Machine learning-based immune phenotypes correlate with STK11/KEAP1 co-mutations and prognosis in resectable NSCLC: a sub-study of the TNM-I trial.

BACKGROUND: We aim to implement an immune cell score model in routine clinical practice for resected non-small-cell lung cancer (NSCLC) patients (NCT03299478). Molecular and genomic features associated with immune phenotypes in NSCLC have not been explored in detail. PATIENTS AND METHODS: We developed a machine learning (ML)-based model to classify tumors into one of three categories: inflamed, altered, and desert, based on the spatial distribution of CD8+ T cells in two prospective (n = 453; TNM-I trial) and retrospective (n = 481) stage I-IIIA NSCLC surgical cohorts. NanoString assays and targeted gene panel sequencing were used to evaluate the association of gene expression and mutations with immune phenotypes. RESULTS: Among the total of 934 patients, 24.4% of tumors were classified as inflamed, 51.3% as altered, and 24.3% as desert. There were significant associations between ML-derived immune phenotypes and adaptive immunity gene expression signatures. We identified a strong association of the nuclear factor-κB pathway and CD8+ T-cell exclusion through a positive enrichment in the desert phenotype. KEAP1 [odds ratio (OR) 0.27, Q = 0.02] and STK11 (OR 0.39, Q = 0.04) were significantly co-mutated in non-inflamed lung adenocarcinoma (LUAD) compared to the inflamed phenotype. In the retrospective cohort, the inflamed phenotype was an independent prognostic factor for prolonged disease-specific survival and time to recurrence (hazard ratio 0.61, P = 0.01 and 0.65, P = 0.02, respectively). CONCLUSIONS: ML-based immune phenotyping by spatial distribution of T cells in resected NSCLC is able to identify patients at greater risk of disease recurrence after surgical resection. LUADs with concurrent KEAP1 and STK11 mutations are enriched for altered and desert immune phenotypes.

Tratamiento quirúrgico de las úlceras por presión sacras con colgajo miocutáneo de gluteus maximus por deslizamiento en V-Y: Técnica quirúrgica / Surgical treatment of sacral pressure ulcers with gluteus maximus myocutaneous flap due to V-Y sliding: surgical technique

Resumen Introducción: La úlcera por presión más frecuente es la sacra. Si compromete el hueso puede provocar osteomielitis por lo que requiere aseo quirúrgico y colgajo miocutáneo de gluteus maximus por deslizamiento en V-Y. Materiales y Método: En el servicio de cirugía plástica del hospital del Salvador entre 2011 y 2020 se han operado 82 pacientes con ulceras sacras grado 4 que requirieron cobertura con colgajo miocutáneo de gluteus maximus en V-Y. De ellas se analizaron los últimos 37 pacientes. Resultados De los 37 pacientes, 12 fueron mujeres, 25 hombres, 17 parapléjicos, 12 tetrapléjicos y 8 deambulaban. 6 pacientes presentaron COVID-19. 24 fueron bilaterales y 13 unilaterales. Los colgajos cicatrizaron bien en 30 pacientes. Las complicaciones fueron de 16% consistente en 2 hematomas, 2 dehiscencias, 2 celulitis y 1 seroma, todas resueltas sin problemas. Seguimiento de entre 3 y 6 meses. Discusión El tratamiento quirúrgico con colgajo miocutáneo de gluteus maximus en V-Y, aparte de aportar volumen para ocluir la úlcera, aporta irrigación excelente con oxígeno, nutrientes y antibióticos que aseguran una óptima cicatrización. Dependiendo del diámetro de la úlcera el colgajo puede ser uni o bilateral. Dado lo complejo del tratamiento, en general, el porcentaje de complicaciones de 16% se considera bajo. Conclusión: El tratamiento quirúrgico de las úlceras por presión sacras con colgajos miocutáneos deslizantes de gluteus maximus ha sido exitoso con buenos resultados quirúrgicos con buen flujo sanguíneo y buena evolución.

Introduction: Pressure sores are the result of the compression of soft tissues in the prominent bones areas, mainly in patients without movement. If the depth of the ulcer compromises the sacral bone, the treatment will be the gluteus maximus myocutaneous flap in V-Y. Materials and Method: In the plastic surgery service of the hospital del Salvador 82 patients with sacral pressure sores grade 4 were operated on between 2011 and 2020 with gluteus maximus myocutaneous V-Y flap. The last 37 patients were analyzed. Results: With this treatment the flaps were doing well in all cases with good blood supply. Complications: dehiscence: 2 patients, cellulitis: 2 patients, hematoma: 2 patients and seroma: 1 patient. The overall complication was 16%. Follow up between three and six months. Discussion: The most important part in pressure sores is their prevention. When the ulcer is in prominent parts of the body, the sore, could be in different grades of depth. The classification of them is in grades 1: erythema, 2: subcutaneous tissue. These two grades are solved with conservative treatment. When the ulcers are in grade 3 or 4, and with little ulcer in the skin but with damage of the deep plane, the treatment will be with surgery. In our casuistic the most frequent pressure sore is in the sacrum treated with gluteus maximus sliding myocutaneous flap in V-Y. With this treatment the flaps were doing well in all cases with good blood supply. The complications of 16% were considered low. Conclusion: The sliding gluteus Maximus myocutaneous flap in V-Y for treatment for sacral pressures sores have been successful for our patients.

Cierre progresivo de heridas en pacientes con pie diabético / Progressive suture in diabetic foot patients with difficult healing

Resumen Introducción: Los pacientes diabéticos insulino requirientes con heridas del pie, producto de amputaciones con exposición de huesos, cartílagos o tendones, son de difícil manejo por el déficit de irrigación distal. Alternativa de tratamiento a los colgajos pediculados o microquirúrgicos es el cierre progresivo de las heridas. Objetivo: Reportar la técnica de cierre progresivo de heridas de pie en pacientes diabéticos insulino requirientes. Materiales y Método: Con esta técnica se operó a 15 pacientes diabéticos insulino requirientes que, después de amputación, presentaron heridas del pie con exposición de huesos, cartílagos y tendones. Lesiones de talón: 4, lesiones de antepie: 5 y lesiones plantares: 6. Las edades fluctuaron entre 45 y 70 años. Fueron 11 hombres y 4 mujeres operados entre 2014 y 2019. En ambos bordes de la herida se instaló dos placas de Ventrofil® unidas por sutura en U transversa y se tensó cada 3 días hasta obtener cicatrización. Resultados: 14 pacientes obtuvieron cicatrización en un plazo de entre 15 y 21 días y sólo uno presentó sufrimiento de los bordes de la herida por afrontamiento muy seguido. El seguimiento fue de tres meses sin recidiva de las heridas. Discusión: En pacientes diabéticos las heridas, producto de amputaciones y con exposición de huesos, cartílagos y tendones, son de muy difícil tratamiento debido el déficit de irrigación distal. En estas condiciones el uso de complejos colgajos locales o microquirúrgicos es de alto riesgo dada la posibilidad de necrosis. En esta situación, el cierre progresivo con sutura de Ventrofil® es una alternativa viable, segura, reproducible y con buenos resultados. Conclusión: Es un procedimiento rápido, seguro y reproducible.

Introduction: The closure of wounds in diabetic foot patients, after amputation with esposure of bones, is difficult because of lack of blood supply to this area. The progressive suture with Ventrofil® is a good alternative. Aim: Report the technique of progressive closure of foot wounds in insulin-requiring diabetic patients. Materials and Method: 15 patients with diabetic foot were operated on in the Hospital del Salvador, between 2014 and 2019.The ages were among 45 and 70 years. 11 men and 4 women. In those patients two plaques of Ventrofil® were positioned in both borders of the wound an tied through a horizontal suture.This suture was tensioned every 3 days until get the complete wound healing. Results: 14 patients healed very well and in just only one patient there was suffering of the edges of the wound. The follow up was of 3 months without relapse. Discussion: In patients with diabetic foot with wounds after amputation the closure is difficult because of lack of adecuate blood supply. In these case the progressive suture with plaques of Ventrofil® is a good alternative to a more complex flaps like microsurgicals ones. Conclusion: This technique is sure, easy to perfom and safe.

High expression of miR-17-5p in tumor epithelium is a predictor for poor prognosis for prostate cancer patients.

MicroRNAs (miRs) are small non-coding RNA molecules, which are involved in the development of various malignancies, including prostate cancer (PCa). miR-17-5p is considered the most prominent member of the miR-17-92 cluster, with an essential regulatory function of fundamental cellular processes. In many malignancies, up-regulation of miR-17-5p is associated with worse outcome. In PCa, miR-17-5p has been reported to increase cell proliferation and the risk of metastasis. In this study, prostatectomy specimens from 535 patients were collected. Tissue microarrays were constructed and in situ hybridization was performed, followed by scoring of miR-17-5p expression on different tumor compartments. High expression of miR-17-5p in tumor epithelium was associated with biochemical failure (BF, p < 0.001) and clinical failure (CF, p = 0.019). In multivariate analyses, high miR-17-5p expression in tumor epithelial cells was an independent negative prognostic factor for BF (HR 1.87, 95% CI 1.32-2.67, p < 0.001). In vitro analyses confirmed association between overexpression of miR-17-5p and proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145). In conclusion, our study suggests that a high cancer cell expression of miR-17-5p was an independent negative prognostic factor in PCa.

Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT.

Epithelial to mesenchymal transition (EMT) is a critical cellular process that has been well characterized during embryonic development and cancer metastasis and it also is implicated in several physiological and pathological events including embryonic stem cell differentiation. During early stages of differentiation, human embryonic stem cells pass through EMT where deeper morphological, molecular and biochemical changes occur. Though initially considered as a decision between two states, EMT process is now regarded as a fluid transition where cells exist on a spectrum of intermediate states. In this work, using a CRISPR interference system in human embryonic stem cells, we describe a molecular characterization of the effects of downregulation of E-cadherin, one of the main initiation events of EMT, as a unique start signal. Our results suggest that the decrease and delocalization of E-cadherin causes an incomplete EMT where cells retain their undifferentiated state while expressing several characteristics of a mesenchymal-like phenotype. Namely, we found that E-cadherin downregulation induces SNAI1 and SNAI2 upregulation, promotes MALAT1 and LINC-ROR downregulation, modulates the expression of tight junction occludin 1 and gap junction connexin 43, increases human embryonic stem cells migratory capacity and delocalize ß-catenin. Altogether, we believe our results provide a useful tool to model the molecular events of an unstable intermediate state and further identify multiple layers of molecular changes that occur during partial EMT.

Active targeting of cancer cells by CD44 binding peptide-functionalized oil core-based nanocapsules.

Selectivity in tumor targeting is one of the major issues in cancer treatment. Therefore, surface functionalization of drug delivery systems with active moieties, able to selectively target tumors, has become a worldwide-recognized strategy. The CD44 receptor is largely used as a biomarker, being overexpressed in several tumors, and consequently as a target thanks to the identification of the CD44 binding peptide. Here we implemented the CD44 binding peptide logic onto an oil core-polymer multilayer shell, taking into account and optimizing all relevant features of drug delivery systems, such as small size (down to 100 nm), narrow size distribution, drug loading capability, antifouling and biodegradability. Besides promoting active targeting, the oil core-based system enables the delivery of natural and synthetic therapeutic compounds. Biological tests, using curcumin as a bioactive compound and fluorescent tag, demonstrated that CD44 binding peptide-functionalized nanocapsules selectively accumulate and internalize in cancer cells, compared to the control, thanks to ligand-receptor binding.

[What factors contributed to the higher incidence rate of in-hospital falls at the time of Covid 19? A paradigm shift?] / Quali sono I fattori contribuenti la caduta dei pazienti in ospedale al tempo del Covid 19? Un cambio di paradigma?

The COVID-19 pandemic has put a strain on all health systems as there has been a growing rapidity in the demand for health care from COVID 19 positive patients in hospitals around the world. With the intensification of the pandemic, determining in real time the consequent needs for health resources (beds, personnel, equipment) has in fact become the fundamental priority for many countries to ensure health services consistent with the health needs expressed by the population. In Italy, the demand has often been satisfied with the conversion of existing beds and the remodeling of the healthcare offer or where the available resources allow it also with the opening of new beds dedicated to pandemic assistance. This work analyzes the falls detected at the time of COVID in patients and hospitalized in direct hospital beds (600 beds) of a Local Health Authority of Lazio (ASL ROMA 2). Although the data on the incidence of falls recorded in the three centers were equal to 2.21 every 1000 days of beds occupied and that the data recorded are lower than those reported in the literature, it is also true that the increase in average hospital stay and the reduction in the rotation rate of beds had an impact on the still low occupancy rates compared to the literature data.The COVID-19 pandemic has put a strain on all health systems as there has been a growing rapidity in the demand for health care from COVID 19 positive patients in hospitals around the world. With the intensification of the pandemic, determining in real time the consequent needs for health resources (beds, personnel, equipment) has in fact become the fundamental priority for many countries to ensure health services consistent with the health needs expressed by the population. In Italy, the demand has often been satisfied with the conversion of existing beds and the remodeling of the healthcare offer or where the available resources allow it also with the opening of new beds dedicated to pandemic assistance. This work analyzes the falls detected at the time of COVID in patients and hospitalized in direct hospital beds (600 beds) of a Local Health Authority of Lazio (ASL ROMA 2). Although the data on the incidence of falls recorded in the three centers were equal to 2.21 every 1000 days of beds occupied and that the data recorded are lower than those reported in the literature, it is also true that the increase in average hospital stay and the reduction in the rotation rate of beds had an impact on the still low occupancy rates compared to the literature data. In fact, the scientific literature shows that in England and Wales, whose national health service is very similar to the Italian one, the falls of patients in hospitals with optimal bed occupancy rates and optimal average hospitalization rates (equal to 4.5 days in general medicine, 3.5 days in general surgery, 3 days in orthopedics) represent the first sentinel event in terms of incidence and frequency, albeit with a very variable damage detection. The average falls is 6.63 falls per 1,000 bed-occupied days, which equates to approximately 1,700 falls per year in an 800-bed hospital with an optimal occupancy rate. Regarding damage, the literature documents that physical injuries and fractures occur in 30-50% of events and fractures occur in 1-3% of cases. The data collected in ASL ROMA 2 have documented that despite the increase in staff dedicated to assistance by 15 - 30%, an increase due to the application of COVID pathways and to the activities of compression of the risk of circulation of the virus among hospitalized patients , the rate of falls has nevertheless increased by 13.5% despite the persistence of standards of quality and safety of patients in care activities, debunking the paradigm that falls can be caused by an undersizing of the care staff and by the possible overcrowding of the emergency departments - urgency.

Oncological outcomes in oncoplastic breast surgery: a single institution analysis.

Oncoplastic surgery is a well-acknowledged technique that combines conserving treatment in breast cancer with plastic surgery reconstruction. The aim of our analysis is to evaluate the safety of this surgical procedure in the setting of invasive primary breast cancer, and then compare breast oncoplastic surgery with the Veronesi quadrantectomy.We have analyzed 1541 patients who underwent breast surgery for primary breast tumor between October 2004 and May 2018 at Sant'Andrea University Hospital in Rome: 880 women experienced the breast oncoplastic approach, while 660 patients received conservative surgery alone. The median follow-up time was 14 years with a completeness of 70% (1067 pts vs 1554). The statistic comparison across these subpopulations suggested that there are no statistically significant results in term of Overall Survival, Disease Related Survival, Local recurrence or positive margins. Therefore oncoplastic surgery for primary invasive breast cancer represents a feasible procedure and an oncological safe surgical option.

Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs.

Two inhibitors of phosphatidylinositol 3-kinase (PI3K) pathway taselisib, targeting the mutant PI3K-subunit-alpha (PI3KA) and ipatasertib, AKT-inhibitor, are currently under clinical investigation in breast cancer (BC) patients. We have previously demonstrated the anti-tumor efficacy of these anti-PI3K/AKT-inibitors in combination with anti-microtubule drugs in human BC cell lines, through a complete cytoskeleton disorganization. In this work, we generated ex-vivo three-dimensional (3D) cultures from human BC as a model to test drug efficacy and to identify new molecular biomarkers for selection of BC patients suitable for anti-PI3K/AKT-inibitors treatment. We have established 3D cultures from 25/27 human BC samples, in which the ability of growth in vitro replicates the clinical and biological aggressiveness of the original tumors. According to the results of next generation sequencing analysis, a direct correlation was found between PI3KA mutations and the sensitivity in 3D models in vitro to taselisib and ipatasertib alone and combined with anti-microtubule agents. Moreover, mutations in HER and MAPK families related genes, including EGFR, KRAS and BRAF, were found in resistant samples, suggesting their potential role as negative predictive factors of response to these agents. Thus, we demonstrated that ex vivo 3D cultures from human BC patients allow a rapid and efficient drug screening for chemotherapies and targeted agents in genetically selected patients and represent an innovative model to identify new biomarkers of drug resistance.

A Gradient-Based Approach for Breast DCE-MRI Analysis.

Breast cancer is the main cause of female malignancy worldwide. Effective early detection by imaging studies remains critical to decrease mortality rates, particularly in women at high risk for developing breast cancer. Breast Magnetic Resonance Imaging (MRI) is a common diagnostic tool in the management of breast diseases, especially for high-risk women. However, during this examination, both normal and abnormal breast tissues enhance after contrast material administration. Specifically, the normal breast tissue enhancement is known as background parenchymal enhancement: it may represent breast activity and depends on several factors, varying in degree and distribution in different patients as well as in the same patient over time. While a light degree of normal breast tissue enhancement generally causes no interpretative difficulties, a higher degree may cause difficulty to detect and classify breast lesions at Magnetic Resonance Imaging even for experienced radiologists. In this work, we intend to investigate the exploitation of some statistical measurements to automatically characterize the enhancement trend of the whole breast area in both normal and abnormal tissues independently from the presence of a background parenchymal enhancement thus to provide a diagnostic support tool for radiologists in the MRI analysis.

Adenomyoepithelioma of the breast: case report and literature review.

Adenomyoepithelioma are uncommon tumors. The majority of them occur in women in the fifth and sixth decades who usually present with a self-palpated, solitary breast mass or a lesion identified on mammography. We report the case of adenomyoepithelioma of the breast with malignant transformation of both myoepitheliel and epithelial components diagnosed as malignancy during the preoperative stage in a seventy-six year old woman.

The outpatient total hip arthroplasty : a paradigm change.

AIMS: To examine incidence of complications associated with outpatient total hip arthroplasty (THA), and to see if medical comorbidities are associated with complications or extended length of stay. PATIENTS AND METHODS: From June 2013 to December 2016, 1279 patients underwent 1472 outpatient THAs at our free-standing ambulatory surgery centre. Records were reviewed to determine frequency of pre-operative medical comorbidities and post-operative need for overnight stay and complications which arose. RESULTS: In 87 procedures, the patient stayed overnight for 23-hour observation, with 39 for convenience reasons and 48 (3.3%) for medical observation, most frequently urinary retention (13), obstructive sleep apnoea (nine), emesis (four), hypoxia (four), and pain management (six). Five patients (0.3%) experienced major complications within 48 hours, including three transferred to an acute facility; there was one death. Overall complication rate requiring unplanned care was 2.2% (32/1472). One or more major comorbidities were present in 647 patients (44%), including previous coronary artery disease (CAD; 50), valvular disease (nine), arrhythmia (219), thromboembolism history (28), obstructive sleep apnoea (171), chronic obstructive pulmonary disease (COPD; 124), asthma (118), frequent urination or benign prostatic hypertrophy (BPH; 217), or mild chronic renal insufficiency (11). CONCLUSION: The presence of these comorbidities was not associated with medical or surgical complications. However, presence of one or more major comorbidity was associated with an increased risk of overnight observation. Specific comorbidities associated with increased risk were CAD, COPD, and frequent urination/BPH. Outpatient THA is safe for a large proportion of patients without the need for a standardised risk assessment score. Risk of complications is not associated with presence of medical comorbidities. Cite this article: Bone Joint J 2018;100-B(1 Supple A):31-5.

The patient-specific Triflange acetabular implant for revision total hip arthroplasty in patients with severe acetabular defects: planning, implantation, and results.

AIMS: Few reconstructive techniques are available for patients requiring complex acetabular revisions such as those involving Paprosky type 2C, 3A and 3B deficiencies and pelvic discontinuity. Our aim was to describe the development of the patient specific Triflange acetabular component for use in these patients, the surgical technique and mid-term results. We include a description of the pre-operative CT scanning, the construction of a model, operative planning, and surgical technique. All implants were coated with porous plasma spray and hydroxyapatite if desired. PATIENTS AND METHODS: A multicentre, retrospective review of 95 complex acetabular reconstructions in 94 patients was performed. A total of 61 (64.2%) were female. The mean age of the patients was 66 (38 to 85). The mean body mass index was 29 kg/m2 (18 to 51). Outcome was reported using the Harris Hip Score (HHS), complications, failures and survival. RESULTS: The mean follow-up was 3.5 years (1 to 11). The mean HHS improved from 46 (15 to 90) pre-operatively to 75 (14 to 100). A total of 21 hips (22%) had at least one complication with some having more than one; including dislocation (6%), infection (6%), and femoral complications (2%). The implant was subsequently removed in five hips (5%), only one for suspected aseptic loosening. CONCLUSION: The Triflange patient specific acetabular component provides predictable fixation with complication rates which are similar to those of other techniques. Cite this article: Bone Joint J 2018;100-B(1 Supple A):50-4.

Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence.

In 2014, the Food and Drug Administration approved a new human papillomavirus 9-valent vaccine (9vHPV), targeting nine HPV types: HPV types 6, 11, 16, and 18, which are also targeted by the quadrivalent HPV vaccine (qHPV), plus five additional high cancer risk HPV types (HPV types 31, 33, 45, 52, and 58). The aim of the current study was to systematically retrieve, qualitatively and quantitatively pool, as well as critically appraise all available evidence on 9vHPV from randomized controlled trials (RCTs). We conducted a systematic review of the literature on 9vHPV efficacy, immunogenicity and safety, as well as a systematic search of registered, completed, and ongoing RCTs. We retrieved and screened 227 records for eligibility. A total of 10 publications reported on RCTs' results on 9vHPV and were included in the review. Sixteen RCTs on 9vHPV have been registered on RCT registries. There is evidence that 9vHPV generated a response to HPV types 6, 11, 16 and 18 that was non-inferior to qHPV. Vaccine efficacy against five additional HPV type-related diseases was directly assessed on females aged 16-26 years (risk reduction against high-grade cervical, vulvar or vaginal disease = 96·7%, 95% CI 80·9%-99·8%). Bridging efficacy was demonstrated for males and females aged 9-15 years and males aged 16-26 years (the lower bound of the 95% CIs of both the geometric mean titer ratio and difference in seroconversion rates meeting the criteria for non-inferiority for all HPV types). Overall, 9vHPV has been proved to be safe and well tolerated. Other RCTs addressed: 9vHPV co-administration with other vaccines, 9vHPV administration in subjects that previously received qHPV and 9vHPV efficacy in regimens containing fewer than three doses. The inclusion of additional HPV types in 9vHPV offers great potential to expand protection against HPV infection. However, the impact of 9vHPV on reducing the global burden of HPV-related disease will greatly depend on vaccine uptake, coverage, availability, and affordability.

A miRNA signature suggestive of nodal metastases from laryngeal carcinoma.

The discovery that miRNAs are frequently deregulated in tumours offers the opportunity to identify them as prognostic and diagnostic markers. The aim of this multicentric study is to identify a miRNA expression profile specific for laryngeal cancer. The secondary endpoint was to identify specific deregulated miRNAs with potential as prognostic biomarkers for tumour spread and nodal involvement, and specifically to search for a miRNA pattern pathognomonic for N+ laryngeal cancer and for N- tissues. We identified 20 miRNAs specific for laryngeal cancer and a tissue-specific miRNA signature that is predictive of lymph node metastases in laryngeal carcinoma characterised by 11 miRNAs, seven of which are overexpressed (upregulated) and four downregulated. These results allow the identification of a group of potential specific tumour biomarkers for laryngeal carcinoma that can be used to improve its diagnosis, particularly in early stages, as well as its prognosis.

Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients.

The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improved in vivo and in vitro cytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients.

Radiological Decision Aid to determine suitability for medial unicompartmental knee arthroplasty: development and preliminary validation.

AIMS: An evidence-based radiographic Decision Aid for meniscal-bearing unicompartmental knee arthroplasty (UKA) has been developed and this study investigates its performance at an independent centre. PATIENTS AND METHODS: Pre-operative radiographs, including stress views, from a consecutive cohort of 550 knees undergoing arthroplasty (UKA or total knee arthroplasty; TKA) by a single-surgeon were assessed. Suitability for UKA was determined using the Decision Aid, with the assessor blinded to treatment received, and compared with actual treatment received, which was determined by an experienced UKA surgeon based on history, examination, radiographic assessment including stress radiographs, and intra-operative assessment in line with the recommended indications as described in the literature. RESULTS: The sensitivity and specificity of the Decision Aid was 92% and 88%, respectively. Excluding knees where a clear pre-operative plan was made to perform TKA, i.e. patient request, the sensitivity was 93% and specificity 96%. The false-positive rate was low (2.4%) with all affected patients readily identifiable during joint inspection at surgery. In patients meeting Decision Aid criteria and receiving UKA, the five-year survival was 99% (95% confidence intervals (CI) 97 to 100). The false negatives (3.5%), who received UKA but did not meet the criteria, had significantly worse functional outcomes (flexion p < 0.001, American Knee Society Score - Functional p < 0.001, University of California Los Angeles score p = 0.04), and lower implant survival of 93.1% (95% CI 77.6 to 100). CONCLUSION: The radiographic Decision Aid safely and reliably identifies appropriate patients for meniscal-bearing UKA and achieves good results in this population. The widespread use of the Decision Aid should improve the results of UKA. Cite this article: Bone Joint J 2016;98-B(10 Suppl B):3-10.

Early outcomes of twin-peg mobile-bearing unicompartmental knee arthroplasty compared with primary total knee arthroplasty.

AIMS: Since redesign of the Oxford phase III mobile-bearing unicompartmental knee arthroplasty (UKA) femoral component to a twin-peg design, there has not been a direct comparison to total knee arthroplasty (TKA). Thus, we explored differences between the two cohorts. PATIENTS AND METHODS: A total of 168 patients (201 knees) underwent medial UKA with the Oxford Partial Knee Twin-Peg. These patients were compared with a randomly selected group of 177 patients (189 knees) with primary Vanguard TKA. Patient demographics, Knee Society (KS) scores and range of movement (ROM) were compared between the two cohorts. Additionally, revision, re-operation and manipulation under anaesthesia rates were analysed. RESULTS: The mean follow-up for UKA and TKA groups was 5.4 and 5.5 years, respectively. Six TKA (3.2%) versus three UKAs (1.5%) were revised which was not significant (p = 0.269). Manipulation was more frequent after TKA (16; 8.5%) versus none in the UKA group (p < 0.001). UKA patients had higher post-operative KS function scores versus TKA patients (78 versus 66, p < 0.001) with a trend toward greater improvement, but there was no difference in ROM and KS clinical improvement (p = 0.382 and 0.420, respectively). CONCLUSION: We found fewer manipulations, and higher functional outcomes for patients treated with medial mobile-bearing UKA compared with TKA. TKA had twice the revision rate as UKA although this did not reach statistical significance with the numbers available. Cite this article: Bone Joint J 2016;98-B(10 Suppl B):28-33.

Congenital factor XI and factor VII deficiencies assure an apparent opposite protection against arterial or venous thrombosis: An intriguing observation.

OBJECTIVE: To investigate the prevalence and type of thrombotic events reported in patients with congenital factor XI (FXI) or factor VII (FVII) deficiency. PATIENTS AND METHODS: Data on all patients with congenital FXI or FVII deficiency and a thrombotic event were gathered by means of a time unlimited PubMed search carried out in June 2014 and in February 2015. Appropriate keywords including the medical subject headings were used in both instances. Side tables were also consulted and cross-checking of the references was carried out to avoid omissions. The thrombosis event had to be proven by objective methods. RESULTS: Forty-three patients with FXI deficiency had arterial thrombosis and only eight had venous thrombosis. On the contrary, only five patients with FVII deficiency had arterial thrombosis whereas 31 patients had venous thrombosis. The arterial/venous ratios were 5.37 and 0.17 for FXI or FVII, respectively. CONCLUSIONS: Arterial thrombosis is frequent in FXI deficiency whereas venous thrombosis is rare. The reverse is true for FVII deficiency. The significance of these findings is discussed especially in view of the recent use of synthetic anti-FXI compounds in the prophylaxis of post-orthopedic surgery of venous thrombosis complications.

Expression and regulation of the estrogen receptors in PC-3 human prostate cancer cells.

The aim of this study was to identify the expression, cellular localization and regulation of classic estrogen receptors ERα and ERß, ER-α36 isoform and GPER in the androgen-independent prostate cancer cell line PC-3. In addition, we evaluated the relative contribution of these receptors to the activation of the ERK1/2 (extracellular signal-regulated protein kinases) signaling pathway. These four estrogen receptors were detected by Western blot assays and were shown by immunofluorescence assays to localize preferentially in extranuclear regions of PC-3 cells. In addition, treatment with 17ß-estradiol (E2) (1 µM) for 24 h led to down-regulation of the classic estrogen receptors, whereas E2 at physiological concentration (0.1 nM) for 24h tended to increase the levels of ERα and ERß. Furthermore, the ERα-selective agonist PPT selectively increased the expression of ERß and the ERß-selective agonist DPN increased ERα levels. None of these treatments affected expression of the ER-α36 isoform. The unusual cytoplasmic localization of the classic estrogen receptors in these cells differs from the nuclear localization in the majority of estrogen target cells and suggests that rapid signaling pathways may be preferentially activated. In fact, treatment with selective agonists of ERα, ERß and GPER induced ERK1/2 phosphorylation that was blocked by the respective antagonists. On the other hand, activation of ERK1/2 induced by E2 may involve additional mechanisms because it was not blocked by the three antagonists. Taken together, the results indicate that there is a crosstalk between ERα and ERß to regulate the expression of each other, and suggest the involvement of other receptors, such as ER-α36, in the rapid ERK1/2 activation by E2. The identification of new isoforms of ERs, regulation of the receptors and signaling pathways is important to develop new therapeutic strategies for the castration-resistant prostate cancer.