Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy: A Single-Center Experience.

BACKGROUND: The use of surgery in patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy is increasing. However, most series do not report on the total cohort of patients undergoing surgical exploration; therefore, this single-center study investigates outcomes among all consecutive patients with LAPC who underwent surgical exploration. METHODS: We conducted a retrospective, single-center analysis including all consecutive patients with LAPC (Dutch Pancreatic Cancer Group criteria) who underwent surgical exploration with curative intent (January 2014-June 2023) after induction therapy. Primary outcomes were resection rate and overall survival (OS) from the time of diagnosis. RESULTS: Overall, 127 patients underwent surgical exploration for LAPC, whereby 100 patients (78.7%) underwent resection and 27 patients (21.3%) underwent a non-therapeutic laparotomy due to the extent of vascular involvement (n = 11, 8.7%) or occult metastases (n = 16, 12.6%). The overall in-hospital/30-day mortality rate was 0.8% and major morbidity was 31.3% (in patients after resection: 1.0% and 33.3%, respectively). The overall 90-day mortality rate was 5.5%, which included 3.1% mortality due to disease progression. Resection was associated with longer median OS {29 months (95% confidence interval [CI] 26-43) vs. 17 months (95% CI 11-26); p < 0.001} compared with patients undergoing non-therapeutic laparotomy, with corresponding 5-year OS rates of 28.4% and 7.7%. In Cox proportional hazard regression analysis, only pancreatic body/tail tumors independently predicted OS (hazard ratio 1.788 [95% CI 1.042-3.068]). CONCLUSION: This single-center series found a resection rate of 78.7% in patients with LAPC selected for surgical exploration, with a low risk of mortality and morbidity in all explored patients and a 5-year OS rate after resection of 28.4%.

Deciphering difficult-to-treat psoriatic arthritis (D2T-PsA): a GRAPPA perspective from an international survey of healthcare professionals.

Objectives: This study contributes to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)'s effort to define 'difficult-to-treat' PsA (D2T-PsA), leveraging insights of healthcare professionals who are GRAPPA members. The primary objective is to inform GRAPPA's D2T PsA project, ensuring the consensus definition reflects clinical experience and expertise. Methods: An online survey was conducted among GRAPPA's healthcare professionals managing PsA patients. The survey covered demographic details, structured questions, and open-ended queries to gather comprehensive insights into the experts' viewpoints. Results: About 223 physicians completed the survey, comprising 179 (80.2%) rheumatologists and 40 (17.9%) dermatologists. The majority, 184 (82.5%), favoured establishing distinct definitions for D2T-PsA and complex-to-manage PsA (C2M-PsA). Furthermore, 202 (90.5%) supported a definition that includes objective inflammation signs (clinical, laboratory, imaging, among others). However, opinions varied on the criteria for prior treatment failures, with most (93, 41.7%) favouring a definition that includes at least one conventional synthetic disease-modifying anti-rheumatic drug and two or more biological- or targeted-synthetic-DMARDs with different mechanisms of action. Conclusion: The survey reveals a majority opinion among GRAPPA experts favouring the differentiation between D2T-PsA and C2M-PsA, and the inclusion of objective inflammatory markers in these definitions. However, there is less than 50% agreement on the specific treatment failure criteria, particularly regarding the number of therapies needed to classify PsA as D2T. These findings suggest a need for continued discussion to reach a more unified approach in defining D2T-PsA, reflecting the complexity of the condition.

Candida parapsilosis: heterogeneous and strain-specific expression of secreted aspartic proteases (Sapp1 and Sapp2).

The increasing prevalence of Candida parapsilosis as a causative agent of fungal infections underscores the need to comprehensively understand its virulence factors. Secreted aspartic proteases (Saps) play a significant role in adhesion events, promoting biofilm formation, causing tissue damage and evading the host immune response. The present study investigates the production dynamics of Sapp1 and Sapp2 across 10 clinical isolates of C. parapsilosis using various approaches. Each fungal isolate demonstrated the capability to utilize bovine serum albumin (BSA) as the sole nitrogen source, as evidenced by its degradation in cell-free culture medium, forming low molecular mass polypeptides. Interestingly, the degradation of different proteinaceous substrates, such as BSA, human serum albumin (HSA), gelatin and hemoglobin, was typically isolate-dependent. Notably, higher proteolysis of HSA compared to BSA, gelatin and hemoglobin was observed. A quantitative assay revealed that the cleavage of a peptide fluorogenic substrate (cathepsin D) was isolate-specific, ranging from 44.15 to 270.61 FAU, with a mean proteolysis of 150.7 FAU. The presence of both Sapp1 and Sapp2 antigens on the cell surface of these fungal isolates was confirmed through immunological detection employing specific anti-Sapp1 and anti-Sapp2 antibodies. The surface levels of Sapp1 were consistently higher, up to fourfold, compared to Sapp2. Similarly, higher levels of Sapp1 than Sapp2 were detected in fungal secretions. This study provides insights into the dynamic expression and regulation of Sapps in C. parapsilosis, highlighting a known virulence factor that is considered a potential target for drug development against this increasingly prominent pathogen.

The fungal pathogen Candida parapsilosis can secrete aspartic proteases (Sapps) as part of its arsenal of virulence factors. We demonstrated that Sapps were able to cleave key host proteins, and the production of Sapp1 and Sapp2 antigens was typically dependent on the fungal isolate when grown in both planktonic- and biofilm-forming cells.

Diseases Involving the Lung Peribronchovascular Region: a CT-Pathologic Classification.

TOPIC IMPORTANCE: Chest computed tomography (CT) holds a major role in the diagnosis of lung disease, many of which affect the peri-bronchovascular (PBV) region. Identification and categorization of PBV abnormalities on CT can assist in formulating a differential diagnosis and directing further diagnostic evaluation. REVIEW FINDINGS: The PBV region of the lung encompasses the pulmonary arteries, airways, and lung interstitium. Understanding disease processes associated with structures of the PBV region and their appearances on CT aids in prompt diagnosis. This manuscript reviews current knowledge in anatomy and pathology of the lung interstitium composed of intercommunicating pre-lymphatic spaces, lymphatics, collagen bundles, lymph nodes, bronchial arteries; diffuse lung diseases that present in a PBV distribution; and an approach to classifying diseases according to patterns of imaging presentations. Lung PBV diseases can appear on CT as diffuse thickening, fibrosis, masses/mass-like consolidation, ground glass or air-space consolidation, and cysts, acknowledging some disease may have multiple presentations.

Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

The Use of a Just Noticeable Difference Approach to Improve Perceptual Acuity Ability in Male Runners.

We were interested in micro-variations in an athlete's psychophysical state that separate peak exertion from physiological collapse. Thus, we measured perceptual acuity in runners using a classic psychophysical approach, the just noticeable difference (JND) on two standard stimuli runs at treadmill speed corresponding to 70%VO2max and 80%VO2max. Thirty-four male runners (M age = 35.26, SD = 7.33 years) first performed a maximal treadmill test to determine the speed of a standard exercise bout for the JND trials. The JND trials consisted of four 5-minute running bouts on a treadmill with 5-minute rests between bouts. For bouts 1 and 3, participants ran at the standard stimuli pace, but for bouts 2 and 4, they adjusted their speeds to achieve a level of exertion at a JND above/below the SS. They achieved differences in the final 30 seconds of the VO2 between each JND bout and the previous standard stimuli at just above (JND-A) and just below (JND-B) the JND perceived exertions. We used a Generalized Linear Model analysis to compare the JND-A and JND-B within and between ventilatory threshold groups (lower/higher) in absolute and relative VO2 and in terms of the total JND magnitude. The magnitude of JND-A was greater than that of JND-B at 70%VO2max and 80%VO2max in absolute units (70%VO2 Δ = 2.62; SE = 0.37; p < .001; 80%VO2 Δ = 1.67; SE = 0.44; p = .002) and in relative units (70%VO2max Δ = 4.70; SE = 0.66; p < .001; 80%VO2max Δ = 2.96; SE = 0.80; p = .002). The total magnitude was greater in the 70%VO2max trial than 80%VO2max in absolute units (70%VO2 M = 3.78, SE = 0.31 mL·kg-1·min-1; 80%VO2 M = 2.62, SE = 0.37 mL·kg-1·min-1; p = .020) and in relative units (70%VO2max M = 6.57, SE = 0.53%VO2max; 80%VO2max M = 4.71, SE = 0.64%VO2max; p = .030). The JND range narrowed when physiologic demand increased, for both physical (speed) and psychological (RPE) variables.

Invasion and Grading of Pulmonary Non-Mucinous Adenocarcinoma.

Lung adenocarcinoma staging and grading were recently updated to reflect the link between histologic growth patterns and outcomes. The lepidic growth pattern is regarded as "in-situ," whereas all other patterns are regarded as invasive, though with stratification. Solid, micropapillary, and complex glandular patterns are associated with worse prognosis than papillary and acinar patterns. These recent changes have improved prognostic stratification. However, multiple pitfalls exist in measuring invasive size and in classifying lung adenocarcinoma growth patterns. Awareness of these limitations and recommended practices will help the pathology community achieve consistent prognostic performance and potentially contribute to improved patient management.

The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion.

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8+ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.

New Chalcogen-Functionalized Naphthoquinones: Design, Synthesis, and Evaluation, In Vitro and In Silico, against Squamous Cell Carcinoma.

Due to the growth in the number of patients and the complexity involved in anticancer therapies, new therapeutic approaches are urgent and necessary. In this context, compounds containing the selenium atom can be employed in developing new medicines due to their potential therapeutic efficacy and unique modes of action. Furthermore, tellurium, a previously unknown element, has emerged as a promising possibility in chalcogen-containing compounds. In this study, 13 target compounds (9a-i, 10a-c, and 11) were effectively synthesized as potential anticancer agents, employing a CuI-catalyzed Csp-chalcogen bond formation procedure. The developed methodology yielded excellent results, ranging from 30 to 85%, and the compounds were carefully characterized. Eight of these compounds showed promise as potential therapeutic drugs due to their high yields and remarkable selectivity against SCC-9 cells (squamous cell carcinoma). Compound 10a, in particular, demonstrated exceptional selectivity, making it an excellent choice for cancer cell targeting while sparing healthy cells. Furthermore, complementing in silico and molecular docking studies shed light on their physical features and putative modes of action. This research highlights the potential of these compounds in anticancer treatments and lays the way for future drug development efforts.

Assessment of barriers to cancer screening and interventions implemented to overcome these barriers in 27 Latin American and Caribbean countries.

There is a gap in the understanding of the barriers to cancer screening participation and complying with downstream management in the Community of Latin American and Caribbean states (CELAC). Our study aimed to assess barriers across the cancer screening pathway from the health system perspective, and interventions in place to improve screening in CELAC. A standardized tool was used to collect information on the barriers across the screening pathway through engagement with the health authorities of 27 member states of CELAC. Barriers were organized in a framework adapted from the Tanahashi conceptual model and consisted of the following dimensions: availability of services, access (covering accessibility and affordability), acceptability, user-provider interaction, and effectiveness of services (which includes governance, protocols and guidelines, information system, and quality assurance). The tool also collected information of interventions in place, categorized in user-directed interventions to increase demand, user-directed interventions to increase access, provider-directed interventions, and policy and system-level interventions. All countries prioritized barriers related to the information systems, such as the population register not being accurate or complete (N = 19; 70.4%). All countries implemented some kind of intervention to improve cancer screening, group education being the most reported (N = 23; 85.2%). Training on screening delivery was the most referred provider-directed intervention (N = 19; 70.4%). The study has identified several barriers to the implementation of cancer screening in the region and interventions in place to overcome some of the barriers. Further analysis is required to evaluate the effectiveness of these interventions in achieving their objectives.

Architecture and regulation of filamentous human cystathionine beta-synthase.

Cystathionine beta-synthase (CBS) is an essential metabolic enzyme across all domains of life for the production of glutathione, cysteine, and hydrogen sulfide. Appended to the conserved catalytic domain of human CBS is a regulatory domain that modulates activity by S-adenosyl-L-methionine (SAM) and promotes oligomerisation. Here we show using cryo-electron microscopy that full-length human CBS in the basal and SAM-bound activated states polymerises as filaments mediated by a conserved regulatory domain loop. In the basal state, CBS regulatory domains sterically block the catalytic domain active site, resulting in a low-activity filament with three CBS dimers per turn. This steric block is removed when in the activated state, one SAM molecule binds to the regulatory domain, forming a high-activity filament with two CBS dimers per turn. These large conformational changes result in a central filament of SAM-stabilised regulatory domains at the core, decorated with highly flexible catalytic domains. Polymerisation stabilises CBS and reduces thermal denaturation. In PC-3 cells, we observed nutrient-responsive CBS filamentation that disassembles when methionine is depleted and reversed in the presence of SAM. Together our findings extend our understanding of CBS enzyme regulation, and open new avenues for investigating the pathogenic mechanism and therapeutic opportunities for CBS-associated disorders.

Torsion of the inferior vena cava: An unprecedented variant of post-pneumonectomy syndrome.

Post-pneumonectomy syndrome (PPS) is a rare complication after pneumonectomy defined by mediastinum shift toward the vacated pleural space with compression of the distal trachea or mainstem bronchi, resulting in dyspnea. This report describes a 32-year-old woman who presents with limiting symptoms of progressive dyspnea and chest pain 2 years after a right pneumonectomy. In computed tomography scan, there was no evidence of airway compression but suggested torsion of the inferior vena cava with preload compromise, confirmed during the surgical mediastinum repositioning using a transesophageal echocardiography-guided approach. This case report presents this unprecedented variant of PPS syndrome, highlighting the diagnostic and peri-operative management challenges.

The Grading System for Lung Adenocarcinoma: Brief Review of its Prognostic Performance and Future Directions.

Histologic grading of tumors is associated with prognosis in many organs. In the lung, the most recent grading system proposed by International association for the Study of Lung Cancer (IASLC) and adopted by the World Health Organization (WHO) incorporates the predominant histologic pattern, as well as the presence of high-grade architectural patterns (solid, micropapillary, and complex glandular pattern) in proportions >20% of the tumor surface. This system has shown improved prognostic ability when compared with the prior grading system based on the predominant pattern alone, across different patient populations. Interobserver agreement is moderate to excellent, depending on the study. IASLC/WHO grading system has been shown to correlate with molecular alterations and PD-L1 expression in tumor cells. Recent studies interrogating gene expression has shown correlation with tumor grade and molecular alterations in the tumor microenvironment that can further stratify risk of recurrence. The use of machine learning algorithms to grade nonmucinous adenocarcinoma under this system has shown accuracy comparable to that of expert pulmonary pathologists. Future directions include evaluation of tumor grade in the context of adjuvant and neoadjuvant therapies, as well as the development of better prognostic indicators for mucinous adenocarcinoma.

Mid-Term Outcome after Extracorporeal Life Support in Postcardiotomy Cardiogenic Shock: Recovery and Quality of Life.

Background: Extracorporeal life support (ECLS) therapy for refractory postcardiotomy cardiogenic shock (rPCS) is associated with high early mortality rates. This study aimed to identify negative predictors of mid-term survival and to assess health-related quality of life (HRQoL) and recovery of the survivors. Methods: Between 2017 and 2020, 142 consecutive patients received ECLS therapy following cardiac surgery. The median age was 66.0 [57.0-73.0] years, 67.6% were male and the median EuroSCORE II was 10.5% [4.2-21.3]. In 48 patients, HRQoL was examined using the 36-Item Short Form Survey (SF-36) and the modified Rankin-Scale (mRS) at a median follow-up time of 2.2 [1.9-3.2] years. Results: Estimated survival rates at 3, 12, 24 and 36 months were 47%, 46%, 43% and 43% (SE: 4%). Multivariable Cox Proportional Hazard regression analysis revealed preoperative EuroSCORE II (p = 0.013), impaired renal function (p = 0.010), cardiopulmonary bypass duration (p = 0.015) and pre-ECLS lactate levels (p = 0.004) as independent predictors of mid-term mortality. At the time of follow-up, 83.3% of the survivors were free of moderate to severe disability (mRS < 3). SF-36 analysis showed a physical component summary of 45.5 ± 10.2 and a mental component summary of 50.6 ± 12.5. Conclusions: Considering the disease to be treated, ECLS for rPCS is associated with acceptable mid-term survival, health-related quality of life and functional status. Preoperative EuroSCORE II, impaired renal function, cardiopulmonary bypass duration and lactate levels prior to ECLS implantation were identified as negative predictors and should be included in the decision-making process.

[Cancer of the Esophagogastric Junction: Double Tract Reconstruction - Evidence and Technique]. / Adenokarzinome des ösophagogastralen Überganges: Double-Tract-Rekonstruktion ­ Evidenz und Technik.

Adenocarcinoma of the esophagogastric junction (AEG) still represent a certain surgical challenge. In contrary to the trend of thoracoabdominal surgery for AEG I and AEG II cancer, the proximal gastrectomy is regaining popularity through new reconstruction methods such as the double tract reconstruction. Proximal gastrectomy followed by double tract reconstruction represents an alternative for the thoracoabdominal approach for suitable AEG II cancer and an alternative to the total gastrectomy for AEG III cancers. Latest studies suggest a functional benefit of proximal gastrectomy and double tract reconstruction in comparison to total gastrectomy. The accurate indication for proximal gastrectomy for locally advanced cancers has to be established in the near future as well as the influence of the size of the remnant stomach on the outcome, as Asian techniques for early lesions sometimes significantly differ from European. The following article reflects the present evidence on proximal gastrectomy and double tract reconstruction as well as technical aspects in the context of cancer of the esophagogastric junction.

Intraoperative thermal mapping of mammary tumors in dogs.

In this study, videothermometry's application in detecting mammary tumors in dogs is explored in-depth. The research hypothesizes that this technique can effectively identify cancerous tissues during surgery by analyzing thermal patterns. The methodology involved comparing thermal imaging results from dogs with palpable mammary nodules against a control group, focusing on capturing real-time thermal patterns. Results were significant, showing distinct thermal patterns in carcinomas. This indicates videothermometry's capability in accurately identifying micro metastases and differentiating between neoplastic and non-neoplastic changes. The study concludes that videothermometry has considerable potential in enhancing surgical precision, especially in tumor resection and safety margin definition, but emphasizes the need for further research to thoroughly understand the thermal signatures of various mammary tumors in dogs.

Structural insights into a functional unit from an immunogenic mollusk hemocyanin.

Mollusk hemocyanins, among the largest known proteins, are used as immunostimulants in biomedical and clinical applications. The hemocyanin of the Chilean gastropod Concholepas concholepas (CCH) exhibits unique properties, which makes it safe and effective for human immunotherapy, as observed in animal models of bladder cancer and melanoma, and dendritical cell vaccine trials. Despite its potential, the structure and amino acid sequence of CCH remain unknown. This study reports two sequence fragments of CCH, representing three complete functional units (FUs). We also determined the high-resolution (1.5 Å) X-ray crystal structure of an "FU-g type" from the CCHB subunit. This structure enables in-depth analysis of chemical interactions at the copper-binding center and unveils an unusual, truncated N-glycosylation pattern. These features are linked to eliciting more robust immunological responses in animals, offering insights into CCH's enhanced immunostimulatory properties and opening new avenues for its potential applications in biomedical research and therapies.

Bio-oxidation of progesterone by Penicillium oxalicum CBMAI 1185 and evaluation of the cytotoxic activity.

We report the biotransformation of progesterone 1 by whole cells of Brazilian marine-derived fungi. A preliminary screening with 12 fungi revealed that the strains Penicillium oxalicum CBMAI 1996, Mucor racemous CBMAI 847, Cladosporium sp. CBMAI 1237, Penicillium oxalicum CBMAI 1185 and Aspergillus sydowii CBMAI 935 were efficient in the biotransformation of progesterone 1 in the first days of the reaction, with conversion values ranging from 75 % to 99 %. The fungus P. oxalicum CBMAI 1185 was employed in the reactions in quintuplicate to purify and characterize the main biotransformation products of progesterone 1. The compounds testololactone 1a, 12ß-hydroxyandrostenedione 1b and 1ß-hydroxyandrostenedione 1c were isolated and characterized by NMR, MS, [α]D and MP. In addition, the chromatographic yield of compound 1a was determined by HPLC-PDA in the screening experiments. In this study, we show a biotransformation pathway of progesterone 1, suggesting the presence of several enzymes such as Baeyer-Villiger monooxygenases, dehydrogenases and cytochrome P450 monooxygenases in the fungus P. oxalicum CBMAI 1185. In summary, the results obtained in this study contribute to the synthetic area and have environmental importance, since the marine-derived fungi can be employed in the biodegradation of steroids present in wastewater and the environment. The cytotoxic results demonstrate that the biodegradation products were inactive against the cell lines, in contrast to progesterone.

Quantifying terpenes in tomato leaf extracts from different species using gas chromatography-mass spectrometry (GC-MS).

Terpenes play a vital role in plant defense; tomato plants produce a diverse range of terpenes within specialized glandular trichomes, influencing interactions with herbivores, predators, and pollinators. This study employed two distinct methods, namely leaf dip and maceration, to extract trichomes from tomato leaves. Terpene quantification was carried out using Gas Chromatography-Mass Spectrometry (GC-MS). The leaf dip method proved effective in selectively targeting trichome content, revealing unique extraction patterns compared to maceration. The GC-MS method demonstrated high linearity, accuracy, sensitivity, and low limits of detection and quantification. Application of the method to different tomato species (Solanum pennellii, Solanum pimpinellifolium, Solanum galapagense, Solanum habrochaites, and Solanum lycopersicum) identified significant variation in terpene content among these species, highlighting the potential of specific accessions for breeding programs. Notably, the terpene α-zingiberene, known for its repellency against whiteflies, was found in high quantities (211.90-9155.13 µg g-1) in Solanum habrochaites accession PI209978. These findings provide valuable insights into terpenoid diversity for plant defense mechanisms, guiding future research on developing pest-resistant tomato cultivars. Additionally, the study underscores the broader applications of terpenes in agriculture.