A. Linari

Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1

PURPOSE We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). RESULTS From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. CONCLUSION IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.

Analysis of early infectious complications in pediatric patients undergoing bone marrow transplantation.

Abstract The purpose of the present study was to analyze the characteristics of infectious complications occurring during the first 100 days after bone marrow transplantation (BMT) in a cohort of 123 pediatric patients with hematological malignancies (n=73), solid tumors (n=32) and nonmalignant disorders (n=18). Fifty-eight patients received allogeneic grafts, and 65 patients an autologous transplant. Fever developed in 107 (87%) children; 82% of infectious complications occurred during the neutropenic period. Documented infection developed in 33 (31%) patients, while 74 (69%) patients had possible infection (i.e. fever of unknown origin). The incidence of bacteremia was 21%, and gram-positive cocci were the predominant pathogens; non-bacteremic microbiologically documented infection developed in 6% of patients; clinically evident infection developed in 4% of subjects. The incidence of primary febrile episodes was not significantly different between autologous and allogeneic BMT (86% vs 88%); nor did the median number of days to the onset of fever (5 days in both groups) or the median duration of fever (5 days in both groups) differ. In contrast, the frequency of secondary febrile episodes was significantly higher (P=0.0001) in allogeneic BMT recipients (40%) than in autologous recipients (15%). The mortality rate due to infections was 2/36 (5%) for matched sibling donor BMT, and 1/13 (8%) for matched unrelated donor BMT. No deaths occurred in the 65 patients who were autografted. Invasive fungal infections accounted for 2 of the 3 infectious deaths. In conclusion, the majority of children undergoing BMT experienced at least one infectious episode; allogeneic BMT recipients were at high risk of developing secondary febrile episodes, but the overall mortality rate due to infection in the first 100 days after transplantation was low.

ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells

Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT–PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker.

Accuracy of core-needle biopsy after contrast-enhanced ultrasound in soft-tissue tumours

ObjectivePercutaneous biopsies are gaining acceptance in the diagnosis of soft-tissue tumours. Sampling in the most representative area is not easy in sarcomas of huge dimension. We hypothesised that ultrasound (US) contrast medium could identify the representative area for focus core-needle biopsy (CNB)MethodsThis is a retrospective cohort series of 115 soft-tissue masses treated from January 2007 to November 2008. Accuracy of US-guided CNB after contrast-enhanced US (CEUS) was determined by comparing the histology of the biopsy with the definitive diagnosis in 105 surgically excised samples (42 benign, 63 malignant) and with the expected outcome in the remaining ten malignant cases not surgically treated. A myxoid component was present in 21 sarcomas (34.4%).ResultsOf samples, 94.8% were adequate for diagnosis with 97.1% sensitivity and 92.5% specificity. Sensitivity and specificity in specific histopathological subgroupings were 100%, and in grading definition they were 100% and 96.8%.DiscussionUS-guided CNB is safe and effective. US contrast medium depicts tumour vascular supply and identifies the representative area(s) for sampling. Sensitivity and specificity are also high in subgrouping and grading, including myxoid types. Discussion about biopsy is part of the essential multidisciplinary strategy for these tumours.

Perfusion pattern and time of vascularisation with CEUS increase accuracy in differentiating between benign and malignant tumours in 216 musculoskeletal soft tissue masses

INTRODUCTION Musculoskeletal Soft Tissue Tumours (STT) are frequent heterogeneous lesions. Guidelines consider a mass larger than 5 cm and deep with respect to the deep fascia potentially malignant. Contrast Enhanced Ultrasound (CEUS) can detect both vascularity and tumour neoangiogenesis. We hypothesised that perfusion patterns and vascularisation time could improve the accuracy of CEUS in discriminating malignant tumours from benign lesions. MATERIALS AND METHODS 216 STT were studied: 40% benign lesions, 60% malignant tumours, 56% in the lower limbs. Seven CEUS perfusion patterns and three types of vascularisation (arterial-venous uptake, absence of uptake) were applied. Accuracy was evaluated by comparing imaging with the histological diagnosis. Univariate and multivariate analysis, Chi-square test and t-test for independent variables were applied; significance was set at p<0.05 level, 95% computed CI. RESULTS CEUS pattern 6 (inhomogeneous perfusion), arterial uptake and location in the lower limb were associated with high risk of malignancy. CEUS pattern has PPV 77%, rapidity of vascularisation PPV 69%; location in the limbs is the most sensitive indicator, but NPV 52%, PPV 65%. The combination of CEUS-pattern and vascularisation has 74% PPV, 60% NPV, 70% sensitivity. No correlation with size and location in relation to the deep fascia was found. CONCLUSION US with CEUS qualitative analysis could be an accurate technique to identify potentially malignant STT, for which second line imaging and biopsy are indicated in Referral Centers. Intense inhomogeneous enhancement with avascular areas and rapid vascularisation time could be useful in discriminating benign from malignant SST, overall when the lower limbs are involved.

Study of neurinomas with ultrasound contrast media: review of a case series to identify characteristic imaging patterns

PurposeThe aim of this study was to evaluate whether there exists a characteristic distribution pattern of vessels within neurinomas that may be used to characterise this type of lesion by employing a contrast-specific ultrasound technique.Materials and methodsBetween January 2003 and May 2010, 66 suspected neurinomas were evaluated according to their sonographic features (solid fusiform mass with well-defined margins located in direct continuity with the nerve that was not always discernible and heterogeneous as a result of the presence of small cystic areas or calcifications). The lesions were examined using a sonographic contrast medium consisting of sulphur hexafluoride microbubbles and equipment with dedicated contrast-specific software [contrast tuned imaging (CnTI)]. Of these lesions, five were excluded from the analysis because the definitive diagnosis was not available (in two cases, the follow-up was still in progress, whereas in the remaining three, there was no follow-up). Our study, therefore, is based on 61 surgically excised lesions that were confirmed to be neurinomas by histology, which is regarded as the gold standard.ResultsIn 41/61 cases (67.2%), we identified an enhancement pattern that we termed reticular owing to the interweaving of blood vessels, of which two subtypes were identified depending on whether the interwoven vessels were densely or sparsely packed: loose-knit reticular in 18/41, and tight-knit reticular in 23/41. In 20/61 (32.8%) cases, we observed a vascular pattern of diffuse heterogeneous enhancement, which was divided into two subtypes based on the presence of one (7/20) or more (13/20) avascular areas.ConclusionsResults showed that all neurinomas studied could be divided into two groups according to the type of enhancement pattern observed: reticular or diffuse heterogeneous.RiassuntoObiettivoScopo dello studio è valutare, mediante l’impiego di una tecnica ecografica contrasto-specifica, se esiste una distribuzione caratteristica dei vasi all’interno dei neurinomi che possa essere usata per una caratterizzazione del tipo di lesione.Materiali e metodiNel periodo compreso tra gennaio 2003 e maggio 2010 sono state valutate nel nostro dipartimento 66 lesioni sospette per neurinoma in base alle loro caratteristiche ecografiche (formazioni solide, fusiformi, a margini netti, in diretta continuità con la fibra nervosa, non sempre riconoscibile, disomogenee per l’eventuale presenza di piccole aree similcistiche o calcificazioni), ed esaminate con mezzo di contrasto (MdC) ecografico, costituito da microbolle a base di esafluoruro di zolfo e apparecchiatura dotata di software dedicato Contrast Tuned Imaging (CnTI) contrasto specifico. Di queste lesioni, 5 sono state escluse dall’analisi in quanto non era disponibile una diagnosi definitiva (n=2 follow-up in corso; n=3 assenza di follow-up). Pertanto il nostro studio si basa unicamente sulle 61 lesioni asportate chirurgicamente e confermate come neurinomi all’esame istologico, considerato come gold standard.RisultatiIn 41/61 (67,2%) casi abbiamo identificato una distribuzione del mezzo di contrasto definita “a reticolo” in base all’intreccio formato dalle strutture vascolari, in cui si riconoscono due sottotipi: “reticolo a maglie larghe” in 18/41 e “reticolo a maglie strette” in 23/41, distinti in base all’aspetto dell’incrocio dei vasi, se più rado o più fitto. In 20/61 (32,8%) casi abbiamo osservato un diverso pattern di vascolarizzazione, denominato “impregnazione diffusa disomogenea”, a sua volta suddiviso in due sottotipi in base alla presenza di una (7/20) o più aree avascolari (13/20).ConclusioniI risultati ottenuti in questo studio hanno dimostrato che tutti i neurinomi analizzati possono essere distinti in due gruppi, in base al tipo di pattern vascolare riscontrato: di tipo reticolare o ad impregnazione diffusa disomogenea.