The Musculoskeletal Tumor Society Scoring system is a valid subjective and objective tool to evaluate outcomes of surgical treatment of patients affected by upper and lower extremity tumors.

PURPOSE: The main purpose of the present study was to evaluate if there is a difference between objective or subjective administration of the MSTS score in a cohort of patients affected by musculoskeletal oncological diseases. MATERIALS AND METHODS: All patients who underwent surgery for bone or soft tissue localization of neoplastic disease in lower or upper limb from June 2015 to June 2020 were considered eligible. In order to administer the score as a PROM, the MSTS was first translated and cross-culturally adapted in Italian. During follow up visits, all patients filled out Italian versions of SF36, TESS and MSTS. Psychometric properties of the Italian version of MSTS were analyzed. Correlation between objective and self-administered MSTS score was assessed through Pearson's coefficient. RESULTS: A finale sample of 110 patients were included: 59 affected by lower extremity involvement and 51 affected by upper extremity involvement. The Italian version of the MSTS score showed good psychometric properties for both lower and upper extremity. The correlation between self-administered and hetero-administered version of the questionnaire was as high as r = 0.97 for lower extremities and r = 0.96 for upper extremities. CONCLUSIONS: The Italian version of the MSTS is a valid tool to evaluate outcomes of surgical treatment of patients affected by extremities tumors and it can be used as a subjective tool for both lower and upper extremity.

Cross-cultural adaptation and validation of the Italian version of the Western Ontario Rotator Cuff (WORC) index.

The aim of the study was to accomplish translation, cross-cultural adaptation and validation of the Western Ontario Rotator Cuff (WORC) Index questionnaire for its use in Italy. The WORC original version was translated and cross-culturally adapted into Italian. Subsequently, it was administered to a population of 60 patients suffering from rotator cuff disease to evaluate the validity and reliability of the Italian version. The content validity evaluated the correlation between questions and total score of each domain through Pearson's correlation coefficient. The construct validity was similarly assessed through Pearson's correlation coefficient by testing the correlation between the Italian WORC and the Italian version of the Disability of the Arm, Shoulder and Hand (DASH) questionnaire. Reliability was assessed using two methods: internal consistency by calculating the Cronbach's alpha coefficient for each domain; and test-retest by means of the intraclass correlation coefficient (ICC). The translation and cross-cultural adaptation of the Italian version did not reveal any major problems. No significant floor or ceiling effects were found. All the questions were linearly related to the concept expressed by the domain of belonging. Overall correlation with the DASH score was 0.75. Internal consistency was very high overall (α = 0.93) as well as reliability (overall ICC = 0.87). The Italian version of the WORC questionnaire is a valid and reproducible measuring instrument and can be considered a valid tool for the evaluation of the effectiveness of a treatment in terms of quality of life, in Italian patients affected by rotator cuff diseases.Level of evidence Diagnostic study, level II.

Magnetic resonance arthrography accuracy in the detection of labral tears in young patients with chronic unstable shoulder: correlation with arthroscopy.

The aim of this study is to determine the diagnostic performance of Magnetic Resonance Arthrography (MRA) in evaluating lesions of the glenoid labrum, in young active patients with chronic unstable shoulder, compared to shoulder arthroscopy. We retrospectively considered 65 MRA examinations, performed between December 2011 and January 2018. Among them, thirty-five patients (31 men, 4 women; mean age, 27.3 years; range, 16-53 years; 4 patients with a previous arthroscopy of the same shoulder) underwent shoulder arthroscopy after MRA. Arthroscopic reports were collected and analyzed for the correlation with MRA results.

"No pain, No gain" still true with immunotherapy: When the finger shows the moon, look at the moon!

There is a rising evidence that the proverbial statement "No pain, No gain" first coined at the light of pioneering clinical experiences with canonical chemotherapy still holds true in the era of modern treatments of cancer. This close relationship between the occurrence of specific drug-related toxicity and treatment outcome has been confirmed since then with a large variety of treatments, ranging from cytotoxics, hormonotherapy, targeted therapy and much interestingly even with the latest immune checkpoint inhibitors. In the current context of precision medicine, and along with the constant quest for identifying predictive biomarkers, close monitoring of treatment-related toxicities could therefore be convenient to help predicting therapeutic response, but presents several caveats. The purpose of this review is to briefly describe these relationships across the different treatments, to comment on possible underlying mechanisms and to comment on possible strategies aiming at exploiting this relationship while keeping the maximal safety ensured in patients with cancer. In particular, this review will investigate on how drug exposure along with germinal and somatic genetic issues does impact on the "No Pain, No Gain" aphorism, and why the temptation to use treatment-related toxicities as a cheap and convenient way to predict clinical outcome or to adapt dosing should be resisted. We do advocate instead for developing comprehensive genomic support along with extensive biomathematical modeling to better customize dosing and shift towards a new "No Pain, Maximal Gain" paradigm.

Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer.

INTRODUCTION: Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT. METHODS: 122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C>T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T>G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity. RESULTS: All 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side-effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis. CONCLUSION: Relevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases.

Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies: a systematic review and meta-analysis.

Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.

[Safety and efficacy of kyphoplasty in the treatment of tumoral disease of the spine]. / Seguridad y eficacia de la cifoplastia en el tratamiento de la enfermedad tumoral de la columna vertebral.

UNLABELLED: Vertebral fractures in oncology patients cause significant pain and disability, with decreased quality of life. The aim of the study is to assess the efficacy and safety of kyphoplasty in this type of vertebral fracture in the acute phase. MATERIALS AND METHODS: A retrospective study was conducted on 75 consecutive oncology patients with 122 acute vertebral fractures, who underwent bilateral balloon kyphoplasty, with a mean follow up of 11 months. RESULTS: Almost all (91%) of the patients improved their pain level. The mean improvement in the Visual Analogue Scale (VAS) was 4.28 points (preoperative value 7.49 [SD 1.19], postoperative 3.21 [SD 0.95]). Before surgery, 53% of patients needed major opioids (40 cases), and one month after surgery only 12% (9 patients) required them. Quality of life determined by the Karnofsky index improved from 60.2 (SD 10) to 80.7 (SD 12.1). Cement leaks were found in 5.7% (7 cases), all without neurological repercussions. New fractures appeared in 11 patients. This subgroup showed a slight worsening of the initially acquired clinical improvement. No neurological or pulmonary complications related to surgical technique were found. CONCLUSIONS: Kyphoplasty is an effective and safe for treating vertebral fractures in patients with cancer. LEVEL OF EVIDENCE: Level IV.

Frequent intragenic rearrangements of DPYD in colorectal tumours.

Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because of the presence of an intragenic fragile site FRA1E. We evaluated DPYD copy number variations (CNVs) in a prospective series of 242 stage I-III colorectal tumours (including 87 patients receiving 5FU-based treatment). CNVs in one or more exons of DPYD were detected in 27% of tumours (deletions or amplifications of one or more DPYD exons observed in 17% and 10% of cases, respectively). A significant relationship was observed between the DPYD intragenic rearrangement status and dihydropyrimidine dehydrogenase (DPD) mRNA levels (both at the tumour level). The presence of somatic DPYD aberrations was not associated with known prognostic or predictive biomarkers, except for LOH of chromosome 8p. No association was observed between DPYD aberrations and patient survival, suggesting that assessment of somatic DPYD intragenic rearrangement status is not a powerful biomarker to predict the outcome of 5FU-based chemotherapy in patients with colorectal cancer.

[Review and expert opinion in age related macular degeneration. Focus on the pathophysiology, angiogenesis and pharmacological and clinical data]. / Expertises croisées dans la dégénérescence maculaire liée à l'âge. Focus sur la physiopathologie, l'angiogenèse, les données pharmacologiques et cliniques.

Age related macular degeneration (AMD) is a pathological aging of the macula, brought about by the interaction of genetic and environmental factors. It induces geographic atrophy of the retina and/or choroidal neovascularization. In the latter, abnormal vessels develop from the choriocapillaris, with the involvement of VEGF (vascular endothelial growth factor). The VEGF family includes several factors, including VEGF-A, B, C, D, F and PlGF (placental growth factor). Their biological properties and their affinities to the VEGFR1, VEGFR2 and VEGFR3 receptors found on endothelial cells differ. Exudative AMD involves mainly VEGF-A and VEGF-R2. Anti-VEGF agents used in ophthalmology (ranibizumab, bevacizumab and aflibercept) are designed to primarily target this pathway. In vitro, all have sufficient affinity to their ligands. Their therapeutic efficacy must therefore be judged based on clinical criteria. In clinical practice, the minimum number of injections required for a satisfactory result appears to be comparable with all the three. The few available studies on therapeutic substitutions of anti-VEGF compounds suggest that some patients may benefit from substituting the anti-VEGF in cases of an unsatisfactory response to an initial molecule. Although local side effects, including increased risk of geographic atrophy, and systemic effects, including vascular accidents, have been suggested, these risks remain low, specially compared to the benefits of the treatment. Differences in safety between anti-VEGF are theoretically possible but unproven.

[Combination of stereotactic irradiation and chemotherapy or targeted therapies: state of the art and preliminary recommendations]. / Association d'une chimiothérapie ou d'un traitement ciblé à une irradiation stéréotaxique: état des lieux et recommandations préliminaires.

The clinical management of systemic treatments and irradiation has long been studied for conventional irradiation. Yet, many associations are of difficult management and some drugs are contra-indicated in the concomitant setting owing to excessive toxicities. Sequential regimens using a therapeutic window of variable duration (based on drug half-life and tissue wash out) between each modality may be preferred for easier logistics and to avoid toxicities. The use of intra- and extracranial stereotactic ablative radiation therapy (hypofractionated) is expanding rapidly. Yet, little is known regarding associations between stereotactic ablative radiation therapy and systemic treatments. The short stereotactic ablative radiation therapy course in one day to two weeks offers a theoretical advantage compared to longer conventional irradiation with respect to shorter discontinuation of therapy. This may be of particular interest in situations where cancer is addicted to systemic treatment. While it is believed that stereotactic ablative radiation therapy might be safer because of limited irradiation volumes and steep gradients sparing most organs at risk, it should be noted that irradiation of normal tissues cannot be considered null; that stereotactic ablative radiation therapy has vascular effects in addition to other cell death radiation-induced mechanisms and cancer progression with discontinuation of systemic treatment is often reversible. To date, based on several phase II studies, combined stereotactic ablative radiation therapy and cetuximab can be recommended in head and neck tumours. Other stereotactic ablative radiation therapy-based combinations require prospective phase I-II studies and sufficient therapeutic window (in the order of at least 5 half-lives) between the systemic and local modalities must be left in routine practice.

Bone substitutes in orthopaedic surgery: from basic science to clinical practice.

Bone substitutes are being increasingly used in surgery as over two millions bone grafting procedures are performed worldwide per year. Autografts still represent the gold standard for bone substitution, though the morbidity and the inherent limited availability are the main limitations. Allografts, i.e. banked bone, are osteoconductive and weakly osteoinductive, though there are still concerns about the residual infective risks, costs and donor availability issues. As an alternative, xenograft substitutes are cheap, but their use provided contrasting results, so far. Ceramic-based synthetic bone substitutes are alternatively based on hydroxyapatite (HA) and tricalcium phosphates, and are widely used in the clinical practice. Indeed, despite being completely resorbable and weaker than cortical bone, they have exhaustively proved to be effective. Biomimetic HAs are the evolution of traditional HA and contains ions (carbonates, Si, Sr, Fl, Mg) that mimic natural HA (biomimetic HA). Injectable cements represent another evolution, enabling mininvasive techniques. Bone morphogenetic proteins (namely BMP2 and 7) are the only bone inducing growth factors approved for human use in spine surgery and for the treatment of tibial nonunion. Demineralized bone matrix and platelet rich plasma did not prove to be effective and their use as bone substitutes remains controversial. Experimental cell-based approaches are considered the best suitable emerging strategies in several regenerative medicine application, including bone regeneration. In some cases, cells have been used as bioactive vehicles delivering osteoinductive genes locally to achieve bone regeneration. In particular, mesenchymal stem cells have been widely exploited for this purpose, being multipotent cells capable of efficient osteogenic potential. Here we intend to review and update the alternative available techniques used for bone fusion, along with some hints on the advancements achieved through the experimental research in this field.

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Detection of circulating tumor cells from lung cancer patients in the era of targeted therapy: promises, drawbacks and pitfalls.

Interest in biomarkers in the field of thoracic oncology is focused on the search for new robust tests for diagnosis (in particular for screening), prognosis and theragnosis. These biomarkers can be detected in tissues and/or cells, but also in biological fluids, mainly the blood. In this context, there is growing interest in the detection of circulating tumor cells (CTCs) in the blood of lung cancer patients since CTC identification, enumeration and characterization may have a direct impact on diagnosis, prognosis and theragnosis in the daily clinical practice. Many direct and indirect methods have been developed to detect and characterize CTCs in lung cancer patients. However, these different approaches still hold limitations and many of them have demonstrated unequal sensitivity and specificity. Indeed, these methods hold advantages but also certain disadvantages. Therefore, despite the promises, it is currently difficult and premature to apply this methodology to the routine care of lung cancer patients. This situation is the consequence of the analysis of the methodological approaches for the detection and characterization of CTCs and of the results published to date. Finally, the advent of targeted cancer therapies in thoracic oncology has stimulated considerable interest in non-invasive detection of genomic alterations in tumors over time through the analysis of CTCs, an approach that may help clinicians to optimize therapeutic strategies for lung cancer patients. We describe here the main methods for CTC detection, the advantages and limitations of these different approaches and the potential usefulness and value of CTC characterization in the field of thoracic oncology.