Kca3.1-Related Cellular Signalling Involved in Cancer Proliferation.

Anomalous expression of potassium channels in cancer tissues is associated with several cancer hallmarks that support deregulated proliferation and tumor progression. Ion channels seem to influence cell proliferation; however, the crucial molecular mechanisms involved remain elusive. Some results show how extracellular mitogenic signals modulate ion channel activity through intracellular secondary messengers. It is relevant because we are beginning to understand how potassium channels can affect the proliferative capacity of cells, either in normal mitogen-dependent proliferation or in mitogen-unresponsive proliferation. Calciumdependent potassium channels have been implicated in cell cycle signaling in many cancerous cell lines. In particular, the so-called intermediate conductance KCa3.1 (IKCa) is reported to play a significant role in uncontrolled cell cycle signaling, among other malignant processes driven by cancer hallmarks. In addition to these features, this channel can be subjected to specific pharmacological regulation, making it a promising cornerstone for understanding the signaling behavior of several types of cancer and as a target for chemotherapeutic approaches. This review is dedicated to the connection of KCa3.1 activity, in canonical and non-canonical ways, to the cell cycle signaling, including the cooperation with calcium channels to generate calcium signals and its role as a mediator of proliferative signals.

Microfracture-coagulation for the real robotic liver parenchymal transection.

The use of the robotic approach in liver surgery is exponentially increasing. Although technically the robot introduces several innovative features, the instruments linked with the traditional laparoscopic approach for the liver parenchymal transection are not available, which may result in multiple technical variants that may bias the comparative analysis between the different series worldwide. A real robotic approach, minimally efficient for the liver parenchymal transection, with no requirement of external tool, available for the already existing platforms, and applicable to any type of liver resection, counting on the selective use of the plugged bipolar forceps and the monopolar scissors, or "microfracture-coagulation" (MFC) transection method, is described in detail. The relevant aspects of the technique, its indications and methodological basis are discussed.

The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS).

OBJECTIVE: To develop and update evidence-based and consensus-based guidelines on laparoscopic and robotic pancreatic surgery. SUMMARY BACKGROUND DATA: Minimally invasive pancreatic surgery (MIPS), including laparoscopic and robotic surgery, is complex and technically demanding. Minimizing the risk for patients requires stringent, evidence-based guidelines. Since the International Miami Guidelines on MIPS in 2019, new developments and key publications have been reported, necessitating an update. METHODS: Evidence-based guidelines on 22 topics in 8 domains were proposed: terminology, indications, patients, procedures, surgical techniques and instrumentation, assessment tools, implementation and training, and artificial intelligence. The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS, September 2022) used the Scottish Intercollegiate Guidelines Network (SIGN) methodology to assess the evidence and develop guideline recommendations, the Delphi method to establish consensus on the recommendations among the Expert Committee, and the AGREE II-GRS tool for guideline quality assessment and external validation by a Validation Committee. RESULTS: Overall, 27 European experts, 6 international experts, 22 international Validation Committee members, 11 Jury Committee members, 18 Research Committee members, and 121 registered attendees of the 2-day meeting were involved in the development and validation of the guidelines. In total, 98 recommendations were developed, including 33 on laparoscopic, 34 on robotic, and 31 on general MIPS, covering 22 topics in 8 domains. Out of 98 recommendations, 97 reached at least 80% consensus among the experts and congress attendees, and all recommendations were externally validated by the Validation Committee. CONCLUSIONS: The EGUMIPS evidence-based guidelines on laparoscopic and robotic MIPS can be applied in current clinical practice to provide guidance to patients, surgeons, policy-makers, and medical societies.

Retiro de dispositivo de oclusión septal transcateterismo en una paciente con comunicación interventricular / Removal of Transcatheter Septal Occlusion Device in a Patient with Ventricular Septal Defect

Introducción: Las complicaciones asociadas al procedimiento de colocación de un dispositivo de oclusión septal se presentan en menos del 10 por ciento de los casos. La embolización requiere de cirugía cardíaca, por lo que se incrementa el riesgo de la mortalidad. Objetivo: Presentar el caso en una paciente con comunicación interventricular e hipertensión pulmonar severa que se le retiró el dispositivo de oclusión septal transcateterismo. Presentación de caso: Se presentó una mujer de 24 años de edad con comunicación interventricular, insuficiencia cardíaca (New York Heart Association) clase IV e hipertensión pulmonar tipo 2, que se programó para la colocación de dispositivo de oclusión septal, sin embargo, presentó fallo en la colocación del dispositivo y defecto residual de 7 mm, por lo que se realizó el retiro de este 48 h después sin presentar complicaciones. Conclusiones: Aunque el cierre transcateterismo de la comunicación interventricular es una alternativa segura y efectiva a la cirugía, no está exento de complicaciones. En caso de translocación del dispositivo de oclusión septal este debe ser retirado durante el mismo procedimiento, ya que el riesgo de embolización es elevado y en caso de presentarse, el riesgo de muerte se incrementa(AU)

Introduction: Complications associated with the placement procedure of a septal occlusion device occur in less than 10percent of cases. Embolization requires cardiac surgery, which increases the risk of mortality. Objective: To report the case of a patient with ventricular septal defect and severe pulmonary hypertension who had the transcatheter septal occlusion device removed. Case report: We report the case report of a 24-year-old woman with ventricular septal defect, heart failure (New York Heart Association) class IV and type 2 pulmonary hypertension. She was scheduled for placement of a septal occlusion device, however, the placement of the device failed and had a residual defect of 7 mm, so the placement was removed 48 hours later without complications. Conclusions: Although transcatheter closure of the ventricular septal defect is a safe and effective alternative to surgery, it is not free of complications. In case of translocation of the septal occlusion device, it must be removed during the same procedure, since the risk of embolization is high and if it occurs, the risk of death increases(AU)

Morbidity and mortality of elderly patients with pancreaticobiliary disease according to age and comprehensive geriatric assessment: A prospective observational study.

BACKGROUND: This study was designed to analyze the influence of age and comprehensive geriatric evaluation on clinical results of pancreaticobiliary disease management in elderly patients. METHODS: A prospective observational study has been undertaken, including 140 elderly patients (over 75 years) with benign pancreaticobiliary disease. Patients were divided according to age in the following groups: group 1: 75-79 years old; group 2: 80-84 years old; group 3: 85 years and older. They underwent a comprehensive geriatric assessment with different scales: Barthel Index, Pfeiffer Index, Charlson Index, and Fragility scale, at admission and had been follow-up 90 days after hospital discharge to analyze its influence on morbidity and mortality. RESULTS: Overall, 140 patients have been included (group 1=51; group 2=43 and group 3=46). Most of them, 52 cases (37.8%), had acute cholecystitis, followed by 29 cases of acute cholangitis (20.2%) and acute pancreatitis with 25 cases (17.9%). Significant differences has been observed on complications in different age groups (p=0.033). Especially in patients with a Barthel Index result ≤60, which suggests that these less functional patients had more severe complications after their treatment (p=0.037). The mortality rate was 7.1% (10 patients). CONCLUSIONS: No significant differences were found between age, morbidity and mortality in elderly patients with pancreaticobiliary disease. Comprehensive geriatric scales showed some utility in their association with specific complications.

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

[Severe rhabdomyolysis associated with atorvastatin. Case report]. / Rabdomiólisis severa asociada a atorvastatina. Reporte de caso.

Background: Dyslipidemia is a risk factor for the development of atherosclerosis and ischemic heart disease. Statins are safe drugs that are part of the routine treatment in patients with Acute Myocardial Infarction (AMI), however, rhabdomyolysis associated with severe myonecrosis due to statins can occur and associated complications such as acute kidney injury increase mortality. The main objective of this article is to report the case of a critically ill patient with AMI who presented severe statin-associated rhabdomyolysis documented with muscle biopsy. Description of the case: A 54-year-old man who presented with AMI, cardiogenic shock, and cardiorespiratory arrest requiring cardiopulmonary resuscitation, fibrinolysis, and successful salvage coronary angiography. However, he presented severe rhabdomyolysis associated with atorvastatin that required suspension of the drug and multi-organ support in a Coronary Care Unit. Conclusions: The prevalence of statin-associated rhabdomyolysis is low, however, the late elevation of CPK above 10 times its upper normal value in those patients with successful percutaneous coronary angiography should promptly draw attention, generate a diagnostic approach towards non-traumatic acquired causes of rhabdomyolysis and assess the suspension of statins.

Introducción: la dislipidemia es un factor de riesgo para el desarrollo de ateroesclerosis y cardiopatía isquémica. Las estatinas son fármacos seguros que forman parte del tratamiento de rutina en el paciente con infarto agudo de miocardio (IAM). Sin embargo, la rabdomiólisis asociada a mionecrosis severa por estatinas puede presentarse y las complicaciones asociadas como la lesión renal aguda incrementan la mortalidad. El objetivo principal de este artículo es reportar el caso de un paciente críticamente enfermo con IAM que presentó rabdomiólisis severa asociada a estatinas documentada con biopsia muscular. Caso clínico: hombre de 54 años que presentó IAM, choque cardiogénico y paro cardiorrespiratorio, que ameritó reanimación cardiopulmonar, fibrinólisis y angiografía coronaria de rescate exitosa. Sin embargo, presentó rabdomiólisis severa asociada a atorvastatina que requirió de suspensión del fármaco y soporte multiorgánico en una unidad de cuidados coronarios. Conclusiones: la prevalencia de la rabdomiólisis asociada a estatinas es baja, sin embargo, la elevación tardía de la CPK por arriba de 10 veces su valor superior normal en aquellos pacientes con angiografía coronaria percutánea exitosa debe llamar la atención, generar un abordaje diagnóstico hacia causas adquiridas no traumáticas de rabdomiólisis y valorar la suspensión de estatinas.

Preservation of KCC2 expression in axotomized abducens motoneurons and its enhancement by VEGF.

The potassium chloride cotransporter 2 (KCC2) is the main Cl- extruder in neurons. Any alteration in KCC2 levels leads to changes in Cl- homeostasis and, consequently, in the polarity and amplitude of inhibitory synaptic potentials mediated by GABA or glycine. Axotomy downregulates KCC2 in many different motoneurons and it is suspected that interruption of muscle-derived factors maintaining motoneuron KCC2 expression is in part responsible. In here, we demonstrate that KCC2 is expressed in all oculomotor nuclei of cat and rat, but while trochlear and oculomotor motoneurons downregulate KCC2 after axotomy, expression is unaltered in abducens motoneurons. Exogenous application of vascular endothelial growth factor (VEGF), a neurotrophic factor expressed in muscle, upregulated KCC2 in axotomized abducens motoneurons above control levels. In parallel, a physiological study using cats chronically implanted with electrodes for recording abducens motoneurons in awake animals, demonstrated that inhibitory inputs related to off-fixations and off-directed saccades in VEGF-treated axotomized abducens motoneurons were significantly higher than in control, but eye-related excitatory signals in the on direction were unchanged. This is the first report of lack of KCC2 regulation in a motoneuron type after injury, proposing a role for VEGF in KCC2 regulation and demonstrating the link between KCC2 and synaptic inhibition in awake, behaving animals.

Laparoscopic and robotic distal pancreatectomy: the choice and the future.

INTRODUCTION: Distal pancreatectomy (DP) is currently well established as a minimally invasive surgery (MIS) procedure, using either a laparoscopic (LDP) or robotic (RDP) approach. METHODS: Out of 83 DP performed between January 2018 and March 2022, 57 cases (68.7%) were performed using MIS: 35 LDP and 22 RDP (da Vinci Xi). We have assessed the experience with the two techniques and analyzed the value of the robotic approach. Cases of conversion have been examined in detail. RESULTS: The mean operative times for LDP and RDP were 201.2 (SD 47.8) and 247.54 (SD 35.8) minutes, respectively (P = NS). No differences were observed in length of hospital stay or conversion rate: 6 (5-34) vs. 5.6 (5-22) days, and 4 (11.4%) vs. 3 (13.6%) cases, respectively (P = NS). The readmission rate was 3/35 patients (11.4%) treated with LDP and 6/22 (27.3%) cases of RDP (P = NS). There were no differences in morbidity (Dindo-Clavien ≥ III) between the two groups. Mortality was one case in the robotic group (a patient with early conversion due to vascular involvement). The rate of R0 resection was greater and statistically significant in the RDP group (77.1% vs. 90.9%) (P = .04). CONCLUSION: Minimally invasive distal pancreatectomy (MIDP) is a safe and feasible procedure in selected patients. Surgical planning and stepwise implementation based on prior experience help surgeons successfully perform technically demanding procedures. RDP could be the approach of choice in distal pancreatectomy, and it is not inferior to LDP.

Robotic liver surgery: A new reality. Descriptive analysis of 220 cases of minimally invasive liver surgery in 182 patients.

INTRODUCTION: The level of recommendation of the robotic approach in liver surgery is controversial. The objective of the study is to carry out a single-center retrospective descriptive analysis of the short-term results of the robotic and laparoscopic approach in liver surgery during the same period. METHODS: Descriptive analysis of the short-term results of the robotic and laparoscopic approach on 220 resections in 182 patients undergoing minimally invasive liver surgery. RESULTS: Between April 2018 and June 2022, a total of 92 robotic liver resections (RLR) were performed in 83 patients and 128 laparoscopic (LLR) in 99 patients. The LLR group showed a higher proportion of major surgery (P < .001) and multiple resections (P = .002). The two groups were similar in anatomical resections (RLR 64.1% vs. LLR 56.3%). In the LLS group, the average operating time was 212 min (SD 52.1). Blood loss was 276.5 mL (100-1000) and conversion 12.1%. Mean hospital stay was 5.7 (SD 4.9) days. Morbidity was 27.3% and 2% mortality. In the RLS group, the mean operative time was 217 min (SD 53.6), blood loss 169.5 mL (100.900), and conversion 2.5%. Mean hospital stay was 4.1 (SD 2.1) days. Morbidity was 15%, with no mortality. CONCLUSION: Minimally invasive liver surgery is a safe technique, and in particular, RLS allows liver resections to be performed safely and reproducibly; it appears to be a non-inferior technique to LLS, but randomized studies are needed to determine the minimally invasive approach of choice in liver surgery.

Radiation therapy for vulvar cancer: consensus guidelines of the GINECOR working group of the Spanish Society of Radiation Oncology. Part 1: clinical recommendations.

PURPOSE: The present consensus statement was developed by the GINECOR working group on behalf of the Spanish Society of Radiation Oncology (SEOR). Given the lack of prospective data on the management of vulvar carcinoma, this document provides an up-to-date review of radiotherapy treatment in vulvar cancer and a series of consensus-based recommendations from a group of experts. METHODS: A two-round, online modified Delphi study was conducted to reach consensus treatment recommendations in three clinical settings: 1) adjuvant treatment, 2) locally-advanced vulvar cancer (LAVC), and 3) recurrent disease. After the first round, we comprehensively reviewed the available medical literature from peer-reviewed journals to assess and define the evidence-based treatment options. In the second round, participants were asked to indicate their level of agreement with the preliminary recommendations according to the GRADE (Grade of Recommendation, Assessment, Development, and Evaluation) criteria, as follows: strongly agree; agree; neither agree nor disagree; disagree; strongly disagree. RESULTS: The main recommendations were as follows: 1) following surgical resection, adjuvant radiotherapy is recommended with the presence of adverse risk factors (primarily positive margins and lymph node involvement); 2) radiotherapy (with or without chemotherapy) should be considered in LAVC; and 3) in recurrent disease, radiotherapy should be individualised on a case-by-case basis. A high level of agreement over 80% was reached. CONCLUSIONS: In the absence of robust clinical data, these final recommendations may help to select the optimal radiotherapy approach for this relatively rare cancer.

Radiation therapy for vulvar cancer: consensus technical guidelines of the GINECOR working group of the Spanish Society of Radiation Oncology. Part 2: radiotherapy recommendations.

PURPOSE: The present consensus statement was developed by the GINECOR working group on behalf of the Spanish Society of Radiation Oncology (SEOR). This document provides an up-to-date review of the technical aspects in radiation treatment of vulvar cancer. METHODS: A two-round modified Delphi study was conducted to reach consensus on the appropriateness of technical aspects of external beam radiotherapy and brachytherapy. Three clinical scenarios were proposed: adjuvant treatment of vulvar cancer, radiation treatment of locally advanced vulvar carcinoma and locoregional recurrences. After the first round, an extensive analysis of current medical literature from peer-reviewed journal was performed to define evidence-based treatment options. In the second round, participants were asked to indicate their level of agreement with the preliminary recommendations according to the GRADE (Grade of Recommendation, Assessment, Development, and Evaluation) criteria, as follows: strongly agree; agree; neither agree nor disagree; disagree and strongly disagree. RESULTS: The main recommendations on external beam radiotherapy and brachytherapy, both in adjuvant setting and local advanced disease are summarized. Recommendations include treatment technique, treatment volume, and doses in target and organs at-risk. Taking into consideration the different clinical scenarios of recurrent disease, the radiation treatment should be individualized. CONCLUSIONS: In the absence of robust clinical data, these recommendations may help to select the optimal radiotherapy approach for this relatively rare cancer.

Augmented reality in hepatobiliary-pancreatic surgery: a technology at your fingertips.

Augmented reality is a technology that opens new possibilities in surgery. We present our experience in a hepatobiliary-pancreatic surgery unit in terms of preoperative planning, intraoperative support and teaching. For surgical planning, we have used 3D CT and MRI reconstructions to evaluate complex cases, which has made the interpretation of the anatomy more precise and the planning of the technique simpler. At an intraoperative level, it provides for remote holographic connection between specialists, the substitution of physical elements for virtual elements, and the use of virtual consultation models and surgical guides. In teaching, new lessons include sharing live video of surgery with the support of virtual elements for a better student understanding. As the experience has been satisfactory, augmented reality could be applied in the future to improve the results of hepatobiliary-pancreatic surgery.

Clostridium paraputrificum bacteremia in a 64-year-old woman with colon carcinoma.

Here we report a case of bacteremia caused by Clostridium paraputrificum in a 64-year-old woman with colon carcinoma and gastrointestinal disease. Using the new EUCAST 2022 clinical breakpoints for Clostridium perfringens, the isolate was susceptible to metronidazole and vancomycin, but resistant to benzylpenicillin, meropenem, and clindamycin. Thus, treatment with metronidazole should be considered in all patients with Clostridium bacteremia until antibiotic susceptibility is determined to minimize the risk of treatment failure.

Long-term results of liver-first approach strategy in patients with advanced synchronous liver metastases from colorectal cancer.

BACKGROUND: The "liver-first" approach (LFA) is a strategy indicated for advanced synchronous liver metastases (ASLM) from colorectal cancer (CRC). Includes neoadjuvant chemotherapy, resection of the ASLM followed by CRC resection. METHODS: Retrospective descriptive analysis from a prospective database of hepatectomies from liver metastases (LM) from CRC in two centers. Between 2007-2019, 88 patients with CRC-ASLM were included in a LFA scheme. Bilobar (LM) was present in 65.9%, the mean number of lesions was 5.5 and mean size 42.7 mm. Response to treatment was assessed by RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves. RESULTS: Seventy-five of 88 patients (85.2%) completed the LFA. RECIST evaluation showed partial response in 75.7% and stable disease in 22.8%. Severe morbidity rate (Clavien-Dindo ≥ IIIA) after liver and colorectal surgery was present in 29.4% and 9.3%, respectively. There was no 90-day postoperative mortality in both liver and colorectal surgeries. Recurrence rate was 76%, being the liver the most frequent site, followed by the pulmonary. From the total number of recurrences (106) in 56 patients, surgical with chemotherapy rescue treatment was accomplished in 34 of them (32.1%). The mean PFS was 8.5 and 5-year OS was 53%. CONCLUSIONS: In patients with CRC-ASLM the LFA allows control of the liver disease beforehand and an assessment of the tumor response to neoadjuvant chemotherapy, optimising the chance of potentially curative liver resection, which influences long-term survival.