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Uterine leiomyosarcoma (U-LMS) is the most common histotype among all primary uterine sarcomas. The lung, peritoneum, pelvic or para-aortic lymph nodes, bone and liver are the most common metastatic sites involved. However, some case series of atypical sites of metastasis such as heart, brain and different endocrine glands have been described. Here we report the clinical presentation and therapeutic management of two patients affected by U-LMS with a very atypical behavior, characterized by soft tissue metastases with an impressive and massive enlargement during chemotherapy despite a good control of the other sites of disease.

BACKGROUND: Fungal infections are still a relevant challenge for clinicians involved in the cure of patients with cancer. We retrospectively reviewed charts of hospitalized patients with hematological malignancies (HMs), in which a documented fungemia was diagnosed between January 2011 and December 2015 at 28 adult and 6 pediatric Italian Hematology Departments. METHODS: During the study period we recorded 215 fungal blood stream infections (BSI). Microbiological analyses documented that BSI was due to molds in 17 patients (8%) and yeasts in 198 patients (92%), being Candida spp identified in 174 patients (81%). RESULTS: Mortality rates were 70% and 39% for mold and yeast infections, respectively. Infection was the main cause of death in 53% of the mold and 18% of the yeast groups. At the multivariate analysis, ECOG ≥2 and septic shock were significantly associated with increased mortality, and removal of CVC survival was found to be protective. When considering patients with candidemia only, ECOG >2 and removal of CVC were statistically associated with overall mortality. CONCLUSIONS: Although candidemia represents a group of BSI with a good prognosis, its risk factors largely overlap with those identified for all fungemias, even though the candidemia-related mortality is lower when compared to other fungal BSI. Management of fungal BSI is still a complex issue, in which both patients and disease characteristics should be focused to address a personalized approach. This article is protected by copyright. All rights reserved.

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient's risk category and improve targeted prophylactic strategies. (Clinicaltrial.gov: NCT01315925)

Background: High-grade bone osteosarcoma has a high relapse rate. The best treatment of local recurrence (LR) is under discussion. The aim of this study is to analyze LR patterns and factors prognostic for survival. Methods: LR diagnostic modality (clinical or imaging), pattern of recurrence, and post-LR survival (PLRS) were assessed. Results: Sixty-two patients were identified, with median age 21 years (range, 9–75 years), including 11 (18%) ≤15 years, 30 (48%) from 16 to 29 years; 21 (34%) were older. Patterns of relapse were LR only 58%, LR + distant metastases (DM) 42%. Seventy-nine percent of patients relapsed within 24 months, and diagnosis was clinical in 88%. LR treatment was surgery 85%, chemotherapy 55%, chemotherapy + surgery 45%. Surgical complete remission after LR (CR2) was achieved in 60% (LR 86%; LR + DM 23%). With a median follow-up of 43 months (range, 5–235 months), the five-year PLRS was 37%, significantly better for patients with longer LR-free interval (LRFI; ≤24 months 31% vs>24 months 61.5%, P=0.03), absence of DM (no DM 56%vs DM 11.5%, P=0.0001), and achievement of CR2 (no CR2 0%vs CR2 58.5%, P=0.0001). No difference was found according to age and chemotherapy (LR only: five-year PLRS: 53% without chemotherapy vs 58% with chemotherapy, P=0.9; LR + DM: five-year PLRS: 25% without chemotherapy vs 9% with chemotherapy, P=0.7). Conclusions: Early relapse is detected by symptoms in 90% of cases and associated with worse outcome. The achievement of CR2, not age, is crucial for survival. For patients with LR only, better survival was demonstrated, as compared with DM, and no improvement with chemotherapy after surgery was found.

Background: The aim of this retrospective study is to analyze history and treatment outcomes of pathological fracture (PF) in dedifferentiated chondrosarcoma (DdChS) of the limbs. Methods: We retrospectively reviewed 175 adult patients with primary DdChS of the limbs.Disease-specific survival (OS) and local recurrence (LR) were analyzed. Results: Median age was 66 years (range, 29–91). Most DdChS (121, 69.1%) were localized in the femur. Forty-nine (28.0%) had metastasis at diagnosis; thirty-nine DdChS (22.3%) had a PF.OS rate was lower in patients with metastasis at diagnosis (8.6% Vs 41.0% at 10 years, p < 0.001). A similar OS was observed among patients with localized disease, whether with/without PF (p = 0.638), with/without chemotherapy (p = 0.543) and independently from the type of surgery (resection/amputation) (p = 0.877). Amputation reduces the risk of LR (80.0% vs 63.1% at 5 years, p = 0.039), particularly in the PF group. Conclusion: Patients with metastases have a particularly poor prognosis in DdChS, but pathological fracture does not influence prognosis in terms of survival and local control. Initial curative resection is essential in order to reduce the chance of recurrences. Amputation might be an option in patients with localized disease and a PF to reduce the risk of LR..

To determine the efficacy and safety of a single injection with autologous bone marrow concentrate (BMC) combined with demineralized bone matrix (DBM) and platelet-rich fibrin (PRF) compared to curettage and bone grafting for treating aneurysmal bone cysts (ABC). Two hundred thirty-nine patients were treated with curettage and bone grafting (Curettage Group), and 21 with percutaneous injection of DBM associated with autologous BMC and PRF (DBM + BMC + PRF Group). All patients attended the outpatient clinic to assess ABC healing and clinical results at the first 3, 6, 9 and 18 months after surgery and then annually in the absence of symptoms. The mean follow-up was 42 months for the Curettage Group (range 6-180 months) and 28 months for the DBM + BMC + PRF Group (range, 6-85 months). Out of the 21 patients who had injection with BMC, DBM, and PRF, 17 (80%) require no additional treatment and they were considered healed. Of the 239 patients treated with curettage and bone grafting after core needle or open biopsy, 177 (74%) were considered healed after the first treatment. Injection in comparison with curettage presented the same risk for local recurrence. The overall rate of local recurrence for all patients was 25%. Univariate and multivariate analyses showed a significant difference in local recurrence rates in patients younger than 15 years, and for the cyst located in the long bones of the lower limbs than the cyst located in the long bones of the upper limbs.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p

(1) Background: Restoration of ankle biomechanics after distal fibula (DF) resection in bone sarcomas can be performed with different techniques. We report the functional and oncological outcomes of a case series, (2) Methods: Ten patients (5 females and 5 males) with a mean age of 27 years (range 10–71) were retrospectively evaluated. Following the resection, different techniques were used to reconstruct the ankle: tibiotalar arthrodesis, residual lateral malleolus fixed to the tibia, non-vascularized or rotational vascularized fibula transposition and intercalary allograft. All complications were recorded, and the functional outcomes were evaluated, (3) Results: The mean follow-up time was 54 months (range, 13–116). Six patients were free of disease while four patients died of disease. All patients had a stable ankle and bone union, which was achieved after a mean of 9.4 months (range 3–20). The mean MSTS Score was 26.7 (range 21–30). Chronic ankle pain and peroneal external nerve palsy were observed. Patients underwent additional surgeries for deep infection and for equinus ankle deformity. No local recurrence was observed. Metastasis occurred in four patients after a mean of 14.7 months (range 2–34), (4) Conclusions: After DF resection, the restoration of ankle biomechanics gives acceptable functional results, but a larger series of patients with long-time follow-up are required to confirm the durability of the reconstruction.

Simple Summary Many classifications to assess margins status for soft tissue sarcomas are reported in the literature. Most of the series are heterogeneous and variable in size, making it difficult to compare results from study to study. Thus, which is the best way to assess margins in order to predict the risk of local recurrence is still debated. The aim of this narrative review is to provide a comprehensive assessment of the literature on margins, and to highlight the need for a uniform description of the margin status for patients with soft tissue sarcomas (STS). Abstract Adequacy of margins must take into consideration both the resection margin width (quantity) and anatomic barrier (quality). There are several classification schemes for reporting surgical resection margin status for soft tissue sarcomas (STS). Most of the studies regarding treatment outcomes in STS included all histologic grades and histological subtypes, which include infiltrative and non-infiltrative subtypes and are very heterogeneous in terms of both histologic characteristics and treatment modalities (adjuvant treatments or not). This lack of consistency makes it difficult to compare results from study to study. Therefore, there is a great need for evidence-based standardization concerning the width of resection margins. The aim of this narrative review is to provide a comprehensive assessment of the literature on margins, and to highlight the need for a uniform description of the margin status for patients with STS. Patient cases should be discussed at multidisciplinary tumor boards and treatments should be individualized to clinical and demographic characteristics, which must include also a deep knowledge of specific histotypes behaviors, particularly infiltrative ones.

Opinion statement New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. In particular, the advancement of research on epigenomics and gene regulation is promising. The concrete hypothesis that the pathogenesis of SS might mainly depend on the disruption of the balance of the complex interaction between epigenomic regulatory complexes and the consequences on gene expression opens interesting new perspectives. The standard of care for primary SS is wide surgical resection combined with radiation in selected cases. The role of chemotherapy is still under refinement and can be considered in patients at high risk of metastasis or in those with advanced disease. Cytotoxic chemotherapy (anthracyclines, ifosfamide, trabectedin, and pazopanib) is the treatment of choice, despite several possible side effects. Many possible drug-able targets have been identified. However, the impact of these strategies in improving SS outcome is still limited, thus making current and future research strongly needed to improve the survival of patients with SS.

Tumor-like lesions of the upper limb are more frequent than malignant neoplastic lesions and they represent a wide and heterogeneous group of disorders. The combination of clinical evaluation and imaging is the first pivotal step to attempt a distinction between benign and malignant masses, since there are important implications for further management, such as the requirement for conservative or interventional treatment. The classification of these pseudo tumoral lumps remains arbitrary and is still a matter of debate, currently based on a conjunct clinico-radiologic approach. In this article, we review various types of tumor-like lesions of the upper limb in terms of imaging approach and related clinic features, proponing a descriptive classification, useful in clinical practice to recognize these disorders, and to avoid unnecessary or potentially harmful procedures.

Background: The necessity to reconstruct the pelvic ring after an iliac or iliosacral resection is still debated. Different reconstructive techniques are available, including autologous and homologous graft and custom-made prosthesis. The aim of this study was to evaluate the functional outcome and complications of patients who underwent resection of iliac bone and part of the sacrum for primary bone tumour and reconstruction with an allograft or autograft. Methods: We retrospectively evaluated 18 patients (10 males and 8 female) with a mean age of 28years (range 9–56) who were operated between 1992 and 2015. Six patients were reconstructed with an autograft (Group A) and 12 patients with an allograft (Group B). All complications were recorded. At final follow-up, patients with the original reconstruction still in site were functionally evaluated with MSTS Score. Results: Mean follow-up time was 107months (range 4–221). Two patients (11.1%) had an external hemipelvectomy for local recurrence, and 3 patients died of the disease. Mean MSTS Score was comparable between the two groups 21.7 (range 20–25) in Group A and 19.9 (range 4–28) in Group B. Patients with partial sacral resection had an increased risk of local recurrence and lower MSTS Score [15.5 (range 7–20) vs. 22.2 (range 4–28)]. Conclusions: Biological reconstruction of pelvic ring with autologous or homologous bone graft gives acceptable functional results. However, the decision on how to reconstruct the pelvic ring after iliac resection should be taken on a patient-by-patient basis.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Background Prostheses can be used in elbow reconstruction in both primary and metastatic lesions. Several authors have reported their experience with different types of implant, but not with modular prostheses. Hypothesis Limb salvage using an elbow prosthesis is effective in obtaining good functional results and reliable local tumor control. Material and methods Forty-seven patients treated at the Rizzoli Institute for elbow neoplasm from 1990 to 2012 were evaluated. There were 30 primary tumors (64%), 24 bone tumors and 6 soft tissue sarcomas, and 17 bone metastases. Elbow reconstruction used a modular prosthesis in 25 patients and a standard prosthesis in 22. Reconstruction was primary in 30 patients and secondary in 17. Results At last control, 15 (32%) were dead of disease (DOD) at a mean follow-up of 35 months, 12 (25%) were alive with disease (AWD) at a mean follow-up of 29 months, 19 (40%) showed no evidence of disease (NED) at a mean follow-up of 80 months. Early complications were related to unexpected neurological damage, observed in 12 patients (25%): in 5 cases the deficit resolved in a mean 6 months; in the others, no or only partial recovery was observed. Two implants (4%) developed infection: 1 was treated with antibiotic therapy, and the other required implant revision. One implant showing cement extrusion was revised. In 3 patients (6%) radiography showed a radiolucent halo around the stem (2 humeral, 1 ulnar); no measures were taken, as the patients were completely asymptomatic at every follow-up. In 3 patients (6%) partial resorption of the allograft was observed on X-ray, but remained unchanged at last follow-up, without pain or functional impairment. Seven local recurrences (15%) were observed, at a mean of 16 months after surgery; 5 were treated by resection and/or radiotherapy, and 2 by amputation. Mean functional scores on MEPS and MSTS were respectively 84% and 22/30 (73%). Conclusions Elbow prostheses provided better function in primary than in metastatic tumor. Elbow prosthesis reconstruction after tumor resection is a viable option both for primary and secondary bone neoplasms. Type of study Therapeutic. Level of evidence IV, retrospective study.

Background: Many papers have reported the results achieved with combined therapy for Ewing's tumors, but little is known about the treatment and outcome of those 30-40% of patients who relapse. Patients and methods: In a retrospective study, we evaluated 195 patients with Ewing's tumors treated at our institution from 1979 to 1997 with chemotherapy, radiotherapy, surgery or combined therapies after recurrence. Results: A second complete remission was achieved in only 26 patients (13.3%); 12 relapsed again and died of the tumor. The 5-year post-relapse event-free survival and overall survival were 9.7% and 13.8%, respectively; both of which were significantly better for patients who had relapsed ≥2 years after the beginning of the first treatment (14.3% versus 2.5%; P

Introduction. The management of pelvic tumors is a challenge for orthopaedic oncologists due to the complex anatomy of the pelvis and the need to have extensive exposure. Various reconstructive techniques have been proposed with poor functional results and a high percentage of complications. Our purpose is to determine the functional results and the rate of complications of iliac stem prosthesis for acetabular defects following resections for periacetabular tumors.Materials and Methods. Between 1999 and 2012, 45 patients underwent pelvic resections for periacetabular bone tumors followed by reconstruction with stem cup prosthesis. The most common diagnosis was CS (chondrosarcoma, 29 cases), followed by OS (osteosarcoma, 9 cases) and metastasis (3 cases). In 33 cases, this implant was associated with massive bone allografts. Minimum follow-up required to evaluate functional outcome was 2 years. We classified pelvic resections according to Enneking and Dunham’s classification and we used MSTS (musculoskeletal tumor system) score to evaluate functional outcomes.Results and Discussion. Sixteen patients died of their disease, three were lost to follow-up, four are alive with disease, and twenty-two are alive with no evidence of disease. Fifteen patients had local recurrence. Sixteen patients had bone or lung metastasis. We have had 6 infections, 2 aseptic loosening, and 2 cases of hip dislocation. Iliac sovracetabular osteotomy was fused in all cases at 10 months from surgery. Functional results were good or excellent in 25 of 31 patients with long-term follow-up (77%), with a percentage similar to that reported in the literature.Conclusion. The use of iliac stem prosthesis is a simple reconstructive technique that reduces operative times and risk of infection. It allows having good results and low rate of complications, but it should be performed in selected cases and centres of reference.

En bloc or extralesional resection means resection of the tumor in one piece together with a layer of healthy tissue: the margin is either marginal or wide. The prerequisite for an en bloc or extralesional spondylectomy is a tumor involvement of no more than one side of the posterior structures, so that a corridor can be created through which the spinal cord is released. This article presents a two-stage, combined anterior and posterolateral, three-level en bloc spondylectomy, and local flap wound coverage for a patient with a recurrent post-radiation sarcoma of the lumbar spine and infected wound after intralesional treatment. The patient had radiation therapy for an L4 Hodgkin’s lymphoma 5 years before the development of the post-radiation sarcoma. Two-stage, three-level en bloc spondylectomy was done through a combined anterior and posterolateral approach. The resection margins were microscopically negative. Dural tear occurred intraoperatively because of tightly adherent dense scar tissue. Two years after spondylectomy, there was no evidence of tumor or infection recurrence; however, the patient died from her lymphoma. In surgically difficult spinal resections, we recommend the two-stage, combined anterior and posterolateral approach for en bloc spondylectomy. The staged procedure may provide for reduced perioperative complications and mortality, and meticulous dissection in the irradiated area, especially if infected. The combined approach provides for easier and safer dissection of the tumor and the spine from the anterior elements under direct visual control, and wide tumor resection.

Background: The purpose of this study is to present data on the effects of pre-hospital electrocardiogram (PH-ECG) on the outcome of ST elevation myocardial infarction (STEMI) patients treated with percutaneous coronary angioplasty (PCI) included in a registry undertaken in the Italian region of Lombardy. Pre-hospital 12-lead electrocardiogram is recommended by current guidelines in order to achieve faster times to reperfusion in patients with STEMI. Methods: The registry includes 3901 STEMI patients who underwent primary PCI over an 18-month period. Results: Mean age was 63 ± 12 years. Admission through the emergency medical system (EMS) occurred in 1603 patients (40%): they were older, more frequently had previous MI, TIMI flow = 0 at entry and were more frequently in Killip class >1 than patients who were not admitted through the EMS. Among the patients admitted through the EMS, PH-ECG was obtained in 475 patients (12%). These patients had less frequently an anterior MI, but more frequently had absence of TIMI flow at entry than patients whose ECG was not teletransmitted. Moreover, they had a significantly shorter first medical contact-to-balloon time and a trend toward a lower 30-day death rate (5.3% vs 7.9 %, p = 0.06). However, only patients in Killip class 2-3 had a significantly lower mortality when the diagnostic ECG was transmitted, whereas no difference was found in Killip class 1 or Killip class 4 patients. Conclusions: In this registry, PH-ECG significantly decreased first medical contact-to-balloon time. Attempts to achieve faster reperfusion times should be undertaken, as this may result in improved outcome, particularly in patients with mild to moderate symptoms of heart failu

Large vessel involvement by skeletal and soft tissue sarcomas of the extremities does not change the modern limb sparing surgery for those neoplasms. An arterial and, if the vein is open, a venous bypass should always be offered to any patient young or old, with high or low grade sarcoma, because preserving the limb permits quicker rehabilitation, which is particularly useful in the case of a short life expectancy. In 650 cases of skeletal sarcomas, 10 arterial (1.5%) and four venous bypasses were done, all with autologous veins but one in PTFE; we had no problems except a silent arterial occlusion. Of 1000 patients with soft tissue sarcomas, 32 (3%) had vessel involvement permitting limb sparing surgery. The arterial bypass, which is the limb-saving operation, was performed 16 times with a PTFE with one early occlusion and four cases of prosthesis infection, with two amputations despite redo operation with an autologous vein. The more recent 16 cases were, therefore, always done with biological vessel substitution--autologous vein or tissue bank vessel--with only one infection that healed without operation and one case of homograft rupture followed by amputation. Since 1999 in all 13 resected cases with an open vein, we did the arterial and the venous bypass (twice PTFE, six autologous vein, and five bank vessel) with the aim of avoiding postoperative venous hypertension, but only four of the venous bypasses remained open. Venous bypasses are a harmless, but still experimental, procedure.

AimsThe study evaluated the correlation between pretreatment serum lactate dehydrogenase (LDH) levels with the stage of disease and its clinical prognostic value.MethodsPretreatment serum LDH of 1421 patients with osteosarcoma of the extremity were assessed to investigate whether the enzyme correlates with the stage of the tumor. In 860 assessable patients with localized disease, treated according to 10 different protocols of adjuvant (four) and neoadjuvant chemotherapy (six), we also evaluated the correlation between the serum levels of LDH and outcome.ResultsAccording to the stage of disease, the rate of high serum level of LDH was significantly higher in 199 patients with metastatic disease at presentation than in 1222 patients with localized disease (36.6% vs 18.8%; P ConclusionsSerum LDH has a prognostic value and it should be considered in evaluating the results of therapeutic trials of chemotherapy, as well as defining a category of patients at high-risk of relapse to be treated with a more aggressive regimen.

We evaluated the long-term results obtained in 402 patients with non-metastatic Ewing's sarcoma (ES) of the bone treated in a single institution with adjuvant and neoadjuvant chemotherapies between 1972 and 1992. Multivariate analyses showed male gender, age older than 14 years, high serum lactate dehydrogenase (LDH) level, axial location of the tumour, use of radiotherapy alone as a local treatment, and poor histological response to chemotherapy, to be independent, adverse prognostic factors for event-free survival (EFS). At a mean follow-up of about 18 years (10-30 years), 177 patients (44.0%) remained continuously free of disease, 2 died of doxorubicin-induced cardiotoxicity and 8 developed a second neoplasm (5 died, and 3 are alive and free of disease). 215 patients relapsed with metastases and/or local recurrence: 14 are alive and free of disease, 1 is alive with uncontrolled disease, and 200 died. The overall survival (OS) at real follow-ups of 5-, 10-, 15- and 20-years was 57.2, 49.3, 44.9 and 38.4%, respectively. We conclude that since local or systemic relapses, treatment-complications and second malignancies are more common after 5 years or more from the beginning of treatment; a long-term follow-up is mandatory for patients with ES. © 2003 Elsevier Ltd. All rights reserved.