Flotillin-mediated stabilization of unfolded proteins in bacterial membrane microdomains.

The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. However, the mechanism and the biological function of these membrane microdomains remain unclear. Here, we show that FMMs in the pathogen methicillin-resistant Staphylococcus aureus (MRSA) are dedicated to confining and stabilizing proteins unfolded due to cellular stress. The FMM scaffold protein flotillin forms a clamp-shaped oligomer that holds unfolded proteins, stabilizing them and favoring their correct folding. This process does not impose a direct energy cost on the cell and is crucial to survival of ATP-depleted bacteria, and thus to pathogenesis. Consequently, FMM disassembling causes the accumulation of unfolded proteins, which compromise MRSA viability during infection and cause penicillin re-sensitization due to PBP2a unfolding. Thus, our results indicate that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability during infection.

Short-term outcomes of dogs and cats undergoing lung lobectomy using either a self-ligating loop or a thoracoabdominal stapler.

OBJECTIVE: To assess clinical outcomes of lung lobectomies in dogs and cats using either self-ligating loops (SLLs) or thoracoabdominal (TA) staplers, aiming to inform sample size calculations for future superiority trials. STUDY DESIGN: Retrospective study. ANIMALS: A total of 72 dogs and 15 cats. METHODS: Records from January 2003 to October 2023 at a single institution were reviewed. Cases with lung lobectomy performed via TA stapler or SLL with a minimum 14-day postoperative follow-up were included. Pre-, intra-, and postoperative data were collected, with outcomes of interest including the frequency of intra- and postoperative complications. Outcome comparisons between techniques were performed to inform sample size calculations. RESULTS: A total of 101 lung lobectomies were performed. The TA stapler was used in 83 (82.2%) and the SLL in 18 (17.8%) lung lobectomies. Intraoperative complications were identified in 14/101 lung lobectomies (13.9%), including intraoperative hemorrhage in 12/101 lobectomies (11.8%) and air leakage in 2/101 lobectomies (1.9%). Postoperative complications were identified in 12/87 cases (13.8%), including 4 (4.6%) catastrophic complications and 5 (5.8%) major complications. All intra- and postoperative complications occurred in cases having undergone stapled lung lobectomy; however, no differences were identified between surgical technique and either intraoperative (p = .069) or postoperative complications (p = .112). A sample size of 103 lobectomies per technique group would be required for appropriate evaluation. CONCLUSION: Lung lobectomy using either surgical technique provided a good short-term outcome in this population. CLINICAL SIGNIFICANCE: Self-ligating loop lung lobectomy provided a comparable alternative to stapled lung lobectomy. Further studies are needed to assess technique superiority.

Sigmoid adenocarcinoma hosted in a giant inguinoscrotal hernia.

Colorectal cancer is the most frequently diagnosed neoplasm in the population worldwide, regardless of sex. Its presentation is variable, from asymptomatic cases that are diagnosed in the population screening programme, to perforation or intestinal obstruction that appear urgently. The location of the neoplasia inside an inguinal hernia, although it is described in the literature, is uncommon and may increase the risk of incarceration or strangulation with the need for urgent surgery. We report a patient who presents adenocarcinoma of the sigmoid colon lodged in a giant inguino-scrotal hernia.

Retifanlimab in Advanced Penile Squamous Cell Carcinoma: The Phase 2 ORPHEUS Study.

BACKGROUND AND OBJECTIVE: Patients with advanced penile squamous cell carcinoma (PSCC) have poor outcomes and very limited therapeutic options are available. Most PSCC cases have high PD-L1 expression, which is associated with worse prognosis. Immunotherapy targeting PD-L1 could benefit patients with PSCC. Our aim was to evaluate the efficacy and safety of the anti-PD-1 antibody retifanlimab in patients with advanced/metastatic PSCC. METHODS: ORPHEUS was a single-arm, multicenter, phase 2 trial in 18 patients with advanced/metastatic PSCC, previously untreated with anti-PD-1/anti-PD-L1 agents. Patients received retifanlimab 500 mg intravenously every 4 wk for up to 2 yr. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included the clinical benefit rate (CBR), disease control rate, duration of response (DoR), time to response, progression-free survival (PFS), overall survival (OS), maximum tumor shrinkage, and safety. The Wilson method was used for the primary endpoint, and the Clopper-Pearson and Kaplan-Meier methods for secondary endpoints. KEY FINDINGS AND LIMITATIONS: Median follow-up was 7.2 mo. The ORR was 16.7% (95% confidence interval [CI] 5.8-39.2); three patients had a partial response. Median DoR was 3.3 mo (range 1.8-8.5). The CBR was 22.2% (95% CI 6.4-47.6%). Median PFS was 2.0 mo (95% CI 1.6-3.3) and median OS was 7.2 mo (95% CI 3.0-9.8). One patient (5.6%) experienced grade 3 treatment-related adverse events (AEs). There were no grade >= 4 treatment-related AEs. The small sample size is the main limitation. CONCLUSIONS AND CLINICAL IMPLICATIONS: Single-agent retifanlimab exhibited signals of clinical activity in advanced/metastatic PSCC, with no new safety signals. Further investigation of retifanlimab in this setting is warranted. PATIENT SUMMARY: Advanced penile cancer of the squamous cell type is a rare tumor with poor prognosis. The aggressiveness of this cancer is usually associated with high levels of a protein called PD-L1. We investigated whether retifanlimab, an immunotherapy drug against PD-1, has activity against this type of penile cancer. Tumor regression or stabilization occurred in one-third of the patients and the side effects were manageable.

Endoplasmic Reticulum Stress in Gliomas: Exploiting a Dual-Effect Dysfunction through Chemical Pharmaceutical Compounds and Natural Derivatives for Therapeutical Uses.

The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), which aims to restore proteostasis and avoid cell death. However, endoplasmic response-associated degradation (ERAD) is sometimes triggered to degrade the misfolded and unassembled proteins instead. If stress persists, cells activate three sensors: PERK, IRE-1, and ATF6. Glioma cells can use these sensors to remain unresponsive to chemotherapeutic treatments. In such cases, the activation of ATF4 via PERK and some proteins via IRE-1 can promote several types of cell death. The search for new antitumor compounds that can successfully and directly induce an endoplasmic reticulum stress response ranges from ligands to oxygen-dependent metabolic pathways in the cell capable of activating cell death pathways. Herein, we discuss the importance of the ER stress mechanism in glioma and likely therapeutic targets within the UPR pathway, as well as chemicals, pharmaceutical compounds, and natural derivatives of potential use against gliomas.

Extended septal myectomy versus alcohol septal ablation: clinical results at a national referral centre.

OBJECTIVES: Extended septal myectomy and alcohol septal ablation are 2 invasive treatments for hypertrophic obstructive cardiomyopathy. Our goal was to compare which of these techniques achieved a higher reduction in gradients, improvement in New York Heart Association (NYHA) functional class and reduction in medical treatment. METHODS: It is a single-centre observational and retrospective analysis. We used multivariable regression analyses to assess the association of ablation/myectomy with different outcomes. The odds ratio or coefficient along with the 95% confidence interval was estimated according to the group and adjusted for the corresponding preprocedural variables and EuroSCORE II. RESULTS: A total of 78 patients underwent septal myectomy, and 25 patients underwent alcohol septal ablation. Basal and Valsalva gradients after myectomy were reduced to a higher degree in comparison to ablation: 21.0 mmHg [P < 0.001, 95% confidence interval -30.7; -11.3], and 34.3 mmHg (P < 0.001, -49.1; -19.5) respectively. Those patients who received a myectomy had a lower probability of having moderate mitral regurgitation (odds ratio = 0.18, P = 0.054). Patients after septal myectomy were more likely to be NYHA functional class I (80.4%), whereas patients after ablation were more likely to be NYHA functional class III (48%). Both groups continued with beta-blocker therapy, but disopyramide could be discontinued after the myectomy in more cases (20%-36% vs 59%-1.3%; P < 0.001), and there was a tendency to discontinue calcium channel blockers (48%-16% vs 15.4-3.8%; P = 0.054). CONCLUSIONS: After adjustment using preprocedural gradients and EuroSCORE II, myectomy achieves greater reduction in left ventricular outflow tract gradients compared to septal ablation.

A Healthy Brazil Nut Beverage with Opuntia stricta var. dillenii Green Extract: Beverage Stability and Changes in Bioactives and Antioxidant Activity during Cold Storage.

Plant-based beverages are one of the foods that currently arouse a lot of interest in the population due to their composition with compounds beneficial to health in addition to their being used as milk substitutes for people who suffer from food disorders. Also, their fortification with different nutrients or healthy ingredients with the aim of improving plant-based health potential is actually gaining importance in the food industry. For this reason, the aim of the present investigation was the preparation of a healthy Brazil nut beverage enriched with Opuntia stricta var. dillenii pulp green extracts (ODPs), in order to produce a healthy plant-based beverage with improved nutritional characteristics. The microstructural characterization of the Brazil nut beverage, its stability during cold storage for up to 24 days at 5 °C, the composition of bioactive compounds provided via ODP extract (betalains and phenolic compounds), and their antioxidant activity were evaluated in this study. Green ODP extracts (0.5 and 1 g/100 g beverage) were added to a standardized Brazil nut beverage (reduced fat beverage). The characterization of the bioactive composition (betalains and phenolic compounds) of the elaborated beverage was achieved via HPLC (UV-vis and MS-QT of detection), and the antioxidant activity measurements via ORAC were also carried out. Optical microscopy, particle size, and Z potential analysis was conducted to characterize the structure of the Brazil nut beverages as food emulsions in which ODP extract was added. Most of the bioactive compounds from the green ODP extract added to the beverages showed good retention and remained stable throughout the 24 days of storage at 7 °C, with encapsulation efficiencies ranging from 98.34% to 92.35% for betalains and from 93.67% and 81.20% for phenolic compounds. According to the results of this study, Brazil nut beverage seems to be a healthy and efficient food emulsion system to encapsulate ODP extract rich in betalains and phenolic compounds, with high antioxidant activity, making possible the development of a Brazil nut beverage with improved health potential.

Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

The frozen elephant trunk: seeking a more definitive treatment for acute type A aortic dissection.

OBJECTIVES: Conventional treatment for type A aortic dissection includes replacement of the ascending aorta with an open distal anastomosis in the hemiarch position. The frozen elephant trunk (FET) is a hybrid technique that extends the repair to the descending thoracic aorta. The goal is to improve resolution of malperfusion syndrome and to induce positive aortic remodelling and reduce the need for reintervention on the downstream aorta. We aim to summarize the data on the short and long-term outcomes of this technique. METHODS: A thorough search of the literature was conducted isolating all articles dealing with aortic remodelling after the use of FET in case of type A acute aortic dissection. Keywords 'aortic dissection', 'frozen elephant trunk', 'aortic remodelling' and 'false lumen thrombosis' were used. Data for type B and chronic aortic dissections were excluded. RESULTS: FET use favourably influences aortic remodelling. The main advantages lie in the exclusion of distal entry tears in either the aortic arch or descending aorta thus restoring antegrade blood flow in the true lumen and inducing false lumen thrombosis. False lumen thrombosis is not only induced at the level of the stent deployment but also lower in the distal descending aorta. Moreover, it offers an adequate landing zone in the mid-descending aorta for second-stage endovascular or open surgical aortic repair, if needed. CONCLUSIONS: FET can be advantageous in the treatment of acute type A aortic dissection dealing with extended aortic pathology.

3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.

BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. FUNDING: F Hoffmann-La Roche.

Human milk oligosaccharides differentially support gut barrier integrity and enhance Th1 and Th17 cell effector responses in vitro.

Human milk oligosaccharides (HMOs) can modulate the intestinal barrier and regulate immune cells to favor the maturation of the infant intestinal tract and immune system, but the precise functions of individual HMOs are unclear. To determine the structure-dependent effects of individual HMOs (representing different structural classes) on the intestinal epithelium as well as innate and adaptive immune cells, we assessed fucosylated (2'FL and 3FL), sialylated (3'SL and 6'SL) and neutral non-fucosylated (LNT and LNT2) HMOs for their ability to support intestinal barrier integrity, to stimulate the secretion of chemokines from intestinal epithelial cells, and to modulate cytokine release from LPS-activated dendritic cells (DCs), M1 macrophages (MØs), and co-cultures with naïve CD4+ T cells. The fucosylated and neutral non-fucosylated HMOs increased barrier integrity and protected the barrier following an inflammatory insult but exerted minimal immunomodulatory activity. The sialylated HMOs enhanced the secretion of CXCL10, CCL20 and CXCL8 from intestinal epithelial cells, promoted the secretion of several cytokines (including IL-10, IL-12p70 and IL-23) from LPS-activated DCs and M1 MØs, and increased the secretion of IFN-γ and IL-17A from CD4+ T cells primed by LPS-activated DCs and MØs while reducing the secretion of IL-13. Thus, 3'SL and 6'SL supported Th1 and Th17 responses while reducing Th2 responses. Collectively, our data show that HMOs exert structure-dependent effects on the intestinal epithelium and possess immunomodulatory properties that confer benefits to infants and possibly also later in life.

Assessment and indicators of kinematic behavior and perceived fatigability

SUMMARY OBJECTIVE: The objective of this study was to investigate the relationship between upper limb kinetics and perceived fatigability in elderly individuals during an upper limb position sustained isometric task. METHODS: A total of 31 elderly participants, 16 men (72.94±4.49 years) and 15 women (72.27±6.05 years), performed a upper limb position sustained isometric task. Upper-limb acceleration was measured using an inertial measurement unit. Perceived fatigability was measured using the Borg CR10 scale. RESULTS: Higher mean acceleration in the x-axis throughout the activity was associated with higher final perceived fatigability scores. Moderate correlations were observed between perceived fatigability variation and mean acceleration cutoffs in all axes during the second half of the activity. In women, significant correlations were found between all perceived fatigability cutoffs and mean acceleration in the y- and x-axes. However, in men, the relationships between perceived fatigability variation and mean acceleration were more extensive and stronger. CONCLUSION: The acceleration pattern of the upper limb is linked to perceived fatigability scores and variation, with differences between sexes. Monitoring upper limb acceleration using a single inertial measurement unit can be a useful and straightforward method for identifying individuals who may be at risk of experiencing high perceived fatigability or task failure.

Assessing the effect of prophylactic ankle taping on ankle and knee biomechanics during landing tasks in healthy individuals: A cross-sectional observational study

ABSTRACT BACKGROUND: Current research supports the fact that prophylactic ankle taping (AT) is effective in preventing ankle injuries in amateur and elite sports athletes. OBJECTIVE: This study aimed to investigate the effect of AT on balance, knee valgus during drop jump and single-leg countermovement jump (SL-CMJ) landings, and ankle range of motion (ROM) restriction in healthy participants. DESIGN AND SETTING: A cross-sectional observational study was conducted at the Universidad Europea de Madrid, Madrid, Spain. METHODS: Participants: Thirty-nine healthy individuals participated in this study and performed the movements under two conditions (with and without tape). Outcome measurements: ankle ROM, balance, SL-CMJ height, flight time, ground time, and knee valgus. Before any intervention, a random process was developed with a 1:1 allocation ratio, and the participants were assigned to groups A (tape-no tape) and B (no tape-tape). RESULTS: Significant differences between tape and no-tape moments were observed for drop jump knee valgus flexion (P = 0.007), with an increase in knee valgus in participants with ankle taping. Similarly, the Y-balance testshowed a significant decrease in all variables (P = 0.001 and), ankle dorsiflexion (P = 0.001) in participants with ankle taping. CONCLUSIONS: AT is effective for immediate ankle ROM restriction. However, an increase in knee valgus during drop jump task and a decrease in lower limb balance were observed during drop jump task. Based on these results, it can be concluded that AT application in healthy individuals should not be recommended as it results in increase in injury risk factors.

Is ankle taping effective to limit the ankle dorsiflexion in a single-training session? An observational study in semi-professional basketball players

ABSTRACT BACKGROUND: Ankle taping (AT) is effective in preventing ankle sprain injuries in most common sports and is employed in rehabilitation and prevention sports. OBJECTIVE: This study aimed to investigate the effectiveness of AT to restricting excessive frontal plane ankle movements in semi-professional basketball players throughout the training session. DESIGN AND SETTING: A cross-sectional study was performed at the Universidad Europea de Madrid. METHODS: Forty male and female semi-professional basketball players were divided into two groups. The ankle dorsiflexion range of motion (ROM) and interlimb asymmetries in a weight-bearing lunge position were evaluated at four time points: 1) with no tape, 2) before practice, at 30 min of practice, and 3) immediately after practice. RESULTS: In male basketball players, no differences were observed in the right and left ankles between the baseline and 30 min and between baseline and 90 min of assessment. In female athletes, significant differences were reported between baseline and pre-training assessments for the right ankle and also significant differences between baseline and 90 min in both ankles. CONCLUSIONS: Ankle taping effectively decreased the ankle dorsiflexion ROM in male and female basketball players immediately after application. However, ROM restriction was very low after 30 and 90 min, as assessed in a single basketball practice. Therefore, the classic taping method should be revised to develop new prophylactic approaches, such as the implementation of semi-rigid bracing techniques or the addition of active stripes during training or game pauses.

Evaluation of the validated intraoperative bleeding scale in liver surgery: study protocol for a multicenter prospective study.

Background: Surgical hemostasis has become one of the key principles in the advancement of surgery. Hemostatic agents are commonly administered in many surgical specialties, although the lack of consensus on the definition of intraoperative bleeding or of a standardized system for its classification means that often the most suitable agent is not selected. The recommendations of international organizations highlight the need for a bleeding severity scale, validated in clinical studies, that would allow the selection of the best hemostatic agent in each case. The primary objective of this study is to evaluate the VIBe scale (Validated Intraoperative Bleeding Scale) in humans. Secondary objectives are to evaluate the scale's usefulness in liver surgery; to determine the relationship between the extent of bleeding and the hemostatic agent used; and to assess the relationship between the grade of bleeding and postoperative complications. Methods: Prospective multicenter observational study including 259 liver resections that meet the inclusion criteria: patients scheduled for liver surgery at one of 10 medium-high volume Spanish HPB centers using an open or minimally invasive approach (robotic/laparoscopic/hybrid), regardless of diagnosis, ASA score <4, age ≥18, and who provide signed informed consent during the study period (September 2023 until the required sample size has been recruited). The participating researchers will be responsible for collecting the data and for reporting them to the study coordinators. Discussion: This study will allow us to evaluate the VIBe scale for intraoperative bleeding in humans, with a view to its subsequent incorporation in daily clinical practice. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05369988?term = serradilla&draw = 2&rank = 3, [NCT0536998].

Application of the REAL-score prognostic index in decision making in rectal cancer surgery.

BACKGROUND: Colorectal anastomosis leak (AL) is the most feared complication of rectal cancer surgery (1-19%) as it increases morbidity and mortality and worsens oncological outcomes in terms of local recurrence and survival. The publication of the REAL-score index makes it possible to predict the risk of AL and compare the expected results with those obtained. METHOD: Observational, descriptive, longitudinal and retrospective study of patients operated on for rectal cancer at the Miguel Servet University Hospital, in Zaragoza, Spain, in 2019. Statistical analysis of morbidity and mortality outcome variables and the REAL-score index using ROC curves. RESULTS: Of 80 patients operated on for rectal cancer, colorectal anastomosis was performed in 52 and temporary ileostomy in 11 (21.2%). Morbidity was high (38.4%), but severe only in 7.7% (Clavien-Dindo IIIb), with no deaths. There were four dehiscences: one type B and three type C. A direct relationship between high risk of AL and the practice of temporary stoma is observed when the cut-off point of the REAL-score exceeds 14.74%. CONCLUSIONS: REAL-score can help in decision-making in rectal cancer surgery. Above a cut-off point, the risk of AL would imply a selective ileostomy.

ANTECEDENTES: La dehiscencia de la anastomosis colorrectal (DA) es la complicación más temida de la cirugía del cáncer de recto (1-19%), pues incrementa la morbimortalidad y empeora los resultados oncológicos en términos de recidiva local y supervivencia. La publicación del índice REAL-score permite predecir el riesgo de DA y comparar los resultados esperados con los obtenidos. MÉTODO: Estudio observacional, descriptivo, longitudinal y retrospectivo, de pacientes intervenidos de cáncer de recto en el Hospital Universitario Miguel Servet, en Zaragoza, España, en 2019. Análisis estadístico de variables resultado de morbimortalidad y del índice REAL-score mediante curvas ROC. RESULTADOS: De 80 pacientes intervenidos de cáncer de recto, se realizó anastomosis colorrectal en 52 e ileostomía temporal en 11 (21.2%). La morbilidad fue alta (38.4%), pero grave solo en el 7.7% (Clavien-Dindo IIIb), sin ningún fallecimiento. Hubo cuatro dehiscencias: una de tipo B y tres de tipo C. Se observa una relación directa entre alto riesgo de DA y la práctica de estoma temporal cuando el punto de corte del REAL-score supera el 14.74%. CONCLUSIONES: El REAL-score puede ayudar en la toma de decisiones en la cirugía del cáncer de recto. Por encima de un punto de corte, el riesgo de DA implicaría ileostomía selectiva.

Phase II trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/ CDKN2A.

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors demonstrated activity in terms of progression-free survival (PFS) in advanced dedifferentiated liposarcoma (DD-LPS), a sarcoma with CDK4 amplification. CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors. Preclinical investigators of this study found that CDK4 overexpression, while not of CDKN2A, was the most consistent predictive factor for palbociclib efficacy in sarcomas. Advanced adult-type soft-tissue sarcoma, excluding DD-LPS, or bone sarcoma patients, progressing after at least one systemic line, whose tumors overexpressed CDK4, but not CDKN2A at baseline biopsy, were accrued in this single-arm phase II trial (EudraCT number: 2016-004039-19). With the main endpoint of a 6-month PFS rate, 40% was considered promising in this population. Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles. A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening, archival material (141), and screening, baseline biopsy (95). There were 28 (29%) with favorable mRNA profiles from 95 screened patients at baseline. From 23 enrolled patients, 21 evaluable, the 6-month PFS rate was 29% (95% CI 9-48), and there were 6 patients out of 21 with a PFS longer than 6 months. The median PFS and overall survival were 4.2 (95% CI 3.6-4.8) and 12 (95% CI 8.7-15.4) months, respectively. Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.

Effects of Myofascial Induction Therapy on Ankle Range of Motion and Pressure Pain Threshold in Trigger Points of the Gastrocnemius-A Clinical Trial.

BACKGROUND: The myofascial induction technique (MIT) has been shown to increase shoulder range of motion (ROM) in breast cancer survivors and decrease pain pressure threshold over the radial nerve in patients with epicondylalgia. To the authors' best knowledge, no study on trigger points and MIT has been published to date. The effect on ROM of latent trigger points is also unknown. METHODS: A total of 20 twins with one latent trigger point of the gastrocnemius muscle were evaluated pre- and post-MIT in the calf. We measured static footprint variables in a pre-post study. RESULTS: We found differences in PPT (p = 0.001) and no differences in ROM with knee flexed (p = 0.420) or stretched (p = 0.069). CONCLUSIONS: After Calf MIT, latent myofascial trigger points improve PPT but no change in ankle dorsiflexion with knee bent or knee flexed were found in non-restriction healthy subjects.