Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma.

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.

Prospective analysis on carotid endarterectomy: intermediate-deep ultrasound-guided cervical blockade versus general anesthesia.

BACKGROUND: The best regional anesthesia plan with the best clinical results for Carotid endarterectomy (CEA) has not been defined yet. METHODS: Prospective multicentric observational study of two non-randomized matched cohorts including patients undergoing elective unilateral CEA (N.=100) between January-October 2021. Main outcomes were cerebral oximetry measurements, verbal numeric pain score assessment, peripheral nerve blockades and in-hospital stay. The main objective is to compare results achieved after carotid endarterectomy (CEA) performed under loco-regional blockade (LRB) versus general anesthesia (GA), in terms of intraoperative hemodynamic and neurologic variability. Patients undergoing LRB were performed under ultrasound (US) guidance and mild sedation. RESULTS: The LRB and GA groups showed no differences in comorbidities and risk factors. However, there was a significant difference in the intraoperative hemodynamic behavior due to the amount of vasoactive drugs used (0% vs. 16% for phenylephrine, P=0.006). The results showed neurological stability through the cerebral oximetry measurements during the procedure except for the left hemisphere de-clamp values, which were higher in the GA group (68.7±9.9 vs. 72.7±8.8; P=0.035). There were also significant differences in the verbal pain scale scores assessed 6 hours and 12 hours after the procedure; better pain control was evidenced in the LRB group (0[0-1] vs. 1[0-3], P=0.01; 1[0.5-2] vs. 0[0-2], P=0.01). An increased transient hypoglossal and laryngeal nerves blockade was observed in the LRB group (30% vs. 4%; P<0.001). The in-hospital length of stay was longer in the GA group (77.2±36.3 hours vs. 129.1±41.1 hours; P<0.001). CONCLUSIONS: Although the use of intermediate-deep cervical plexus blockade for CEA confers similar neurologic stability as GA does, there is a difference on the hemodynamic behaviour due to the differences in vasoactive drug consumption. Loco-regional techniques provide a better postoperative pain control and shorten in-hospital length of stay.

Prospective Observational Study after Eversion Carotid Endarterectomy with Ultrasound-Guided Deep-Intermediate Cervical Plexus Blockade.

(1) Introduction: The aim was to describe the anesthetic and surgical technique of eversion carotid endarterectomy performed under intermediate-deep cervical block with sedation, and to analyze the intraoperative and postoperative results. (2) Material and Methods: Thirty cases of unilateral eversion carotid endarterectomy (n = 30), performed between 2019-2020 in a tertiary center under intermediate-deep ultrasound-guided cervical plexus block and sedation, were prospectively observed and analyzed. Hemodynamic (blood pressure, heart rate) and neurological (cerebral oximetry) variables were measured in four intraoperative phases: at the beginning of the operation, prior to carotid clamping, after unclamping and at the end of the operation. We assessed acute postoperative pain in a numerical rating scale at 6, 12 and 24 h, early and 30-day complications, and length of stay. (3) Results: Baseline mean arterial pressure values were 100.4 ± 18 mmHg, pre-clamping 95.8 ± 14 mmHg, post-clamping 94.9 ± 11 mmHg, and at the end of the operation 102.4 ± 16 mmHg. Cerebral oximetry values were 61.7 ± 7/62.7 ± 8, 68.5 ± 9.6/69.1 ± 11.7 and 68.1 ± 10/68.1 ± 10 for the left and right hemispheres at baseline, pre- and post-clamping, respectively. The pain assessment showed a score less than or equal to 3. The incidence of residual nerve block, early complications, and major complications in the first 30 days was 40%, 16.7% and 3.3%, respectively. (4) Conclusions: The combination of intermediate-deep cervical plexus block and low-dose sedation is an effective and safe alternative in awake eversion carotid endarterectomy.

The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment.

The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane-membrane, ligand-receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells. The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect. The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor-host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver-as a critical organ that produces the leading inflammatory markers described to date-will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.

Kidney Transplantation during the First Year of COVID-19 Pandemic in Our Center.

INTRODUCTION: SARS-CoV2 pandemic has altered the normal activity in our day-to-day life. During the most critical moments of the pandemic at the hospital, attendance and programmed activities had to be reduced to a minimum, including kidney transplants. Hospitals with this kind of activity had to suspend or restructure it due to the decrease in the number of donors with a solid organ donation profile, the lack of knowledge as to whether the disease could be transmitted through transplantation or the risk that was believed to be associated with the admission of patients with end-stage chronic kidney disease or immunosuppressive treatment. METHODS: A retrospective review of all patients who had received a kidney transplant at Doctor Peset University Hospital in Valencia was performed from March 2020 to March 2021. The objective was to study the safety of kidney transplantation and the incidence of COVID-19 disease in kidney transplant patients during this pandemic period. RESULTS: 56 cases of kidney transplantation were included, most of them male with an average age of 56 years old, and variable comorbidity such as hypertension, dyslipidemia, an average body mass index of 26 and undergoing renal replacement therapy by hemodialysis. Regarding the organ donors, more than 50% were male patients and the donation was in encephalic death. The average cold ischemia time was 15 hours. Postoperative complications were mostly graded I and II in the Clavien-Dindo classification. 5.4% of the recipients had passed the SARS-CoV2 infection prior to the transplant and 5.4% were infected with COVID-19 after the transplant. CONCLUSION: In our experience, the current kidney transplant program seems viable and safe, even during periods of health emergencies.

Esophageal pharmacobezoar: a very unusual complication of enteral nutrition use.

Enteral nutrition in intensive care has been a great advance in medicine, due to its benefit, cost-effectiveness and few complications. Bronchoaspiration, diarrhea, regurgitation or mechanical problems are the main adverse effects. Esophageal obstruction by bezoar is a very infrequent complication, and there are only a few cases described in the literature.

Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment.

The tumor microenvironment (TME) is a complex and constantly changing cellular system composed of heterogeneous populations of tumor cells and non-transformed stromal cells, such as stem cells, fibroblasts, endothelial cells, pericytes, adipocytes, and innate and adaptive immune cells. Tumor, stromal, and immune cells consume available nutrients to sustain their proliferation and effector functions and, as a result of their metabolism, produce a wide array of by-products that gradually alter the composition of the milieu. The resulting depletion of essential nutrients and enrichment of by-products work together with other features of the hostile TME to inhibit the antitumor functions of immune cells and skew their phenotype to promote tumor progression. This review briefly describes the participation of the innate and adaptive immune cells in recognizing and eliminating tumor cells and how the gradual metabolic changes in the TME alter their antitumor functions. In addition, we discuss the overexpression of the immune checkpoints and their ligands as a result of nutrient deprivation and by-products accumulation, as well as the amplification of the metabolic alterations induced by the immune checkpoints, which creates an immunosuppressive feedback loop in the TME. Finally, the combination of metabolic and immune checkpoint inhibitors as a potential strategy to treat cancer and enhance the outcome of patients is highlighted.

Old and New Players of Inflammation and Their Relationship With Cancer Development.

Pathogens or genotoxic agents continuously affect the human body. Acute inflammatory reaction induced by a non-sterile or sterile environment is triggered for the efficient elimination of insults that caused the damage. According to the insult, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes are released to facilitate the arrival of tissue resident and circulating cells to the injured zone to promote harmful agent elimination and tissue regeneration. However, when inflammation is maintained, a chronic phenomenon is induced, in which phagocytic cells release toxic molecules damaging the harmful agent and the surrounding healthy tissues, thereby inducing DNA lesions. In this regard, chronic inflammation has been recognized as a risk factor of cancer development by increasing the genomic instability of transformed cells and by creating an environment containing proliferation signals. Based on the cancer immunoediting concept, a rigorous and regulated inflammation process triggers participation of innate and adaptive immune responses for efficient elimination of transformed cells. When immune response does not eliminate all transformed cells, an equilibrium phase is induced. Therefore, excessive inflammation amplifies local damage caused by the continuous arrival of inflammatory/immune cells. To regulate the overstimulation of inflammatory/immune cells, a network of mechanisms that inhibit or block the cell overactivity must be activated. Transformed cells may take advantage of this process to proliferate and gradually grow until they become preponderant over the immune cells, preserving, increasing, or creating a microenvironment to evade the host immune response. In this microenvironment, tumor cells resist the attack of the effector immune cells or instruct them to sustain tumor growth and development until its clinical consequences. With tumor development, evolving, complex, and overlapping microenvironments are arising. Therefore, a deeper knowledge of cytokine, immune, and tumor cell interactions and their role in the intricated process will impact the combination of current or forthcoming therapies.

Role of HMGB1 in Cisplatin-Persistent Lung Adenocarcinoma Cell Lines.

Significant advances have been made recently in the development of targeted therapy for lung adenocarcinoma. However, platinum-based chemotherapy remains as the cornerstone in the treatment of this neoplasm. This is the treatment option for adenocarcinomas without EGFR gain-of-function mutations or tumors that have developed resistance to targeted therapy. The High-Mobility Group Box 1 (HMGB1) is a multifunctional protein involved in intrinsic resistance to cisplatin. HMGB1 is released when cytotoxic agents, such as cisplatin, induce cell death. In the extracellular milieu, HMGB1 acts as adjuvant to induce an antitumor immune response. However, the opposite effect favoring tumor progression has also been reported. In this study, the effects of cisplatin in lung adenocarcinoma cell lines harboring clinically relevant mutations, such as EGFR mutations, were studied. Subcellular localization of HMGB1 was detected in the cell lines and in viable cells after a single exposure to cisplatin, which are designated as cisplatin-persistent cells. The mRNA expression of the receptor for advanced glycation end products (RAGE), TLR-2, and TLR-4 receptors was measured in parental cell lines and their persistent variants. Finally, changes in plasma HMGB1 from a cohort of lung adenocarcinoma patients without EGFR mutation and treated with cisplatin-based therapy were analyzed. Cisplatin-susceptible lung adenocarcinoma cell lines died by apoptosis or necrosis and released HMGB1. In cisplatin-persistent cells, nuclear relocalization of HMGB1 and overexpression of HMGB1 and RAGE, but not TLR-2 or TLR-4, were observed. In tumor cells, this HMGB1-RAGE interaction may be associated with the development of cisplatin resistance. The results indicate a direct relationship between the plasma levels of HMGB1 and overall survival. In conclusion, HMGB1 may be an effective biomarker associated with increased overall survival of lung adenocarcinoma patients.