Publications by authors named "Chiara Ratti"

26 Publications

  • Page 1 of 1

Trabecular bone porosity and pore size distribution in osteoporotic patients - A low field nuclear magnetic resonance and microcomputed tomography investigation.

J Mech Behav Biomed Mater 2022 01 29;125:104933. Epub 2021 Oct 29.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume 447, I-34149, Trieste, Italy.

The study of bone morphology is of great importance as bone morphology is influenced by factors such as age and underlying comorbidities and is associated with bone mechanical properties and fracture risk. Standard diagnostic techniques used in bone disease, such as Dual-Energy X-ray absorptiometry and ultrasonography do not provide qualitative and quantitative morphological information. In recent years, techniques such as High Resolution Computed Tomography (HR-CT), micro- CT, Magnetic Resonance Imaging (MRI), and Low Field Nuclear Magnetic Resonance (LF-NMR) have been developed for the study of bone structure and porosity. Data obtained from these techniques have been used to construct models to predict bone mechanical properties thanks to finite element analysis. Cortical porosity has been extensively studied and successfully correlated with disease progression and mechanical properties. Trabecular porosity and pore size distribution, however, have increasingly been taken into consideration to obtain a comprehensive analysis of bone pathology and mechanic. Therefore, we have decided to evaluate the ability of micro- CT (chosen for its high spatial resolving power) and LF-NMR (chosen to analyze the behavior of water molecules within trabecular bone pores) to characterize the morphology of trabecular bone in osteoporosis. Trabecular bone samples from human femoral heads collected during hip replacement surgery were from osteoporosis (test group) and osteoarthritis (control group) patients. Our data show that both micro- CT and LF-NMR can detect qualitative changes in trabecular bone (i.e., transition from plate-like to rod-like morphology). Micro- CT failed to detect significant differences in trabecular bone morphology parameters between osteoporotic and osteoarthritic specimens, with the exception of Trabecular Number and Connectivity Density, which are markers of osteoporosis progression. In contrast, LF-NMR was able to detect significant differences in porosity and pore size of trabecular bone from osteoporotic versus osteoarthritic (control) samples. However, only the combination of these two techniques allowed the detection of structural morphometric changes (increase in the larger pore fraction and enlargement of the larger pores) in the trabecular bone of osteoporotic specimens compared to osteoarthritic ones. In conclusion, the combined use of LF-NMR and micro- CT provides a valuable tool for characterizing the morphology of trabecular bone and may offer the possibility for a new approach to the study and modeling of bone mechanics in the context of aging and disease.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104933DOI Listing
January 2022

Prevention of postoperative surgical wound complications in ankle and distal tibia fractures: results of Incisional Negative Pressure Wound Therapy.

Acta Biomed 2020 12 30;91(14-S):e2020006. Epub 2020 Dec 30.

Orthopaedics and Traumatology Unit, Cattinara Hospital - ASUGI, Department of Medical, Surgical and Life Sciences, Trieste University, Trieste (Italy).

Background And Aim Of The Work: complications in surgical wound healing represent the main postoperative complication in ankle and distal tibia fractures. Whereas the use of Incisional Negative Pressure Wound Therapy (INPWT) is recognized to have a role in wound complications prevention in prosthetic surgery, literature about its use in trauma surgery is scarce. The aim of this study was to compare the effectiveness of INWPT with a conventional dressing in order to prevent surgical wound complications in ankle and distal tibia fractures.

Methods: The study population included patients over 65 years as well as patients under 65 years considered at risk for wound complications (smokers, obese, affected by diabetes), who underwent ORIF for bi/tri-malleolar ankle fractures or distal tibia (pilon) fractures. After surgery, patients were randomized to receive a conventional dressing or INPWT. Complications in surgical wound healing were classified in major (requiring surgical intervention) and minor complications.

Results: 65 patients were included in the study. The rate of minor and major complications between the two groups was not significantly different, although a positive trend towards a lower minor complications rate was noted in the INPWT group (12.6% vs 34.7%). No complications or complaints were reported for the INPWT device.

Conclusions: INPWT proved to be safe, well-tolerated and showed promising results in preventing surgical wound complications in ankle and distal tibia fractures.
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http://dx.doi.org/10.23750/abm.v91i14-S.10784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944683PMC
December 2020

Shoulder arthroplasty for proximal humerus fractures in the elderly: The path from Neer to Grammont.

Orthop Rev (Pavia) 2020 Jun 25;12(Suppl 1):8659. Epub 2020 Jun 25.

Orthopaedic and Trauma Unit, Department of Medicine, Surgery and Health Sciences, University Hospital University of Trieste.

Shoulder replacement is indicated for the surgical treatment of proximal humeral fractures in elderly patients, when severe comminution and osteoporosis jeopardize the chances of success of any fixation technique. Two different implants are available for this purpose: anatomical hemiarthroplasty (HA) and reverse total shoulder arthroplasty (RTSA). HA for fractures was popularized by Charles Neer in the '50s and for several decades remained the only reliable implant for these injuries. However, many authors reported inconsistent results with HA as a consequence of the high rate of tuberosity and rotator cuff failure. In 1987, Paul Grammont designed the first successful RTSA, which was the end result of a long thought process on functional surgery of the shoulder. This implant was initially used to treat cuff tear arthropathy and shoulder pseudoparalysis, but indications have gradually expanded with time. Since RTSA does not rely on a functional cuff for shoulder elevation, it was felt that results in fractures could be improved by this prosthesis. In this study, the salient features of these implants are described to understand the rationale behind both approaches and highlight their pros and cons. Several clinical studies comparing HA vs RTSA for proximal humeral fractures have been published during the last two decades. A literature review is carried out to analyze and compare outcomes of both implants, analyzing clinical results, radiographic findings and complications. The final goal is to provide an overview of the different factors to consider for making a choice between these two prostheses.
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http://dx.doi.org/10.4081/or.2020.8659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459385PMC
June 2020

Predictive value of valgus head-shaft angle in identifying Neer 4-part proximal humerus fractures. A radiographic and CT-scan analysis of 120 cases.

Acta Biomed 2020 05 30;91(4-S):217-223. Epub 2020 May 30.

Orthopaedics and Traumatology Unit, Cattinara Hospital - ASUITS, Strada di Fiume 447, 34149 Trieste (Italy).

Background And Aim Of The Work: Understanding the fracture morphology and its relation to the expected outcome and risk of complications is fundamental for proximal humerus fractures (PHFs) management. Most Neer 3- and 4-part fractures may deserve surgical treatment. Unfortunately, plain x-rays may not be able to differentiate between a 3- or 4-part fractures unless an axillary or analogue projection is carried out. Aim of the present study is to evaluate whether a high valgus head-shaft angle degree is predictive of a Neer 4-part rather than a 3-part fracture.

Methods: The study included 120 3-(75 cases) and 4-(45 cases) part PHFs (valgus displaced in 98 cases), M:F ratio = 1:2.6, mean age 65.7 years, classified on CT scan images. The humeral head shaft angle was calculated on AP x-rays and statistically correlated with 3 and 4-part fractures to identify values predictive of 4-part fracture.

Results: Valgus head/shaft angle was significantly higher in 4-part fractures, especially in the valgus displaced group (p < 0.001). A cutoff value of 168.5° was identified as predictive of a 4-part fracture with a sensibility of 74% and specificity of 78%. Increasing by 1 degree the humeral head-shaft angle, the chance to have a 4-part fracture increases of 3% in the whole population and of 11% in the valgus sub-group.

Conclusion: The severity of PHF can be predicted analysing valgus head shaft angle on AP x-rays with a sensibility of 74% and specificity of 78% in identifying a 4-part fracture with a cutoff value of 168.5°.
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http://dx.doi.org/10.23750/abm.v91i4-S.9717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944809PMC
May 2020

Epidemiology and risk factors for contralateral proximal femur fracture: a single center retrospective cohort study on 1022 patients.

Acta Biomed 2020 05 30;91(4-S):115-121. Epub 2020 May 30.

Orthopaedics and Traumatology Unit, Cattinara Hospital - ASUITS, Strada di Fiume 447, 34149 Trieste (Italy).

Summary.

Background And Aim Of The Work: Given the high impact of proximal femur fractures (PFFs) on elderly patients and healthcare systems, the burden of contralateral PFFs might be overlooked. Aim of the study is to analyze the epidemiology and risk factors of contralateral proximal femur fractures. Secondary aim is to detect mortality rate differences in first and contralateral PPF.

Methods: A population of 1022 patients admitted for proximal femur fractures in a single center was studied. Prevalence at admission as well as incidence of contralateral PFF during a 18 to 36 months follow-up was recorded. Epidemiology of contralateral PFF was studied recording number of events, time to second fracture and fracture type. Mortality at 1-year was recorded for all patients and compared between first and second PFF patients. Comorbidities, pharmacotherapy, BMI, MNA and SPMSQ were studied as possible risk factors.

Results: Prevalence and incidence of contralateral PFFs were 9.4% and 6.5% respectively. Median time to second fracture was 12 months. One-year mortality of contralateral PFFs was significantly lower (20.5% vs 25.1%, p 0.003) than first PFF. Contralateral fracture patients had a significantly lower BMI and a significantly lower proportion of malnourished patients.

Conclusions: The incidence and prevalence of contralateral PFFs is relevant. Mortality of contralateral PFFs results to be lower than first PFF. Patients with higher BMI and malnourished patients have a lower risk of contralateral PFF.
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http://dx.doi.org/10.23750/abm.v91i4-S.9716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944826PMC
May 2020

COVID19: potential cardiovascular issues in pediatric patients.

Acta Biomed 2020 05 11;91(2):177-183. Epub 2020 May 11.

Parma University HospitalDepartment of Mother and ChildPediatric Cardiology Unit.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) has rapidly spread worldwide with increasing hospitalization and mortality rate. Ongoing studies and accumulated data are de- tailing the features and the effects of the new coronavirus disease 19 (COVID 19) in the adult population, and cardiovascular involvement is emerging as the most significant and life-threatening complication, with an in- creased risk of morbidity and mortality in patients with underlying cardiovascular disease. At present, though the limited data on the effects of COVID 19 in pediatric patients, children seem to count for a little proportion of SARS-COV 2 infection, and present with less severe disease and effects However infants and toddlers are at risk of developing critical course. The disease has a range of clinical presentations in children, for which the potential need for further investigation of myocardial injury and cardiovascular issues should be kept in mind to avoid misdiagnosing severe clinical entities. Overlapping with Kawasaki disease is a concern, particularly the incomplete and atypical form. We aim to summarize the initial considerations and potential cardiovascular implications of COVID-19 for children and patients with congenital heart disease.
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http://dx.doi.org/10.23750/abm.v91i2.9655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569665PMC
May 2020

Indications and results of osteosynthesis for proximal humerus fragility fractures in elderly patients.

Orthop Rev (Pavia) 2020 Apr 28;12(1):8559. Epub 2020 Apr 28.

Orthopedic and Trauma Unit, University Hospital "Maggiore della Carità", Department of Health Sciences, University of East Piedmont, Novara, Italy.

Proximal humerus fractures (PHF) are common injuries in the elderly population. Conservative treatment is indicated for undisplaced and stable fractures, which account for almost 80% of the cases. More complex fracture patterns might need surgery, with a wide variety of indication criteria and surgical techniques described in the literature. Surgical treatment should be reserved for patients in good clinical conditions, autonomous in daily living activities and able to adhere to postoperative rehabilitation protocols. In the elderly population with severe osteoporosis, cognitive impairment and clinical comorbidities, the risk of surgical failures is high. In these patients, the choice between surgical and conservative treatment, as well as for the type of procedure, is even more difficult, with no general consensus in the literature. Final indication is usually conditioned by surgeon's experience and preference. Two independent reviewers (B.H and G.G) independently extracted studies on proximal humeral fractures. All selected studies were screened independently (B.H and G.G) based on title and abstract. Then the full text of any article that either judged potentially eligible was acquired and reviewed again. Any disagreement was resolved by discussing the full text manuscripts. Aim of the present paper is to review the literature about indications and results of osteosynthesis for proximal humerus fragility fractures in the elderly population.
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http://dx.doi.org/10.4081/or.2020.8559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206366PMC
April 2020

[Cardiological counseling and perioperative management of heart disease patients. Protocol of the University of Trieste - Year 2019].

G Ital Cardiol (Rome) 2019 Dec;20(12):706-721

S.C. Cardiologia, Azienda Sanitaria Universitaria Integrata di Trieste (ASUITs).

The management of patients with heart disease or suspected heart disease, who are hospitalized and/or who should undergo surgery or an invasive procedure, is very complex for the comorbidities often present, the multiple therapies taken and the frequent presence of advanced cardiac devices.The purpose of this document is to provide indications and standardize the behavior of different clinicians in the management of heart disease patients or those with suspected heart disease in order (i) to manage acute cardiac conditions with appropriate timing and accuracy, and (ii) to define the cardiovascular risk in the individual patient with appropriate timing and indications, allowing patients to face any surgery or invasive procedure with the lowest risk correlated to his heart disease.
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http://dx.doi.org/10.1714/3271.32380DOI Listing
December 2019

Fracture of Cobalt-Crome Modular Neck in Total Hip Arthroplasty.

Acta Biomed 2019 12 5;90(12-S):187-191. Epub 2019 Dec 5.

Orthopaedics and Traumatology Unit, Cattinara Hospital - ASUITS, Strada di Fiume 447, 34149 Trieste (Italy).

Despite the advantages of modular total hip arthroplasty in terms of neck version, offset and length precise reproduction, titanium necks breakage became a concern. Consequently, titanium has been replaced by cobalt-chrome (Co-Cr). However, four cases of Co-Cr modular neck breakage have been reported in the literature. In the present paper, two cases of Co-Cr modular neck fractures are described together with a literature review. The aim of this work is to discuss the risk factors and characteristics of this rare complication. We described two cases of fracture of long varus Co-Cr modular femoral neck connected with cementless press-fit stem. Some risk factors, such as long varus type of modular neck, overweight and/or high demanding physical activity, might have contributed to implant failure.
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http://dx.doi.org/10.23750/abm.v90i12-S.8941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233721PMC
December 2019

Osteoporotic distal femur fractures in the elderly: peculiarities and treatment strategies.

Acta Biomed 2019 12 5;90(12-S):25-32. Epub 2019 Dec 5.

Orthopaedics and Traumatology Unit, Cattinara Hospital, Department of Medical, Surgical and Life Sciences, Trieste University, Trieste, Italy..

Distal femur fractures account for 4-6% of osteoporosis related fractures of the femur in the elderly population. They represent a relevant cause of morbidity and mortality in the geriatric population with a reported 1-year mortality reaching 30%. Non-displaced fractures or even displaced fractures in patients with high operative risk can be treated conservatively. However, operative treatment is the most widely accepted management option for displaced fractures. The advantage resides in early mobilization and weight-bearing, reducing risks related with a prolonged immobilization when compared with conservative treatment. On the other hand, the intrinsic difficulty of fixing an osteoporotic bone is a major concern. The presence of osteosynthesis devices or prosthetic implants in the femur can make the surgical treatment more challenging, sometimes limiting therapeutic options. Aim of the present paper is to review the most recent literature about osteoporotic distal femur fractures in the elderly, including periprosthetic and other hardware related fractures, to highlight current evidence on management options and related results as a guide for the daily clinical practice.
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http://dx.doi.org/10.23750/abm.v90i12-S.8958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233703PMC
December 2019

Post-operative periprosthetic humeral fractures after reverse shoulder arthroplasty: a review of the literature.

Acta Biomed 2019 12 5;90(12-S):8-13. Epub 2019 Dec 5.

Orthopaedics and Traumatology Unit, Cattinara Hospital, Department of Medical, Surgical and Life Sciences, Trieste University, Trieste (Italy).

Background And Aim Of The Work: Post-operative periprosthetic shoulder fractures incidence is gradually raising due to aging of population and increasing of reverse total shoulder arthroplasty (RTSA). Management of this complication represents a challenge for the orthopedic surgeon. Aim of the present study is to critically review the recent literature about epidemiology, risk factors, diagnosis, management and outcome of post-operative periprosthetic humeral  fractures occurring on RTSA.

Methods: A systematic search of Embase, Medline and Pubmed was performed by two reviewers who selected the eligible papers favoring studies published in the last ten years. Epidemiology, risk factors, diagnostic features, clinical management and outcome of different techniques were all reviewed.

Results: 31 studies including reviews, meta-analysis, case reports, clinical and biomechanical studies were selected.

Conclusions: Correct clinical management requires adequate diagnosis and evaluation of risk factors. Conservative treatment is rarely indicated. Locking plate fixation and revision arthroplasty are both valuable treatment methods. Surgical technique should be chosen considering age and functional demand, comorbidities, fracture morphology and location, bone quality and stability of the implant. Given the correct indication all surgical treatment can lead to satisfactory clinical and radiographic results despite a relevant complication rate.
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http://dx.doi.org/10.23750/abm.v90i12-S.8974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233712PMC
December 2019

Poor nutritional status but not cognitive or functional impairment per se independently predict 1 year mortality in elderly patients with hip-fracture.

Clin Nutr 2019 08 31;38(4):1607-1612. Epub 2018 Aug 31.

Department of Medical, Surgical and Health Sciences, University of Trieste, Italy. Electronic address:

Background & Aims: Hip fractures are strongly associated with mortality in the elderly. Studies investigating predisposing factors have suggested a negative impact of poor nutritional, cognitive and functional status on patient survival, however their independent prognostic impact as well as their interactions remain undefined. This study aimed to determine whether poor nutritional status independently predicts 1 year post-fracture mortality after adjusting for cognitive and functional status and for other clinically relevant covariates.

Methods: 1211 surgically treated hip fracture elderly (age ≥ 65) patients consecutively admitted to the Orthopaedic Surgery Unit of the "Azienda Sanitaria Universitaria Integrata Trieste" (ASUITs), Cattinara Hospital, Trieste, Italy and managed by a dedicated orthogeriatric team. Pre-admission nutritional status was evaluated by Mini Nutritional Assessment (MNA) questionnaire, cognitive status by Short Portable Mental Status Questionnaire (SPMSQ) and functional status by Activity of Daily Living (ADL) questionnaire. All other clinical data, including comorbidities, type of surgery, post-operative complications (delirium, deep vein thrombosis, cardiovascular complications, infections, need for blood transfusions) were obtained by hospital clinical records and by mortality registry.

Results: Poor nutritional status (defined as MNA ≤23.5), increased cognitive and functional impairment were all associated with 3-, 6- and 12 month mortality (p < 0.001). Both cognitive and functional impairment were associated with poor nutritional status (p < 0.001). Logistic regression analysis demonstrated that the association between nutritional status and 3-, 6- and 12- month mortality was independent of age, gender, comorbidities, type of surgery and post-operative complications as well as of cognitive and functional impairment (p < 0.001). In contrast, the associations between mortality and cognitive and functional impairment were independent (p < 0.001) of demographic (age, gender) and clinical covariates but not of malnutrition. Kaplan-Meier analysis showed a lower mean survival time (p < 0.001) in patients with poor nutritional status compared with those well-nourished.

Conclusions: In hip fracture elderly patients, poor nutritional status strongly predicts 1 year mortality, independently of demographic, functional, cognitive and clinical risk factors. The negative prognostic impact of functional and cognitive impairment on mortality is mediated by their association with poor nutritional status.
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http://dx.doi.org/10.1016/j.clnu.2018.08.030DOI Listing
August 2019

Predictors of cut-out after cephalomedullary nail fixation of pertrochanteric fractures: a retrospective study of 813 patients.

Arch Orthop Trauma Surg 2018 Mar 23;138(3):351-359. Epub 2017 Dec 23.

Department of medical surgical and health sciences of Trieste University, Orthopaedics and Traumatology Unit, Cattinara Hospital-ASUITS, Strada di Fiume 447, 34149, Trieste, Italy.

Background: Cut-out is the most common mechanical complication of the osteosynthesis of pertrochanteric fractures. This complication determines a significant increase in morbidity in elderly patient. Cut-out is defined as the varus collapse of the femoral head-neck fragment with the extrusion of the cephalic screw. Surgical treatment of cut-out might lead to further complications, longer rehabilitation, increased social burden and healthcare system costs. The aim of the study is to identify the predictors of cut-out to prevent its occurrence.

Materials And Methods: Study population included all patients affected by extracapsular fracture of the proximal femur who were admitted and treated with short cephalomedullary nailing at the Cattinara Hospital-ASUITS of Trieste between 2009 and 2014. A retrospective analysis of clinical and radiographic data was carried out and cut-out cases recorded. The data collected on the study population were analyzed to find an eventual correlation with the occurrence of cut-out. The independent variables were age, gender, side of the fracture, ASA class, Evans classification, nailing system, quality of reduction, TAD, CalTAD, and Parker ratio.

Results: The study population counted 813 cases, with an F:M ratio of 4:1 and a mean age of 84.7 years. The cut-out was recorded in 18 cases (2.2%). There was no statistically significant association between cut-out and age, sex, side of fracture, ASA class, and nailing system. The Evans classification, the quality of reduction, the TAD, the CalTAD, and the Parker's ratio demonstrated a significant correlation at univariate analysis with cut-out. The results of multivariate analysis confirmed that TAD, Parker AP, and quality of reduction were independently significantly correlated to cut-out.

Conclusion: The results of the present study demonstrate that good quality of reduction and correct position of the lag screw are likely to decrease the risk of cut-out complication. A nomogram for cut-out prediction is proposed for clinical validation.
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http://dx.doi.org/10.1007/s00402-017-2863-zDOI Listing
March 2018

Periprosthetic knee fractures. A review of epidemiology, risk factors, diagnosis, management and outcome.

Acta Biomed 2017 06 7;88(2S):118-128. Epub 2017 Jun 7.

.

Background And Aim Of The Work: Periprosthetic knee fractures incidence is gradually raising due to aging of population and increasing of total knee arthroplasties. Management of this complication represents a challenge for the orthopaedic surgeon. Aim of the present study is to critically review the recent literature about epidemiology, risk factors, diagnosis, management and outcome of periprosthetic knee fractures.

Methods: A systematic search of Embase, Medline and Pubmed was performed by two reviewers who selected the eligible papers favoring studies published in the last ten years. Epidemiology, risk factors, diagnostic features, clinical management and outcome of different techniques were all reviewed.

Results: 52 studies including reviews, meta-analysis, clinical and biomechanical studies were selected.

Conclusions: Correct clinical management requires adequate diagnosis and evaluation of risk factors. Conservative treatment is rarely indicated. Locking plate fixation, intramedullary nailing and revision arthroplasty are all valuable treatment methods. Surgical technique should be chosen considering age and functional demand, comorbidities, fracture morphology and location, bone quality and stability of the implant. Given the correct indication all surgical treatment can lead to satisfactory clinical and radiographic results despite a relevant complication rate.
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http://dx.doi.org/10.23750/abm.v88i2 -S.6522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179004PMC
June 2017

Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors.

Clin Cancer Res 2017 Sep 9;23(17):5149-5161. Epub 2017 Jun 9.

Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer. Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression. These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-3186DOI Listing
September 2017

Treatment of intracapsular fractures of the proximal femur with bipolar hemiarthroplasty in patients under the age of 70: clinical and radiographic results at mean 20 years follow-up.

Acta Biomed 2016 04 15;87 Suppl 1:53-9. Epub 2016 Apr 15.

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Background And Aim Of The Work: Hemiarthroplasty (HA) for femoral neck fractures in relatively young patients has been reported to have poor results. Moreover, cotyloiditis has been described for HA as a possible cause of revision. Nontheless, in the literature there is lack of studies specifically evaluating this topic, particularly in relatively young patients. Aim of the study was to evaluate bipolar HA clinical and radiographic results at long term follow up in patients treated under the age of 70.

Methods: Study population counted 137 patients treated between 1990 and 2000. In 2015 alive patients who did not undergo implant revision were clinically evaluated. Harris Hip Score and EQ-5D questionnaire were administrated. Acetabular erosion was identified and classified on follow-up radiographs.

Results: At follow-up there were 39 living patients, mean age 64, 80.5% women. 3 patients were not traceable. Revision rate was 32% (12/37), because of cotyloiditis in 2 cases. In the 22 non-revised patients at mean 20 years follow up 3 cases presented moderate to severe acetabular erosion. Mean HHS and EQ values were 73.23 and 0.527 respectively.

Conclusions: Bipolar HA provided satisfying results in relatively young patients at long term follow-up. In the present study age turned out to be the most relevant variable to influence results. Data suggest that acetabular erosion might have a secondary role in determining both the implant's survival and the long term clinical results.
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April 2016

Treatment of complex regional pain syndrome.

Clin Cases Miner Bone Metab 2015 Jan-Apr;12(Suppl 1):26-30. Epub 2016 Apr 7.

Department of Medical and Surgical Specialties and Dentistry, Second University of Naples, Naples, Italy.

Complex Regional Pain Syndrome (CRPS) is a multifactorial and disabling disorder with complex etiology and pathogenesis. Goals of therapy in CRPS should be pain relief, functional restoration, and psychological stabilization, but early interventions are needed in order to achieve these objectives. Several drugs have been used to reduce pain and to improve functional status in CRPS, despite the lack of scientific evidence supporting their use in this scenario. They include anti-inflammatory drugs, analgesics, anesthetics, anticonvulsants, antidepressants, oral muscle relaxants, corticosteroids, calcitonin, bisphosphonates, calcium channel blockers and topical agents. NSAIDs showed no value in treating CRPS. Glucocorticoids are the only anti-inflammatory drugs for which there is direct clinical trial evidence in early stage of CRPS. Opioids are a reasonable second or third-line treatment option, but tolerance and long term toxicity are unresolved issues. The use of anticonvulsants and tricyclic antidepressants has not been well investigated for pain management in CRPS. During the last years, bisphosphonates have been the mostly studied pharmacologic agents in CRPS treatment and there are good evidence to support their use in this condition. Recently, the efficacy of intravenous (IV) administration of neridronate has been reported in a randomized controlled trial. Significant improvements in VAS score and other indices of pain and quality of life in patients who received four 100 mg IV doses of neridronate versus placebo were reported. These findings were confirmed in the open-extension phase of the study, when patients formerly enrolled in the placebo group received neridronate at the same dosage, and these results were maintained at 1 year follow-up. The current literature concerning sympathetic blocks and sympathectomy techniques lacks evidence of efficacy. Low evidence was recorded for a free radical scavenger, dimethylsulphoxide (DMSO) cream (50%). The same level of efficacy was noted for vitamin C (500 mg per day for 50 days) in prevention of CRPS in patients affected by wrist fracture. In conclusion, the best available therapeutic approach to CRPS is multimodal and is based on the use of several classes of drugs, associated to early physiotherapy. Neridronate at appropriate doses is associated with clinically relevant and persistent benefits in CRPS patients.
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http://dx.doi.org/10.11138/ccmbm/2015.12.3s.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832403PMC
May 2016

Post-traumatic complex regional pain syndrome: clinical features and epidemiology.

Clin Cases Miner Bone Metab 2015 Jan-Apr;12(Suppl 1):11-6. Epub 2016 Apr 7.

Orthopaedic, Traumatologic Clinic, University Hospital "Ospedali Riuniti", Trieste, Italy.

Complex Regional Pain Syndrome (CRPS) is a chronic pain condition that occurs after a tissue injury (fractures, sprain, surgery) of the upper or lower extremities. A clear pathophysiological mechanism has not been established yet and different patterns are considered to play a role in the genesis of the disease. The diagnosis is made by different diagnosis criteria and a gold standard has not been established yet. Incidence of CRPS is unclear and large prospective studies on the incidence and prevalence of CRPS are scarce. The aim of this review is to give an overview on the prevalent data regarding this chronic syndrome.
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http://dx.doi.org/10.11138/ccmbm/2015.12.3s.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832405PMC
May 2016

Osteopontin shapes immunosuppression in the metastatic niche.

Cancer Res 2014 Sep 17;74(17):4706-19. Epub 2014 Jul 17.

Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1(-/-) mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor- and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the monocytic subset was the predominant source of OPN. In Spp1(-/-) mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in Spp1(-/-) mice were less suppressive than their wild-type counterparts due to lower expression of arginase-1, IL6, and phospho-Stat3. Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1(-/-) mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-3334DOI Listing
September 2014

Factors affecting bone strength other than osteoporosis.

Aging Clin Exp Res 2013 Oct 18;25 Suppl 1:S9-11. Epub 2013 Sep 18.

Dipartimento di Ortopedia e Traumatologia, Università Dell'Insubria, Viale Luigi Borri 57, 21100, Varese, Italy.

Osteoporosis is the most common cause of bone fragility, especially in post-menopausal women. Bone strength may be compromised by several other medical conditions and medications, which must be ruled out in the clinical management of patients affected by fragility fractures. Indeed, 20-30% of women and up to 50% of men affected by bone fragility are diagnosed with other conditions affecting bone strength other than osteoporosis. These conditions include disorders of bone homeostasis, impaired bone remodeling, collagen disorders, and medications qualitatively and quantitatively affecting bone strength. Proper diagnosis allows correct treatment to prevent the occurrence of fragility fractures.
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http://dx.doi.org/10.1007/s40520-013-0098-6DOI Listing
October 2013

The incidence of fragility fractures in Italy.

Aging Clin Exp Res 2013 Oct 18;25 Suppl 1:S13-4. Epub 2013 Sep 18.

Dipartimento di Ortopedia e Traumatologia, Universita' Dell'Insubria, Viale Luigi Borri 57, 21100, Varese, Italy.

Osteoporosis can significantly impact on the risk of developing a fracture. Thus, fragility fractures represent a challenge for health professionals and decision makers of the twenty-first century. The aim of this work is to review the literature concerning osteoporotic fractures in Italy in terms of incidence, rate of hospitalization, relative risk of a new fragility fracture, and costs for the national health system. It was estimated that the costs of treating proximal femur fragility fractures in 2002 summed up to 1 billion Euros. The number of fragility fractures in Italy was calculated as follows: 91.494 hip fractures, 61.009 clinical vertebral fractures, 57.401 humeral fragility fractures, and 94.045 forearm/wrist fragility fractures. The incidence of fragility fractures in Italy is very high, and osteoporosis is the leading cause of morbidity in the Italian population.
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http://dx.doi.org/10.1007/s40520-013-0071-4DOI Listing
October 2013

Total hip arthroplasty and bone fragility.

Aging Clin Exp Res 2011 Apr;23(2 Suppl):76-7

Orthopaedic and Trauma Institute, Universitas Studiorum Insubriae, Varese, Italy.

The number of elderly people is steadily increasing: in the United States it will increase from 12.9% to 20% in 2030 with respect to the total population. Italy, with UK, Denmark and Sweden are the countries with the largest number of octogenarians (about 4% of the population) and it is estimated that this rate will increase by 300% over the next 50 years. The number of people affected by osteoarthritis will increase significantly and therefore the number of total hip arthroplasties will progressively increase. The success of an implant depends firstly by a flawless surgical technique, a correct and stable implant fixation and an optimal preoperative planning that should consider the bone quality of the patient, in order to choose a proper implant design. Different approaches could be followed to achieve adequate fixation: northern Europe surgeons prefer the cemented implant, instead American orthopedics generally use systems that allow a direct biological osteointegration. Elderly patients often present with multiple local and general problems that could affect significantly the normal course of a prosthetic surgery procedure and its results: they have bone tissue changes that lead to increased bone fragility and, consequently, difficulties to obtain primary stability. Osteoporotic bone is characterized by reduction of bone mass, decrease of cancellous bone trabeculae and by increased porosity of cortical bone. The bone fragility implies a greater risk of iatrogenic intraoperative fractures. Furthermore, difficulties linked to bone stock deficiencies become even more significant in revision surgery, where cortical bone thinning is associated with enlargement of the isthmus thus making more difficult to obtain distal fixation of prosthetic stems. At the moment, the role played by the drugs used for the treatment of osteoporosis during implant osteointegration is still not clearly understood and is still under investigation.
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April 2011

Oncogene-driven intrinsic inflammation induces leukocyte production of tumor necrosis factor that critically contributes to mammary carcinogenesis.

Cancer Res 2010 Oct 5;70(20):7764-75. Epub 2010 Oct 5.

Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Oncogene activation promotes an intrinsic inflammatory pathway that is crucial for cancer development. Here, we have investigated the actual effect of the inflammatory cytokine tumor necrosis factor (TNF) on the natural history of spontaneous mammary cancer in the HER2/neuT (NeuT) transgenic mouse model. Bone marrow transplantation from TNF knockout mice into NeuT recipients significantly impaired tumor growth, indicating that the source of TNF fostering tumor development was of bone marrow origin. We show that the absence of leukocyte-derived TNF disarranged the tumor vasculature, which lacked pericyte coverage and structural integrity, leading to diffuse vascular hemorrhage and stromal necrosis. In addition, tumor-associated Tie2-expressing monocytes were reduced and cytokine expression skewed from Th2 to Th1 type. Treatment of NeuT mice with anti-TNF antibody partially phenocopied the antitumor effect of TNF-deficient bone marrow cell transplantation, providing a strong preclinical background and rationale for the introduction of TNF antagonists in the treatment of human breast cancer, including basal-like samples for which consolidated targeted therapies do not exist.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-0471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371347PMC
October 2010

Follow-up of collagen meniscus implant patients: clinical, radiological, and magnetic resonance imaging results at 5 years.

Knee 2010 Jun 2;17(3):224-9. Epub 2009 Oct 2.

Department of Orthopedics and Trauma M. Boni, Insubria University, Viale Borri 57, Varese, Italy.

This study investigated at medium term follow-up the clinical outcomes and any progression of knee osteoarthritis in a population of patients that underwent arthroscopic placement of a collagen meniscus implant. Thirty-four patients underwent arthroscopic placement of a collagen meniscus implant for a symptomatic deficiency of medial meniscal tissue. Follow-up evaluation included Lysholm II score and Tegner activity scores and MR arthrography of the knee at 2 and 5 years after surgery. Plain radiographs were also obtained at 5 years. Six patients were excluded. In eight cases arthroscopic second look evaluation was performed. Lysholm and Tegner activity scores at 2 and 5 years after surgery improved significantly compared to the preoperative score. These patients showed good to excellent clinical results after 5 years from a CMI placement. The chondral surfaces of the medial compartment had not degenerated further since placement of the CMI. MR signal had continued to mature between 2 and 5 years after implant, progressively decreasing signal intensity but in any case comparable to the low signal of a normal meniscus. In most of cases the CMI-new tissue complex had a slight reduction in size, compared to a normal medial meniscus, but the new tissue had no apparent negative effects.
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http://dx.doi.org/10.1016/j.knee.2009.08.011DOI Listing
June 2010

Association study and mutational screening of SYNGR1 as a candidate susceptibility gene for schizophrenia.

Psychiatr Genet 2009 Oct;19(5):237-43

Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, Brescia University School of Medicine, Brescia, Italy.

Objective: Synaptogyrin 1 (SYNGR1) is a transmembrane protein of neurotransmitter-containing vesicle. Recently, suggestive association between SYNGR1 intragenic polymorphisms and schizophrenia has been reported in the Indian population. Furthermore, some rare nucleotide changes with a potential pathogenic effect have been found in Indian and Chinese schizophrenia patients. In this study, we have performed an association study and a resequencing analysis in an Italian sample.

Methods: Eight polymorphisms of the SYNGR1 gene were typed in a case-control sample consisting of 274 patients and 335 controls. In parallel, a mutational screening covering all SYNGR1 exons was conducted.

Results: Evidence of association has been found for rs715505 (P = 0.028), a marker already reported to be associated with the disease. Resequencing analysis revealed two novel polymorphisms and several rare variants (13 of 16 as new variants), some of which might have relevance for gene expression and function.

Conclusion: The results of our association study support a contribution of SYNGR1 to schizophrenia susceptibility. In addition, the resequencing analysis evidenced mutations with a potential functional role at the mRNA and/or protein level. Of particular interest is the p.isoc:S26G missense mutation identified in six patients (0.011) and three controls (0.004) which might be involved in the elimination of a potential protein kinase C phosphorylation site.
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http://dx.doi.org/10.1097/YPG.0b013e32832cebf7DOI Listing
October 2009

Triggering CD40 on endothelial cells contributes to tumor growth.

J Exp Med 2006 Oct 16;203(11):2441-50. Epub 2006 Oct 16.

Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy.

Inflammatory cells can either promote or inhibit tumor growth. Here we studied whether CD40, a key molecule for adaptive immune response, has any role in mammary carcinogenesis of BALB/NeuT transgenic tumor-prone mice. We transferred the HER2/neu oncogene into CD40-null background to obtain the CD40-KO/NeuT strain. CD40-KO/NeuT mice showed delayed tumor onset and reduced tumor multiplicity. BM (BM) transplantation experiments excluded a role of BM-derived cells in the reduced tumorigenicity associated with CD40 deficiency. Rather, CD40 expressed by endothelial cells (ECs) takes part to the angiogenic process. Accordingly, large vessels, well organized around the tumor lobular structures, characterize BALB/NeuT tumors, whereas tiny numerous vessels with scarce extracellular matrix are dispersed in the parenchyma of poorly organized CD40-KO/NeuT tumors. Activated platelets, which may interact with and activate ECs, are a possible source of CD40L. Their localization within tumor vessels prompted the idea of treating BALB/NeuT and CD40-KO/NeuT mice chronically with the anti-platelet drug clopidogrel, known to inhibit platelet CD40L expression. Treatment of BALB/NeuT mice reduced tumor growth to a level similar to CD40-deficient mice, whereas CD40-KO/NeuT mice treated or not showed the same attenuated tumor outgrowth, indicating that activated platelets are the likely source of CD40L in this model. Collectively, these data point to a participation of CD40/CD40L in the angiogenic processes associated with mammary carcinogenesis of BALB/NeuT mice.
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http://dx.doi.org/10.1084/jem.20060844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118135PMC
October 2006
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