Biomarkers Found in the Tumor Interstitial Fluid may Help Explain the Differential Behavior Among Keratinocyte Carcinomas.

Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most frequent types of cancer, and both originate from the keratinocyte transformation, giving rise to the group of tumors called keratinocyte carcinomas (KCs). The invasive behavior is different in each group of KC and may be influenced by their tumor microenvironment. The principal aim of the study is to characterize the protein profile of the tumor interstitial fluid (TIF) of KC to evaluate changes in the microenvironment that could be associated with their different invasive and metastatic capabilities. We obtained TIF from 27 skin biopsies and conducted a label-free quantitative proteomic analysis comparing seven BCCs, 16 SCCs, and four normal skins. A total of 2945 proteins were identified, 511 of them quantified in more than half of the samples of each tumoral type. The proteomic analysis revealed differentially expressed TIF proteins that could explain the different metastatic behavior in both KCs. In detail, the SCC samples disclosed an enrichment of proteins related to cytoskeleton, such as Stratafin and Ladinin-1. Previous studies found their upregulation positively correlated with tumor progression. Furthermore, the TIF of SCC samples was enriched with the cytokines S100A8/S100A9. These cytokines influence the metastatic output in other tumors through the activation of NF-kB signaling. According to this, we observed a significant increase in nuclear NF-kB subunit p65 in SCCs but not in BCCs. In addition, the TIF of both tumors was enriched with proteins involved in the immune response, highlighting the relevance of this process in the composition of the tumor environment. Thus, the comparison of the TIF composition of both KCs provides the discovery of a new set of differential biomarkers. Among them, secreted cytokines such as S100A9 may help explain the higher aggressiveness of SCCs, while Cornulin is a specific biomarker for BCCs. Finally, the proteomic landscape of TIF provides key information on tumor growth and metastasis, which can contribute to the identification of clinically applicable biomarkers that may be used in the diagnosis of KC, as well as therapeutic targets.

NK cells and the profile of inflammatory cytokines in the peripheral blood of patients with advanced carcinomas.

BACKGROUND: Natural killer (NK) cells are one of the most crucial immune cells that mediate the antitumoral response due to their ability to immediately recognize and eliminate transformed cells. Because of their great cytotoxic activity, the function of NK cells must be robustly regulated to avoid tissue damage. Such regulation is mediated by a coordinated engagement of activating (NKp46) and inhibitory (CD158b) receptors, which tumor cells may use to escape from immunosurveillance. Also, NK cells are generally divided based on surface molecules, such as CD16 and CD56, and can be classified as CD56brightCD16- (regulatory) and CD56dimCD16+ (cytotoxic) NK cells. Here, we aimed to evaluate the frequency and phenotype of circulating NK cells in patients with advanced carcinomas, as well as their systemic cytokine/chemokine and growth factors production. METHODS: Peripheral blood was collected from 24 patients with advanced solid cancer during or after treatment and from 10 healthy donors. The frequency and the expression of activating (NKp46) and inhibitory (CD158b) molecules of CD56brightCD16- and CD56dimCD16+ NK cells were assessed by flow cytometry and the multiplex Luminex platform was used to quantify the secreted factors in peripheral blood serum. RESULTS: Cancer patients had a lower frequency of the cytotoxic CD56dim CD16+ NK cells subset in comparison with healthy controls. Also, the regulatory CD56bright CD16- NKs isolated from cancer patients exhibited a significantly lower expression of NKp46. Among 29 immunological and growth factors analyzed in the peripheral blood of oncologic patients, MCP-1, IP-10, and eotaxin, and VEGF they have presented a higher proportion. The Pearson correlation test showed that IL-12p40 positively correlates with CD56brightCD16- NK cells. We also observed a positive correlation between MCP-1 and the activating marker NKp46, as well as a negative correlation between IP-10 and TNF-α and NKp46. CD158b expression in CD56dimCD16+ was positively correlated with EGF and negatively correlated with MIP-1ß. CONCLUSIONS: Taken together, these results suggest that cancer patients present a shift towards a poorly cytotoxic and less activated NK profile which may contribute to tumor development and progression. The understanding of NK cell biology and soluble factors during tumor development could aid in the design of possible targeting therapeutic approaches.

Therapeutic outcomes and survival analysis of Extramammary Paget's disease: A multicentre retrospective study of 249 patients.

BACKGROUND: Evidence regarding long-term therapeutic outcomes and disease-specific survival (DSS) in Extramammary Paget's disease (EMPD) is limited. OBJECTIVES: To assess the DSS and outcomes of surgical and nonsurgical therapeutic modalities in a large cohort of EMPD patients. METHODS: Retrospective chart review of EMPD patients from 20 Spanish tertiary care hospitals. RESULTS: Data on 249 patients with a median follow-up of 60 months were analyzed. The estimated 5-, 10-, and 15-year DSS was 95.9%, 92.9%, and 88.5%, respectively. A significantly lower DSS was observed in patients showing deep dermal invasion (≥1 mm) or metastatic disease (P < .05). A ≥50% reduction in EMPD lesion size was achieved in 100% and 75.3% of patients treated with surgery and topical therapies, respectively. Tumor-free resection margins were obtained in 42.4% of the patients after wide local excision (WLE). The 5-year recurrence-free survival after Mohs micrographic surgery (MMS), WLE with tumor-free margins, WLE with positive margins, radiotherapy, and topical treatments was 63.0%, 51.4%, 20.4%, 30.1%, and 20.8%, respectively. LIMITATIONS: Retrospective design. CONCLUSIONS: EMPD is usually a chronic condition with favorable prognosis. MMS represents the therapeutic alternative with the greatest efficacy for the disease. Recurrence rates in patients with positive margins after WLE are similar to the ones observed in patients treated with topical agents.

Efficacy and safety of a new heterologous fibrin biopolymer on socket bone healing after tooth extraction: An experimental pre-clinical study.

AIM: To assess the efficacy of heterologous fibrin biopolymer (HFB) in promoting alveolar bone healing after tooth extraction in rats. MATERIALS AND METHODS: The upper right incisors of 48 Wistar rats were extracted. Toothless sockets were filled with HFB (HFBG, n = 24) or blood clot (BCG, n = 24). The tooth extraction sites were subjected to micro-computed tomography (micro-CT), histological, histomorphometric and immunohistochemical (for Runt-related transcription factor 2/Runx2 and tartrate-resistant acid phosphatase/TRAP) analyses on days 0, 7, 14 and 42 after extraction. RESULTS: Socket volume remained similar between days 0 and 14 (69 ± 5.4 mm3), except in the BCG on day 14, when it was 10% lower (p = .043). Although the number of Runx2+ osteoblasts was high and similar in both groups (34 × 102 cells/mm2), the HFBG showed lower inflammatory process and osteoclast activity than BCG at 7 days. On day 14, the number of Runx2+ osteoblasts remained high and similar to the previous period in both groups. However, osteoclast activity increased. This increase was 55% lower in the HFBG than BCG. In the BCG, the presence of an inflammatory process and larger and numerous osteoclasts on day 14 led to resorption of the alveolar bone ridge and newly formed bone. On day 42, numbers of Runx2+ osteoblast and TRAP+ osteoclasts decreased dramatically in both groups. Although the BCG exhibited a more mature cortical bone formation, it exhibited a higher socket reduction (28.3 ± 6.67%) and smaller bone volume (37 ± 5.8 mm3) compared with HFBG (socket reduction of 14.8 ± 7.14% and total bone volume of 46 ± 5.4 mm3). CONCLUSIONS: HFB effectively suppresses osteoclast activity and reduces alveolar bone resorption compared with blood clot, thus preventing three-dimensional bone loss, particularly during the early healing period. HFB emerges as a promising biopharmaceutical material for enhancing healing processes after tooth extraction.

Treatment of extramammary Paget disease with imiquimod in a real-life setting: a multicentre retrospective analysis in Spain.

BACKGROUND: Topical imiquimod has been shown to be an effective treatment for extramammary Paget disease (EMPD), although available evidence supporting its use is based on case reports and small series of patients. OBJECTIVES: To investigate the therapeutic outcomes and analyse potential clinicopathological factors associated with the imiquimod response in a large cohort of patients with EMPD. METHODS: Retrospective chart review of 125 patients with EMPD treated with imiquimod at 20 Spanish tertiary-care hospitals. RESULTS: During the study period, patients received 134 treatment regimens with imiquimod, with 70 (52.2%) treatments achieving a complete response (CR), 41 (30.6%) a partial response and 23 (17.2%) no response. The cumulative CR rates at 24 and 48 weeks of treatment were 46.3% and 71.8%, respectively, without significant differences between first-time and previously treated EMPD. Larger lesions (≥ 6 cm; P = 0.04) and EMPD affecting > 1 anatomical site (P = 0.002) were significantly associated with a worse treatment response. However, the CR rate did not differ significantly by the number of treatment applications (≤ 4 vs. > 4 times per week; P = 0.112). Among patients who achieved CR, 30 of 69 (43%) treatments resulted in local recurrences during a mean follow-up period of 36 months, with an estimated 3- and 5-year recurrence-free survival of 55.7% and 36.4%, respectively. CONCLUSIONS: Imiquimod appears as an effective therapeutic alternative for both first-line and previously treated EMPD lesions. However, a less favourable therapeutic response could be expected in larger lesions and those affecting > 1 anatomical site. Based on our results, a three to four times weekly regimen of imiquimod with a treatment duration of at least 6 months could be considered an appropriate therapeutic strategy for patients with EMPD.

Real-world adalimumab survival and discontinuation factors in hidradenitis suppurativa.

BACKGROUND AND OBJECTIVES: Survival analyses can provide valuable insights into effectiveness and safety as perceived by prescribers. Here, we aimed to evaluate adalimumab (ADA) survival and the interruption risk factors in a multicentre cohort of patients with hidradenitis suppurativa (HS). Moreover, we performed a subanalysis considering the periods before and after the onset of the COVID-19 pandemic. METHODS: We conducted a retrospective study including 539 adult patients with HS who received ADA from 1 May 2015 to 31 December 2022. Overall drug survival was analysed using Kaplan-Meier survival curves and compared between the subgroups via stratified log-rank test. Possible predictors for overall drug survival and reasons for discontinuation were assessed using univariate and multivariate Cox regression. RESULTS: Overall, 50.1% were females with a mean age of 43.5 ± 1 years and a mean BMI of 29.5 ± 6.7. At the start of ADA, 95.29% were biologic-naïve and 24.63% had undergone surgical treatment. During follow-up, 9.46% of patients required dose escalation, while 39.92% interrupted ADA. Concomitant therapy was used in 64.89% of cases. A subanalyses comparing pre- and post-pandemic periods revealed a tendency to initiate ADA treatment at a younger age, among patient with higher BMI and at a lower HS stage after COVID-19 pandemic. Interestingly, ADA demonstrated extended survival compared to previous studies, with a median overall drug survival of 56.2 months (95% CI 51.2 to 80.3). The primary causes for discontinuation were inefficacy (51.69%), followed by adverse effects (21.35%). Female sex, longer delay in HS diagnosis, higher baseline IHS4 score and concomitant spondyloarthritis were associated with poorer ADA survival or increased risk of discontinuation. CONCLUSIONS: ADA demonstrated prolonged survival (median 56.2 months). While addition of antibiotics did not have a positive effect on survival rate, basal IHS4 proved useful in predicting ADA survival.

Ocular Trauma Characterization in a Reference Emergency Eye Centre in Colombia (FOSCAL).

BACKGROUND: Ocular trauma is one of the most important causes of ocular morbidity and inadequate visual acuity in developed and developing countries. In some countries, eye trauma is the leading cause of monocular blindness. Studies conducted in developing countries like Colombia suggest that there is a lack of awareness of preventive measures. In Colombia, there is no countrywide ocular trauma registry. The purpose of the present study is to describe and analyse characteristics of ocular trauma at a tertiary ophthalmology emergency department in Colombia. PATIENTS/METHODS AND MATERIAL: Patients who consulted or were referred to the ophthalmologic emergency department of FOSCAL due to eye injuries between March 1, 2022, and January 10, 2023, were included in this cross-sectional study. RESULTS: Of 1 957 patients, 2 088 eyes were included. Men comprised 78.5% of the patients, the median age was 36 years, and 75.0% lived in urban areas. The median latency between trauma and ophthalmology consultation was 21.8 hours. Of the eyes, 1 805 (88.4%) had suffered mechanical or mixed (mechanical plus burn) trauma. Of the injuries, 87.5% were unilateral. In terms of the circumstances, 45.9% of injuries occurred during working or educational activities (in 85.6% of these cases, without eye protection), 28.2% in home accidents, and 14.0% in transportation situations. According to the Birmingham Eye Trauma Terminology System (BETT), 1 735 eyes (91.1%) were closed globe injuries, and 49 eyes (2.7%) were open globe injuries. Fifty eyes (2.8%) could not be categorised according to BETT at the initial consultation and were classified as "still to be determined". In the Ocular Trauma Score (OTS), 85.8% were category 5. Of the ocular burn cases, 93.0% were categorised as grade I according to the Roper Hall classification. CONCLUSIONS: In line with global literature, a much higher proportion of men than women sought consultation for ocular trauma. The findings suggest a need for improvement in the referral process from institutions with the lowest level of care. Lack of awareness about eye protection is an issue. Surgical exploration or additional tests may be necessary for precise injury classification. We therefore propose adding a "still to be determined" category to the BETT initial classification. These cases may be reclassified later, thus improving the accuracy of OTS calculation.

Prognostic factors for satellitosis or in-transit metastasis in cutaneous squamous cell carcinoma: A multicentric cohort study.

BACKGROUND: Satellitosis or in-transit metastasis (S-ITM) has clinical outcomes comparable to node-positivity in cutaneous squamous cell carcinoma (cSCC). There is a need to stratify the risk groups. OBJECTIVE: To determine which prognostic factors of S-ITM confer an increased risk of relapse and cSCC-specific-death. METHODS: A retrospective, multicenter cohort study. Patients with cSCC developing S-ITM were included. Multivariate competing risk analysis evaluated which factors were associated with relapse and specific death. RESULTS: Of a total of 111 patients with cSCC and S-ITM, 86 patients were included for analysis. An S-ITM size of ≥20 mm, >5 S-ITM lesions, and a primary tumor deep invasion was associated with an increased cumulative incidence of relapse (subhazard ratio [SHR]: 2.89 [95% CI, 1.44-5.83; P = .003], 2.32 [95% CI, 1.13-4.77; P = .021], and 2.863 [95% CI, 1.25-6.55; P = .013]), respectively. Several >5 S-ITM lesions were also associated with an increased probability of specific death (SHR: 3.48 [95% CI, 1.18-10.2; P = .023]). LIMITATIONS: Retrospective study and heterogeneity of treatments. CONCLUSION: The size and the number of S-ITM lesions confer an increased risk of relapse and the number of S-ITM an increased risk of specific-death in patients with cSCC presenting with S-ITM. These results provide new prognostic information and can be considered in the staging guidelines.

Middle Meningeal Artery Embolization in the Management of Chronic Subdural Hematoma: a Comprehensive Review of Current Literature.

PURPOSE OF REVIEW: Chronic subdural hematoma (cSDH) is a common intracranial hemorrhagic disorder with a high incidence rate among the elderly. While small, asymptomatic cSDH may resolve spontaneously, surgical intervention has been the treatment of choice for larger, symptomatic cases. Surgical evacuation of cSDH may be associated with high rates of recurrence, and even asymptomatic cSDH cases tend to progress. Over the last few years, middle meningeal artery (MMA) embolization has proven to be a safe non-invasive treatment of choice with favorable outcomes and a low recurrence rate. The ensuing paper discusses current treatment modalities for cSDH and reviews existing literature on the anatomy of MMA and its embolization as a treatment option for cSDH. RECENT FINDINGS: Recent studies show that traumatic head injury leading to subdural hemorrhage can induce neovascularization that may initiate a cycle of recurrent subdural hematoma. Distal branches of MMA supply blood to the dural layers. Several studies have revealed that embolization of the MMA can stop the neovascularization process and blood flow. In addition, patients who underwent MMA embolization had a significantly quicker brain re-expansion and lower recurrence rate. Although the management of cSDH is still very much a dilemma, recent research findings bring MMA embolization to light as a promising treatment alternative and adjunctive therapy.

Systolic Blood Pressure and the Risk of Kidney Replacement Therapy and Mortality in Patients with Chronic Kidney Disease Stages 4-5.

INTRODUCTION: In patients with chronic kidney disease stages 4 and 5 (CKD stages 4-5) without dialysis and arterial hypertension, it is unknown if the values of systolic blood pressure (SBP) considered in control (<120 mm Hg) are associated with kidney replacement therapy (KRT) and mortality. METHODS: In this retrospective cohort study, hypertensive CKD stages 4-5 patients attending the Renal Health Clinic at the Hospital Civil de Guadalajara were enrolled. We divided them into those that achieved SBP <120 mm Hg (controlled group) and those who did not (>120 mm Hg), the uncontrolled group. Our primary objective was to analyze the association between the controlled group and KRT; the secondary objective was the mortality risk and if there were subgroups of patients that achieved more benefit. Data were analyzed using Stata software, version 15.1. RESULTS: During 2017-2022, a total of 275 hypertensive CKD stages 4-5 patients met the inclusion criteria for the analysis: 62 in the controlled group and 213 in the uncontrolled group; mean age 61 years; 49.82% were male; SBP was significantly lower in the controlled group (111 mm Hg) compared to the uncontrolled group (140 mm Hg); eGFR was similar between groups (20.41 mL/min/1.73 m2). There was a tendency to increase the mortality risk in the uncontrolled group (HR 6.47 [0.78-53.27]; p = 0.082) and an association by the Kaplan-Meir analysis (Log-rank p = 0.043). The subgroup analysis for risk of KRT in the controlled group revealed that patients ≥61 years had a lower risk of KRT (HR 0.87 [95% CI, 0-76-0.99]; p = 0.03, p of interaction = 0.005), but no differences were found in the subgroup analysis for mortality. In a follow-up of 1.34 years, no association was found in the risk of KRT according to the controlled or uncontrolled groups in a multivariate Cox analysis. CONCLUSION: In a retrospective cohort of patients with CKD stages 4-5 and hypertension, SBP >120 mm Hg was not associated with risk of KRT but could be associated with the risk of death. Clinical trials are required in this group of patients to demonstrate the impact of reaching the SBP goals recommended by the KDIGO guidelines.

Real-World Experience with Vismodegib on Advanced and Multiple BCCs: Data from the RELIVIS Study.

BACKGROUND: Vismodegib is approved for advanced cases of basal cell carcinomas not amenable to surgery or radiotherapy. Large studies on the use of vismodegib in clinical practice are scarce. OBJECTIVES: The main objective of the study was to analyse the evolution and therapeutic management of relapses and lack of response in patients who had received vismodegib for locally advanced and/or multiple basal cell carcinomas in a real-life multicentre setting. METHODS: This nationwide retrospective study collected data on patients treated with vismodegib in 15 specialized centres. We included patients who first received vismodegib until intolerable toxicity, maximum response, or progressive disease. Exploratory research variables referred to patient and tumour characteristics, vismodegib effectiveness and safety, relapse rate and management, and mortality. A multivariable logistic regression model was used to identify predictors of complete clinical response. RESULTS: 133 patients with advanced BCC were included in the registry. The objective response rate (ORR) was 77.5% and nearly half of the patients (45.9%) achieved complete remission. Long-term information and detailed information of subsequent treatments after a regime of vismodegib was available for 115 patients. Only 34% of the patients in this group were subsequently treated with other therapies or vismodegib rechallenge. Sixty-nine percent of the patients who had shown a complete remission with vismodegib remained free of recurrence while 30.7% relapsed. Almost half of the patients who received additional therapies after the first course of vismodegib achieved complete tumour remission. Three and 2 out of 9 patients who were rechallenged with vismodegib achieved complete and partial responses, respectively, with an ORR of 55.5%. CONCLUSION: Our study confirms efficacy of vismodegib in routine clinical practice. The risk of recurrence after achieving complete response with vismodegib was lower than previous reports. Rechallenge with vismodegib is feasible and most patients responded to re-treatment.

Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4-5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial.

BACKGROUND: The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4-5 KDIGO. METHODS: A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as 'bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study's registration number was NCT03923933. RESULTS: Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2-29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p < 0.001) and Day 30 (intervention: -3.05 vs. control: -0.15, p < 0.000). There was also a decrease in systolic blood pressure on Day 7 (intervention: -18 vs. control: -7.5, p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018). CONCLUSION: In CKD stage 4-5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.

Force and Torque Characterization in the Actuation of a Walking-Assistance, Cable-Driven Exosuit.

Soft exosuits stand out when it comes to the development of walking-assistance devices thanks to both their higher degree of wearability, lower weight, and price compared to the bulkier equivalent rigid exoskeletons. In cable-driven exosuits, the acting force is driven by cables from the actuation system to the anchor points; thus, the user's movement is not restricted by a rigid structure. In this paper, a 3D inverse dynamics model is proposed and integrated with a model for a cable-driven actuation to predict the required motor torque and traction force in cables for a walking-assistance exosuit during gait. Joint torques are to be shared between the user and the exosuit for different design configurations, focusing on both hip and ankle assistance. The model is expected to guide the design of the exosuit regarding aspects such as the location of the anchor points, the cable system design, and the actuation units. An inverse dynamics analysis is performed using gait kinematic data from a public dataset to predict the cable forces and position of the exosuit during gait. The obtained joint reactions and cable forces are compared with those in the literature, and prove the model to be accurate and ready to be implemented in an exosuit control scheme. The results obtained in this study are similar to those found in the literature regarding the walking study itself as well as the forces under which cables operate during gait and the cable position cycle.

A.L.L. Y.O.U. N.E.E.D. I.S. L.O.V.E. Manual on health self-management and patient-reported outcomes among low-income young adult Mexicans on chronic dialysis: Feasibility study.

PURPOSE: We evaluated disease knowledge/self-management skills among low-income Mexican young adults maintained on dialysis and to test the effectiveness of the A.L.L. Y.O.U. N.E.E.D. I.S. L.O.V.E (AYNIL) Manual - Spanish Version on patient-reported outcomes. This is a low literacy teaching tool designed with patients and educators' input. DESIGN AND METHODS: A quasi-experimental study was conducted in 17 chronic dialysis patients at Mexico City's Hospital General de México, Dr. Eduardo Liceaga. Ages 18-30-year-old completed disease knowledge/self-management and quality of life measures before the intervention and 6 weeks later. RESULTS: Significant increases were observed on disease knowledge/self-management scores in the STARx questionnaire from 47 (IQ: 40,51) to 50 (IQ: 48,54) p = 0.04. The UNC-TRxANSITION Index increased significantly from 4.8 (IQ: 3.9,5.7) to 7.7 (IQ: 7.5,8.2) p ≤0.001. Significant increases in scores were detected in the "Burden of kidney disease" (p = 0.008), "Effects of kidney disease" " (p = 0.03) and " Dialysis staff encouragement" (p = 0.027) based on the KDQoL survey. CONCLUSIONS: In this vulnerable population, the Spanish version of the A.L.L. Y.O.U. N.E.E.D. I.S. L.O.V.E. - AYNIL Manual improved CKD/ESRD disease knowledge/self-management skills and HRQoL. This study highlighted the need for low-literacy educational tools to improve patient-reported outcomes. PRACTICE IMPLICATIONS: Young adults with CKD/ESRD can benefit from patient-centered educational interventions to enhance their autonomy and the development of self-management behaviors that improve patient-reported outcomes and potential complications of the disease. Special attention is needed in low-income patients with low rates of adherence to treatments and poor self-management skills.

Repeated superselective intraarterial bevacizumab after blood brain barrier disruption for newly diagnosed glioblastoma: a phase I/II clinical trial.

PURPOSE: Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood-brain barrier disruption (BBBD). METHODS: Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan-Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively). RESULTS: Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7-78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7-48.3 cm3). Median PFS was 11.5 months (95% CI 7.7-25.9) with 6, 12, 24 and 60 month PFS estimated to be 91.3% (95% CI 69.5-97.8), 47.4% (26.3-65.9), 32.5% (14.4-52.2) and 5.4% (0.4-21.8), respectively. Median OS was 23.1 months (95% CI 12.2-36.9) with 12, 24, and 36 month OS as 77.3% (95% CI 53.6-89.9), 45.0% (22.3-65.3) and 32.1% (12.5-53.8), respectively. CONCLUSIONS: Repeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

In vitro and in vivo characterization of cancer stem cell subpopulations in oral squamous cell carcinoma.

BACKGROUND: Despite advances in cancer diagnosis and therapeutics, the overall 5-year survival rate of oral squamous cell carcinoma (OSCC) remains low. Tumor formation, progression, recurrence, and chemo-resistance are associated with the presence of cancer stem cells (CSC) that show phenotypic heterogeneity, but how they influence tumor behavior remains poorly understood. We aimed to describe how two CSC phenotypes from an OSCC cell line, CD44High ESAHigh (Epi-CSC) and CD44High ESALow (EMT-CSC), behave in vitro and in vivo. METHODS: In vitro behavior of FACS-sorted Epi-CSC and EMT-CSC from OSCC cells was characterized by their ability to form colonies, migrate, proliferate, and to invade a solid matrix. In vivo experiments were conducted in immunodeficient (NOD/SCID) mice by orthotopic xenografting of FACS-sorted OSCC subpopulations. RESULTS: In vitro, the Epi-CSC phenotype was more proliferative and generated more holoclones than the EMT phenotype. On the other hand, EMT-CSC migrate and invaded more than Epi-CSC cells in 3D culture, suggesting the CSC phenotype affects tumor cell behavior. When inoculated orthotopically into the tongues of immunodeficient mice, both subpopulations generated OSCC, but EMT-CSC formed fewer and smaller tumors. CONCLUSIONS: Our results suggest that while cells in the Epi-CSC form the subpopulation that enables tumor growth, the EMT-CSC are related to migration and invasion. Clinically, this may reflect the importance of Epi-CSC for tumorigenesis and of the EMT-CSC for metastasis and highlights that variation in the proportion of CSC phenotypes from patient to patient may be relevant to the design of individual treatment protocols.

Common late complications of longitudinal forefoot amputations in neuropathic foot treatment.

OBJECTIVE: To describe and quantify the complications arising in consecutive neuropathic patients undergoing partial longitudinal amputations of the foot. METHOD: A retrospective study was conducted with data collected from the medical records of patients monitored at the Insensitive Foot Clinic of the Foot and Ankle Group of our institution who underwent partial amputation of foot rays from 2000 to 2016. RESULTS: A total of 28 patients met the inclusion criteria, with a total of 31 amputated/partially amputated feet. Of these, 18 (58.1%) feet were amputated/partially amputated due to diabetes, seven (22.6%) due to leprosy, two (6.5%) due to alcoholic neuropathy, two (6.5%) secondary to traumatic peripheral nerve injury, and two (6.5%) due to other causes. Fifth ray amputation was the most frequent type (n=12). The cause of amputation was the presence of an infected ulcer in 93.6% of the samples. At a mean follow-up time of 60 months, 13 (41.9%) feet required new amputations-five (38.5%) transtibial, five (38.5%) transmetatarsal, two (15.4%) of the toes, and one (7.7%) at Chopart's joint. Patients with diabetes had a 50.0% reamputation rate. Patients who initially underwent amputation of the fifth ray had a 58.3% reamputation rate. CONCLUSION: Partial longitudinal amputation of the foot in neuropathic patients exhibited a high reoperation rate, especially in patients with diabetes or in patients with initial amputation of the peripheral rays. Declaration of interest: The authors have no conflicts of interest.

Risk factors for early-onset basal cell carcinomas and the trend towards their female predominance.

BACKGROUND: A dramatic rise in the incidence rates of basal cell carcinoma (BCC) in young women has been reported. OBJECTIVES: We investigate potential risk factors (RF) for sporadic BCC in young patients and the current distribution of such RF in the general population of Catalonia, comparing the differences among men and women. PATIENTS AND METHODS: A case-control study was performed, 69 BCCs diagnosed in patients ≤ 45 years of age vs. 69 healthy controls. Afterward, 1,078 participants from the general population completed an RF questionnaire. RESULTS: Repeated sunburns were more frequent in instances of early-onset BCC in covered skin than in sun-exposed skin (P  =  0.029). In the general population, 39.1 % of participants reported sunbed use (50.1 % in women, 10.9 % in men). Sunbed use was the only relevant RF more predominant in women than men, favoring the trend to female predominance of BCCs above other RF. Additionally, we found a significant trend in young participants for reduced sunbed use (P < 0.001), although they had the same percentage of repeated sunburns. Repeated sunburns are the most relevant RF for early-onset BCCs that can be targeted in prevention campaigns. CONCLUSIONS: We should be aware of the more relevant RF for early-onset BCCs and their distribution among the general population to address preventive campaigns.

Evaluation of Tumor Interstitial Fluid-Extraction Methods for Proteome Analysis: Comparison of Biopsy Elution versus Centrifugation.

The analysis of tumor interstitial fluid (TIF) composition is a valuable procedure to identify antimetastatic targets, and different laboratories have set up techniques for TIF isolation and proteomic analyses. However, those methods had never been compared in samples from the same tumor and patient. In this work, we compared the two most used methods, elution and centrifugation, in pieces of the same biopsy samples of cutaneous squamous cell carcinoma (cSCC). First, we established that high G-force (10 000g) was required to obtain TIF from cSCC by centrifugation. Second, we compared the centrifugation method with the elution method in pieces of three different cSCC tumors. We found that the mean protein intensities based in the number of peptide spectrum matches was significantly higher in the centrifuged samples than in the eluted samples. Regarding the robustness of the methods, we observed higher overlapping between both methods (77-80%) than among samples (50%). These results suggest that there exists an elevated consistence of TIF composition independently of the method used. However, we observed a 3-fold increase of extracellular proteins in nonoverlapped proteome obtained by centrifugation. We therefore conclude that centrifugation is the method of choice to study the proteome of TIF from cutaneous biopsies.

Correction to: Super selective intra­arterial cerebral infusion of modern chemotherapeutics after blood-brain barrier disruption: where are we now, and where we are going.

The name of author Jason A. Ellis was missing in the intial online publication, and there was a typo in the sixth author's first name. The original article has been corrected.