[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.

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.

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.

Metastatic melanoma to the urinary bladder with synchronous or metachronous metastasis to other organs: Clinicopathological characteristics and outcome.

INTRODUCTION AND IMPORTANCE: Bladder metastatic melanoma is a very uncommon condition. CASE PRESENTATION: On 62 reported cases, 55 studies have been done so far. We describe a 53-year-old woman with a hematuria who underwent transurethral resection of bladder lesions caused by metastatic melanoma for eight years ago after receiving her initial diagnosis of cutaneous malignant melanoma. CLINICAL DISCUSSION: We also review the medical literature to determine the prognosis of bladder metastatic melanoma. Synchronous metastases with metastatic melanoma to the bladder also reduces the mean survival compared with patients with metachronous metastases. CONCLUSION: Bladder metastatic melanoma combined with other factors, such as male, lymph node metastases, primary skin tumor, two or more bladder metastatic foci, and synchronous metastases are predictors of worse prognosis.

Intra thyroid thymic carcinoma: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Intrathyroid thymic carcinoma (ITC) is a malignant epithelial tumor with thymic differentiation within the thyroid gland. Its frequency is up to 0.15 % of all malignant thyroid tumors. It is frequently a low-grade tumor. The clinical status is often misleading to other more advanced tumors like cervical lymph node metastasis of nonkeratinizing squamous cell carcinoma, undifferentiated variant, dedifferentiated carcinoma, and medullary carcinoma of the thyroid. CASE PREPARATION: The patient came to us with the diagnosis of cervical lymph node metastasis of undifferentiated carcinoma. This patient was first diagnosed with cervical lymph node metastasis in the previous hospital. After having an ITC diagnosis, the patient was operated on the rennet of thyroid glands and had a low dose of radio-chemotherapy for recurrent prevention purposes. It is the first case of such a disease diagnosed at our hospital and also the first case reported in Vietnam. CLINICAL DISCUSSION: ITC is rare and appears similar to all thymic carcinoma variants. The most popular type is squamous carcinoma. Immunohistochemical stains are typical for thymic origin tumors with CD5, CD117 positive. ITC is often negative for monoclonal PAX8 but positive in this case (MRQ-50 clone, Sigma-Aldrich). This finding is an exciting one that should considered. CONCLUSION: Reporting the case increases the awareness of the disease, especially among Vietnam Doctors and patients.

Validity of Umbilical Cord Blood Procalcitonin in the Diagnosis of Early-Onset Neonatal Infection.

INTRODUCTION: Early-onset neonatal infection (EONI) poses significant risks to neonatal health, necessitating reliable diagnostic markers for early detection. This study aims to evaluate the diagnostic validity of procalcitonin (PCT) concentration in umbilical cord blood as a biomarker for EONI. METHODS: This prospective study was conducted at Ho Chi Minh University Medical Center from April 2022 to September 2022. The PCT level was measured in umbilical cord blood at birth. Based on clinical, laboratory, and microbiologic results, neonates were classified into infected and non-infected groups. RESULTS: One hundred eighty neonates with risk factors for EONI were recruited. Among the neonates studied, 22 (12.2%) were classified as infected and 158 (87.8%) as non-infected by the classification criteria of clinical manifestations, laboratory tests, and blood culture. The median PCT in the infected group was significantly higher than that in the non-infected group (0.389 ng/mL vs. 0.127 ng/mL, p = 0.007). The optimal PCT cut-off was found by receiver operating characteristic (ROC) to be 0.23 ng/mL, with an area under the curve (AUC) of 0.87. The results were 59.1%, 98.7%, 86.2%, 94%, 45, and 0.41 for sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios, respectively. The post-test probability was 86% if the test was positive and 5% if it was negative. CONCLUSION: Umbilical cord blood PCT might be a reliable marker in the diagnosis of EONI, and its value helps limit the harmful effects of unnecessary prescriptions in non-infected neonates. However, considering the low sensitivity of procalcitonin, further research is necessary to fully integrate this biomarker into clinical practice.

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.

Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants.

COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2, 6, 9, and 15, with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 µM to 0.84 µM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 µM, surpassing nirmatrelvir (IC50: 1.17-152.9 µM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 µM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 µM) and Mpro_Q189I (EC50: 13.2 µM) compared to wild-type SRIPs (EC50: 0.06 µM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants.

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.

[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.

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.

Functional assessments of SARS-CoV-2 single-round infectious particles with variant-specific spike proteins on infectivity, drug sensitivity, and antibody neutralization.

Working with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is restricted to biosafety level III (BSL-3) laboratory. The study used a trans-complementation system consisting of virus-like particles (VLPs) and DNA-launched replicons to generate SARS-CoV-2 single-round infectious particles (SRIPs) with variant-specific spike (S) proteins. S gene of Wuhan-Hu-1 strain (SWH1) or Omicron BA.1 variant (SBA.1), along with the envelope (E) and membrane (M) genes, were cloned into a tricistronic vector, co-expressed in the cells to produce variant-specific S-VLPs. Additionally, the replicon of the WH1-like strain without S, E, M and accessory genes, was engineered under the control by a CMV promoter to produce self-replicating RNAs within VLP-producing cells, led to create SWH1- and SBA.1-based SARS-CoV-2 SRIPs. The SBA.1-based SRIP showed lower virus yield, replication, N protein expression, fusogenicity, and infectivity compared to SWH1-based SRIPs. SBA.1-based SRIP also exhibited intermediate resistance to neutralizing antibodies produced by SWH1-based vaccines, but were effective at infecting cells with low ACE2 expression. Importantly, both S-based SRIPs responded similarly to remdesivir and GC376, with EC50 values ranging from 0.17 to 1.46 µM, respectively. The study demonstrated that this trans-complementation system is a reliable and efficient tool for generating SARS-CoV-2 SRIPs with variant-specific S proteins. SARS-CoV-2 SRIPs, mimicking authentic live viruses, facilitate comprehensive analysis of variant-specific virological characteristics, including antibody neutralization, and drug sensitivity in non-BSL-3 laboratories.

[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.

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.

Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV.

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 µM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 µM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 µM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

The Rationale and Logistics for Incorporating Community Health Workers Into the Multidisciplinary Team.

Community Health Workers (CHWs) have shown value in diabetes care. CHWs are often the individuals who provide behavioral lifestyle intervention to underserved communities and are often the first to assist patients in gaining appropriate access to care. As trusted members of their communities, they have the ability to significantly impact psychosocial and biomedical outcomes, making them important members of the behavioral medicine team. However, lack of recognition of CHWs within multidisciplinary teams (MDTs) gives rise to the issue of the underutilization of their services. Therefore, barriers to including CHWs in MDTs including standardized training and strategies to overcome these are discussed.

Surgery for thoracic oligoprogression in metastatic renal cell cancer in the era of new systemic therapies.

Background: Novel systemic therapies have improved response rates and survival in metastatic renal cell cancer (mRCC) and are considered standard of care for this entity. However, complete remission (CR) is rare and often oligoprogression is observed. Here, we analyse the role of surgery for oligoprogressive lesions in mRCC. Methods: We retrospectively analyzed all patients who underwent surgery for thoracic oligoprogressive lesions of mRCC after receiving systemic therapy including immunotherapy, tyrosine kinase inhibitors (TKI), and/or multikinase inhibitors at our institution between 2007 and 2021 regarding treatment modalities, progression-free survival (PFS) and overall survival (OS). Results: Ten patients with oligoprogressive mRCC were included. The median interval between nephrectomy and oligoprogression was 65 months (range, 16-167). Median PFS after surgery for oligoprogression was 10 months (range, 2-29) and median OS after resection 24 months (range, 2-73). In 4 patients, CR was achieved of whom three showed no progression at last follow-up (PFS median 15 months, range, 10-29). In 6 patients, removal of the progressive site resulted in stable disease (SD) for a median of 4 months (range, 2-29), before 4 of them progressed. Conclusions: In selected cases, surgery can lead to sustained disease control in patients with oligoprogressive mRCC after systemic treatment including immunotherapy and novel treatment agents.

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.