requirements, incentives, and thorough preparation in improving PCOA results.

Cytokine-armed oncolytic herpes simplex viruses: a game-changer in cancer immunotherapy?

Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are agents that mediate antitumor activity by directly killing tumor cells and inducing immune responses. Talimogene laherparepvec is an oncolytic herpes simplex virus type 1 (oHSV), approved for the treatment of recurrent melanoma, and the virus encodes the human cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). A significant advantage of oncolytic viruses is the ability to deliver therapeutic payloads to the tumor site that can help drive antitumor immunity. While cytokines are especially interesting as payloads, the optimal cytokine(s) used in oncolytic viruses remains controversial. In this review, we highlight preliminary data with several cytokines and chemokines, including GM-CSF, interleukin 12, FMS-like tyrosine kinase 3 ligand, tumor necrosis factor α, interleukin 2, interleukin 15, interleukin 18, chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 4, or their combinations, and show how these payloads can further enhance the antitumor immunity of oHSV. A better understanding of cytokine delivery by oHSV can help improve clinical benefit from oncolytic virus immunotherapy in patients with cancer.