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Background: Adoptive immunotherapies are among the pillars of ongoing biological breakthroughs in neuro-oncology, as their potential applications are tremendously wide. The present literature review comprehensively classified adoptive immunotherapies in neuro-oncology, provides an update, and overviews the main translational challenges of this approach. Methods: The PubMed/MEDLINE platform, Medical Subject Heading (MeSH) database, and ClinicalTrials.gov website were the sources. The MeSH terms “Immunotherapy, Adoptive,” “Cell- and Tissue-Based Therapy,” “Tissue Engineering,” and “Cell Engineering” were combined with “Central Nervous System,” and “Brain.” “Brain tumors” and “adoptive immunotherapy” were used for a further unrestricted search. Only articles published in the last 5 years were selected and further sorted based on the best match and relevance. The search terms “Central Nervous System Tumor,” “Malignant Brain Tumor,” “Brain Cancer,” “Brain Neoplasms,” and “Brain Tumor” were used on the ClinicalTrials.gov website. Results: A total of 79 relevant articles and 16 trials were selected. T therapies include chimeric antigen receptor T (CAR T) cell therapy and T cell receptor (TCR) transgenic therapy. Natural killer (NK) cell-based therapies are another approach; combinations are also possible. Trials in phase 1 and 2 comprised 69% and 31% of the studies, respectively, 8 of which were concluded. CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) was demonstrated to reduce the recurrence rate of glioblastoma after standard-of-care treatment. Conclusion: Adoptive immunotherapies can be classified as T, NK, and NKT cell-based. CAR T cell therapy redirected against EGFRvIII has been shown to be the most promising treatment for glioblastoma. Overcoming immune tolerance and immune escape are the main translational challenges in the near future of neuro-oncology. (www.actabiomedica.it)

Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofibromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most frequent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumorigenesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results. (www.actabiomedica.it)

Background: Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach. Methods: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance. Results: The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipotent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively. Conclusion: Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology. (www.actabiomedica.it)

Background: The tailored targeting of specific oncogenes represents a new frontier in the treatment of high-grade glioma in the pursuit of innovative and personalized approaches. The present study consists in a wide-ranging overview of the target therapies and related translational challenges in neuro-oncology. Methods: A review of the literature on PubMed/MEDLINE on recent advances concerning the target therapies for treatment of central nervous system malignancies was carried out. In the Medical Subject Headings, the terms “Target Therapy”, “Target drug” and “Tailored Therapy” were combined with the terms “High-grade gliomas”, “Malignant brain tumor” and “Glioblastoma”. Articles published in the last five years were further sorted, based on the best match and relevance. The ClinicalTrials.gov website was used as a source of the main trials, where the search terms were “Central Nervous System Tumor”, “Malignant Brain Tumor”, “Brain Cancer”, “Brain Neoplasms” and “High-grade gliomas”. Results: A total of 137 relevant articles and 79 trials were selected. Target therapies entailed inhibitors of tyrosine kinases, PI3K/AKT/mTOR pathway, farnesyl transferase enzymes, p53 and pRB proteins, isocitrate dehydrogenases, histone deacetylases, integrins and proteasome complexes. The clinical trials mostly involved combined approaches. They were phase I, II, I/II and III in 33%, 42%, 16%, and 9% of the cases, respectively. Conclusion: Tyrosine kinase and angiogenesis inhibitors, in combination with standard of care, have shown most evidence of the effectiveness in glioblastoma. Resistance remains an issue. A deeper understanding of the molecular pathways involved in gliomagenesis is the key aspect on which the translational research is focusing, in order to optimize the target therapies of newly diagnosed and recurrent brain gliomas. (www.actabiomedica.it)

Background: Gene therapy is the most attractive therapeutic approach against high-grade gliomas (HGGs). This is because of its theoretical capability to rework gene makeup in order to yield oncolytic effects. However, some factors still limit the upgrade of these therapies at a clinical level of evidence. We report an overview of glioblastoma gene therapies, mainly focused on the rationale, classification, advances and translational challenges. Methods: An extensive review of the online literature on gene therapy for HGGs was carried out. The PubMed/MEDLINE and ClinicalTrials.gov websites were the main sources. Articles in English published in the last five years were sorted according to the best match with the multiple relevant keywords chosen. A descriptive analysis of the clinical trials was also reported. Results: A total of 85 articles and 45 clinical trials were selected. The main types of gene therapies are the suicide gene, tumor suppressor gene, immunomodulatory gene and oncolytic therapies (virotherapies). The transfer of genetic material entails replication-deficient and replication-competent oncolytic viruses and nanoparticles, such as liposomes and cationic polymers, each of them having advantages and drawbacks. Forty-eight clinical trials were collected, mostly phase I/II. Conclusion: Gene therapies constitute a promising approach against HGGs. The selection of new and more effective target genes, the implementation of gene-delivery vectors capable of greater and safer spreading capacity, and the optimization of the administration routes constitute the main translational challenges of this approach. (www.actabiomedica.it)

Background and aim: After the first Italian case of Covid-19, the Government imposed the complete closure of all areas involved by the spread of the virus to contain transmissions. There was a massive reorganization of Hospitals, a stop of all elective activities and a convertion of many hospitals in “Covid Centers’’. AITOG (Associazione Italiana Traumatologia e Ortopedia Geriatrica) conducted a retrospective study on all proximal femur fractures surgeries that occurred in this period, to find out whether the pandemic and the correlated lockdown somehow changed the incidence of these events. Methods: 10 Italian orthopedic centers were involved in the study. Considering the geographic location, three groups were created (North, Centre and South). The considered period is the Italian “Phase 1” (February 23rd - May 3rd 2020). Results: the cohort is composed of 412 patients, 116 male and 296 female (mean age 81.1 ± 9.1 years). The same period of 2019 has been used as control group, with 558 patients, 156 male and 402 female (mean age 84.2 ± 8.0 years). In 2020 we counted 323 (78.4%) fractures occurred at home, 61 (14.8%) in retirement houses and 28 (6.8%) in different locations. We mainly treated fractures with intramedullary nails (n.237 57.5%). Among all patients we had 46 (11.1%) Covid-19 positive. The mortality rate within 30 days was of 51 patients (12.4%); 23 of these died because of complications related to Covid-19 while 31 of these were in treatment with anticoagulant/antiaggregant. Conclusions: AITOG analysis demonstrates a decrease in surgical interventions for proximal femur fractures from 2019 to 2020, a reduction in patients mean age and an increase in trauma occurred in domestic environment. We also registered a consistent difference between the North, Center and South of the Country. (www.actabiomedica.it)

Il mixoma juxta-articolare è un tumore benigno raro che si localizza preferenzialmente a livello delle grandi articolazioni. Presentiamo un caso di un ragazzo di 12 anni che si caratterizza per peculiarità relative a età di insorgenza, localizzazione, dimensione della massa e sintomatologia associata., Bollettino della Società Medico Chirurgica di Pavia, Vol 126, N° 2 (2013)

La reflex sympathetic dystrophy syndrome è una artropatia dolorosa associata a turbe trofiche locoregionali dei capi ossei e dei tessuti molli circostanti, la cui forma poliarticolare risulta particolarmente rara. L’artropatia interessa quasi esclusivamente gli arti inferiori con una prevalenza netta per le articolazioni coxo-femorali, potendo tuttavia interessare le articolazioni del ginocchio e della caviglia, mentre un solo caso di interessamento degli arti superiori è riportato in letteratura. Clinicamente la sindrome si presenta con dolore ed impotenza funzionale di vario grado associate ad alterazioni cutanee e del microcircolo. Le principali complicanze sono rappresentate dalle frequenti fratture. La aspecificità del quadro e la condizione di gravidanza limitano il ricorso alle indagini radiologiche. La RMN risulta l’indagine di scelta con un quadro patognomonico caratterizzato da edema midollare ed osteopenia. Il trattamento in gravidanza si avvale del riposo con arto in scarico, della terapia analgesica e della terapia fisica, demandando al post-partum la farmaco-terapia specifica. Noi riportiamo il caso di una primipara di 46 anni che nel corso del terzo trimestre di gravidanza ha presentato una forma di RSDS trattata con successo con magnetoterapia e fisiokinesiterapia e che nel post-partum ha avuto una riesacerbazione della sindrome., Bollettino della Società Medico Chirurgica di Pavia, Vol 125, N° 3 (2012)

Osteosarcoma is the most common of all primary malignancies of bone. In most cases it occurs in young pa-tients under 20 years of age. Almost 60% of cases involves proximal tibia or distal femur. A 6-years-old child received in July 2010 diagnosis of osteosarocma of proximal left tibia without primary metastases. She received neoadjuvant chemiotherapy followed in October 2010 by resection of the tumor, vascularised fibular autograft and adjuvant chemiotherapy. Now she’s free of disease and she can walk but there’s the need of longer surgical follow-up to verify long-term efficacy of this treatment., Bollettino della Società Medico Chirurgica di Pavia, Vol 124, N° 1 (2011)

La necrosi avascolare della testa femorale è una patologia che porta al collasso della testa del femore e quindi alla sostituzione protesica in pazienti giovani. Dal momento che una delle ragioni per cui dopo lo sviluppo della lesione necrotica i processi riparativi si rivelano insufficienti può essere il ridotto numero di cellule progenitrici a livello dell’epifisi prossimale del femore sono state proposte modalità di trattamento volte a stimolare e guidare il rimodellamento osseo al fine di conservare il più a lungo possibile l’integrità della testa femorale. Per questo motivo abbiamo studiato gli effetti su sintomatologia clinica, stadio di malattia e volume dell’osteonecrosi del trapianto di concentrato di cellule staminali mesenchimali autologhe e di concentrato piastrinico direttamente nel sito della lesione necrotica. Tra il 2005 e il 2010 sono stati trattati con questa metodica 12 pazienti (14 anche) affetti da necrosi avascolare della testa femorale in stadio precoce (un’anca in stadio I, dieci anche in stadio II, tre in stadio III) secondo la classificazione di Arlet e Ficat. Tutti i pazienti sono stati sottoposti a core decompression e trapianto di midollo autologo ottenuto dalla cresta iliaca omolaterae. Il volume dell’aspirato midollare è stato ridotto da 30-60 a 6-7 ml tramite centrifugazione al fine di conservare solo le cellule staminali mesenchimali in esso contenute. Al trapianto è stato aggiunto un concentrato piastrinico ottenuto con la stessa tecnica partendo da sangue periferico. Gli outcome valutati sono stati sintomatologia clinica e progressione della malattia. Il follow-up ha avuto una durata media di 2.6 anni (da un minimo di 1 a un massimo di 5 anni). La sostituzione protesica si è resa necessaria per 2 delle 14 anche operate (in cui la malattia è progredita verso il collasso), en-trambe in stadio III all’epoca dell’intervento. Nove anche con necrosi in stadio I o II hanno dimostrato risoluzione completa della sintomatologia clinica e assenza di progressione della malattia valutata tramite RMN pre e post operatorie. Le rimanenti 3 anche (2 pazienti), tutte in stadio II e III hanno dimostrato invece miglioramento della sintomatologia rispetto all’epoca precedente l’intervento ma riferiscono tuttora dolore e limitazione funzionale. In base alla nostra esperienza il trapianto di cellule staminali mesenchimali e fattori di crescita piastrinici in as-sociazione alla core decompression si è dimostrato efficace nel ridurre il dolore e la limitazione funzionale e nel prevenire o evitare la sostituzione protesica in pazienti selezionati. Per questo motivo riteniamo che possa rap-presentare una terapia di scelta per gli stadi I e II della necrosi avascolare della testa femorale., Bollettino della Società Medico Chirurgica di Pavia, Vol 123, N° 3 (2010)

Le fratture bimalleolari e trimalleolari sono le più frequenti fratture di interesse chirurgico. Questo studio retrospettivo è stato condotto su settantanove pazienti che hanno riportato una frattura di caviglia bimalleolare o trimalleolare. L’obbiettivo è quello di definire gli esiti di queste fratture dopo trattamento chirurgico e di individuare i fattori prognostici negativi e positivi. In particolare abbiamo valutato l’esito del trattamento chirurgico dopo un periodo di follow-up di almeno 12 mesi per mezzo dell’esame clinico e radiografico e in base al punteggio ottenuto nel Olerud-Molander Ankle Score (OMAS). Quindi abbiamo valutato anche come si differenziano gli esiti al variare di diversi fattori in base ai quali è stata stratificata la popolazione a abbiamo definito quali fattori possono essere considerati predittivi di un esito sfavorevole e quali invece predittivi di un esito favorevole. I dati ottenuti indicano che sessanta pazienti su settantanove (76%) trattati chirurgicamente hanno ottenuto risultati funzionali buoni o eccellenti (OMAS da 61 a 100). Solo diciannove (24%) hanno ottenuto risultati scadenti o pessimi (OMAS 60 anni, presenza di DM, appartenenza alla classe ASA2 o superiore, BMI>40 e fratture di tipo B e C secondo Danis-Weber., Bollettino della Società Medico Chirurgica di Pavia, Vol 122, N° 4 (2009)

La Sindrome di Marfan è una patologia del tessuto connettivo a penetranza completa, con trasmissione autosomica dominante. L’estrema variabilità fenotipica della patologia è nota; qui è stato dimostrato come possa addirittura presentarsi in soggetti geneticamente identici come i gemelli omozigoti. Il presente studio ha inoltre confermato l’età dipendenza della comparsa dei tratti fenotipici scheletrici, che spesso sono i primi a spingere il paziente ad un iniziale screening per la malattia. La nostra esperienza ha anche mostrato alcune lacune nei criteri diagnostici internazionali di Ghent, che possono mancare la diagnosi, soprattutto nei bambini e negli adolescenti. Questi dati denotano la necessità di uno stretto follow-up nei soggetti con sospetta MFS in età pediatrica e dello sviluppo di nuovi algoritmi diagnostici per la diagnosi precoce, fondamentale per permettere una corretta prevenzione e cura delle complicanze, soprattutto a livello cardiovascolare., Bollettino della Società Medico Chirurgica di Pavia, Vol 122, N° 4 (2009)

Objective. Herein, we present a case series of patients treated with megaprosthesis who sustained high energy trauma with comminuted articular hip or knee fracture, complex periprosthetic fractures or pathological fractures.Methods. We retrospectively reviewed 15 consecutive patients who sustained knee re- placement/revision (7 patients) and 8 patients who underwent hip replacement/revision with megaprosthesis between 2014 and 2018. In the knee group, there was 1 man and 6 women, while in the hip group there were 3 men and 5 women.In knee group, preoperative indications were: periprosthetic fracture; highly comminuted distal femoral fracture; metastatic localization of distal femur; nonunion of distal femoral fracture in one case.In the hip group, preoperative indications were: subtrochanteric pathological fractures; peri- prosthetic fracture; recurrent infection; recurrent tumoral lesions.Preoperative evaluation included standard radiographs; CT-scan with 3D reconstruction for tailored implant planning; MRI only for pathological localization.Results. Mean clinical follow-up with radiographic control was 44 months (range 23-71). All complications were managed before the patient left the hospital. During the follow-up period, 13 of 15 patients regained walking ability as before surgery. At the end of follow-up, 6 patients had died due to causes not related to the surgery.Conclusions. The use of megaprosthesis offers useful solutions for different pathologies such as tumors, infections, comminu ed fractures, and periprosthetic fractures in the elderly patient with good functional results.

An emerging issue for orthopedic surgeons is how to manage patients with active or previous COVID-19 disease, avoiding any major risks for the surgeons and the O.R. personnel. This monocentric prospective observational study aims to assess the prevalence of SARS-CoV-2 viral RT-PCR RNA in cancellous bone samples in patients with active or previous COVID-19 disease. We collected data about 30 consecutive patients from our institution from January 2021 to March 2021 with active or previous COVID-19 disease. The presence of SARS-CoV-2 in the samples was determined using two different PCR-based assays. Eighteen of the thirty patients included in the study had a positive nasopharyngeal swab at the time of surgery. Twelve patients had a negative nasopharyngeal swab with a mean days since negativization of 138 ± 104 days, ranging from 23 to 331 days. Mean days of positivity to the nasal swab were 17 ± 17. Twenty-nine out of thirty (96.7%) samples were negative for the presence of SARS-CoV-2 RNA. In one sample, low SARS-CoV-2 load (Cycle threshold (Ct) 36.6.) was detected but not confirmed using an additional confirmatory assay. The conducted study demonstrates the absence of the viral genome within the analyzed cancellous bone. We think that the use of personal protection equipment (PPE) to only protect from aerosol produced during surgery, both in active and recovered patients, is not strictly necessary. We think that the use of PPE should not be employed by surgeons and the O.R. personnel to protect themselves from aerosols produced from the respiratory tract. Moreover, we think that our results could represent a valid basis for further studies related to the possibility of bone donation in patients that suffered and recovered from COVID-19.

Background: the incidence of Achilles tendon (AT) rupture is rising; however, there is no clear consensus regarding the optimal treatment. The aim of this retrospective study was to compare instrumental and patient-reported outcome scores after fast functional rehabilitation (group A) versus plaster cast immobilization (group B) programs in patients who underwent AT tenorrhaphy. Methods: 33 patients, with similar clinical and demographic features, underwent open AT tenorrhaphy between January and July 2018. Of these, 15 patients were treated with fast functional rehabilitation program (group A), and 18 patients were treated with plaster cast immobilization protocol (group B). Sural triceps hypotrophy and functional scores (American Orthopaedic Foot and Ankle Society (AOFAS) Ankle–Hindfoot Score, and Achilles tendon Total Rupture Score (ATRS)) were recorded at a 12-month follow-up. Ultrasonography (US) and elastosonography (ES) were used to compare the characteristics of the tendons after surgery. Results: At 12 months, no significant differences in any of the patient-reported outcomes or the instrumental measurement tests were seen between the two groups. Conclusions: fast functional rehabilitation after AT surgical repair is safe, effective, and may be the first choice of treatment, especially in young, collaborative, and active patients.

Background Hip fracture is one of the most common orthopedic causes of hospital admission in frail elderly patients. Hip fracture fixation in this class of patients is considered a high-risk procedure. Preoperative physical examination, plasma natriuretic peptide levels (BNP, Pro-BNP), and cardiovascular scoring systems (ASA-PS, RCRI, NSQIP-MICA) have all been demonstrated to underestimate the risk of postoperative complications. We designed a prospective multicenter observational study to assess whether preoperative lung ultrasound examination can predict better postoperative events thanks to the additional information they provide in the form of “indirect” and “direct” cardiac and pulmonary lung ultrasound signs. Methods LUSHIP is an Italian multicenter prospective observational study. Patients will be recruited on a nation-wide scale in the 12 participating centers. Patients aged > 65 years undergoing spinal anesthesia for hip fracture fixation will be enrolled. A lung ultrasound score (LUS) will be generated based on the examination of six areas of each lung and ascribing to each area one of the four recognized aeration patterns—each of which is assigned a subscore of 0, 1, 2, or 3. Thus, the total score will have the potential to range from a minimum of 0 to a maximum of 36. The association between 30-day postoperative complications of cardiac and/or pulmonary origin and the overall mortality will be studied. Considering the fact that cardiac complications in patients undergoing hip surgery occur in approx. 30% of cases, to achieve 80% statistical power, we will need a sample size of 877 patients considering a relative risk of 1.5. Conclusions Lung ultrasound (LU), as a tool within the anesthesiologist’s armamentarium, is becoming increasingly widespread, and its use in the preoperative setting is also starting to become more common. Should the study demonstrate the ability of LU to predict postoperative cardiac and pulmonary complications in hip fracture patients, a randomized clinical trial will be designed with the scope of improving patient outcome. Trial registration ClinicalTrials.gov, NCT04074876. Registered on August 30, 2019.