Long-term efficacy of microbiology-driven periodontal laser-assisted therapy.

Periodontitis represents a highly prevalent health problem, causing severe functional impairment, reduced quality of life and increased risk of systemic disorders, including respiratory, cardiovascular and osteoarticular diseases, diabetes and fertility problems. It is a typical example of a multifactorial disease, where a polymicrobial infection inducing chronic inflammation of periodontal tissues is favoured by environmental factors, life style and genetic background. Since periodontal pathogens can colonise poorly vascularised niches, antiseptics and antibiotics are typically associated with local treatments to manage the defects, with unstable outcomes especially in early-onset cases. Here, the results of a retrospective study are reported, evaluating the efficacy of a protocol (Periodontal Biological Laser-Assisted Therapy, Perioblast™) by which microbial profiling of periodontal pockets is used to determine the extent and duration of local neodymium-doped yttrium aluminium garnet (Nd:YAG) laser irradiation plus conventional treatment. The protocol was applied multicentrically on 2683 patients, and found to produce a significant and enduring improvement of all clinical and bacteriological parameters, even in aggressive cases. Microbiome sequencing of selected pockets revealed major population shifts after treatment, as well as strains potentially associated with periodontitis in the absence of known pathogens. This study, conducted for the first time on such a large series, clearly demonstrates long-term efficacy of microbiology-driven non-invasive treatment of periodontal disease.

X-linked retinoschisis: mutation spectrum and genotype-phenotype relationship in an Italian pediatric cohort.

BACKGROUND: X-linked juvenile retinoschisis (×LRS) is an X-linked vitreoretinal degenerative disease that consists of variable phenotypes ranging from severe early-onset defects to subtle abnormalities diagnosed in elderly patients. XLRS is caused by a loss of function of the protein Retinoschisin (RS1), which is essential to preserve retinal integrity and function of photoreceptor-bipolar synapse. The literature data so far mostly agree on the absence of a clear genotype-phenotype correlation in XLRS. We reviewed clinical and molecular characteristics of a cohort of Italian pediatric XLRS patients to assess the presence of a correlation between genotype and phenotype severity. MATERIALS AND METHODS: We retrospectively examined clinical and genetic features of a cohort of 27 XLRS patients. In this study we included patients with a diagnosis of XLRS confirmed by fundus photography, spectral domain optical coherence tomography, and molecular analysis and with an onset of less than 10 years of age. We sorted RS1 variants according to their effect of RS1 structure and function in three separate groups. RESULTS: According to previous studies, we did not observe a conclusive genotype-phenotype correlation in our cohort; nevertheless, we noticed that patients harboring RS1 variants leading to RS1-secreted mutants show a more homogeneous phenotype, with an overall good visual acuity, compared to the other two groups. CONCLUSIONS: Our data support the hypothesis that secretion profile of RS1 could influence the severity of the phenotype. More extensive and functional studies are needed to acquire notions in view of the opportunity of gene replacement therapy for XLRS patients.

Surgical debridement plus topical cyclosporine A in the treatment of vernal shield ulcers.

Vernal keratoconjunctivitis (VKC) is a severe chronic bilateral inflammation of the ocular surface characterized by seasonal exacerbations. Long-term prognosis is generally good; however, 6% develop sequelae responsible for permanent visual impairment. Corneal involvement is almost always present, consisting of punctate keratitis, shield ulcers (3-11%) and late corneal neovascularization. In recent years, topical cyclosporine A preparations at 2% in oil or at 1% in polyvinyl alcohol, have been successfully proposed for long term VKC treatments. It has been previously proven that medical treatment is not always sufficient, especially when it is employed to treat shield ulcer plaques. In such conditions, surgery may be effective for avoiding long term complications such as amblyopia, strabismus, infections and corneal perforation. In this paper, we show the efficacy of surgical debridement by means of simple scraping associated with topical cyclosporine treatment for the management of vernal shield ulcers complicated with plaques.

Nonmetastatic Ewing family tumors: high-dose chemotherapy with stem cell rescue in poor responder patients. Results of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol.

BACKGROUND: High-dose chemotherapy (HDT) was added to conventional chemotherapy in Ewing sarcoma family tumor (EFT) patients, poor responders (PRs) to induction chemotherapy in order to improve their survival. PATIENTS AND METHODS: Patients aged ≤40 years with nonmetastatic Ewing sarcoma (ES) received vincristine (V), doxorubicin (A), cyclofosfamide (C), actinomycin (Ac), ifosfamide (I) and etoposide (E) (VACAc-IE regimen) as induction chemotherapy. As maintenance treatment, good responders (GR) received nine cycles of VACAc-IE regimen. PRs received three cycles of VAC-IE, mobilizing cycle with CE and HDT with Busulfan and Melphalan with stem cell support. RESULTS: Three hundred patients [median age 15 years (3-40 years)] entered the study. One patient refused local treatment, 242 (81%) underwent surgery [with radiotherapy (RT) in 80] and 57 (19%) RT alone. No toxic deaths were recorded. Overall GR were 146 (49%). Twenty-eight PR did not receive HDT. At a median follow-up of 64 months (21-116 months), 5-year overall and event-free survival (EFS) were 75% and 69%, respectively. Five-year EFS was 75% for GR, 72% for PR treated with HDT and 33% for PR who did not receive HDT. CONCLUSIONS: High-dose therapy added to the VACA-IE regimen in PR patients is feasible and effective. Selected groups of patients with ES can benefit from HDT.

Survival in high-grade osteosarcoma: improvement over 21 years at a single institution.

BACKGROUND: The purpose of this study was to analyze improvements in overall survival over 21 years (1982-2002), with a 5-year minimum follow-up, in the largest series from a single center ever reported. MATERIALS AND METHODS: All diagnoses of high-grade osteosarcoma were included despite histological varieties, age, site and stage. Of the 1656 cases observed, 198 patients were excluded (41 consultation only, 129 low-grade varieties, and 28 lost to follow-up). Within 1458 included patients, 1032 had characteristics to be enrolled in conventional clinical trials (classic histology, age <41, localized, and extremity disease). Data are also analyzed in subgroups to define patients who benefited most. RESULTS: With a median follow-up of 12 years (5-25 years), 754 patients (51.7%) are alive, of whom 613 continuously disease free. Survival at 5, 10, and 15 years is 57%, 52%, and 51%, respectively. Patients candidates for clinical trials have a survival rate of 68%, 64%, and 61%, respectively. Survival for the other patients is 30%, 25%, and 24%, respectively. Trend (joinpoint statistical analysis at real 5-year follow-up) shows a yearly statistically significant improvement of 1.31% (95% confidence interval 0.5% to 2.1%) from 51% for patients treated in 1982 to 68% for those treated in 2002. Patients who statistically benefited were those who relapsed or presented with metastatic disease at diagnosis or had axial tumors. CONCLUSIONS: Despite the lack of new drugs for osteosarcoma, survival has statistically improved, especially for those patients with the worst outcome. Aggressive treatments are recommended for all patients including those with poor prognosis.

Response to high-dose ifosfamide in patients with advanced/recurrent Ewing sarcoma.

AIM: To determine activity and toxicity of high-dose ifosfamide (HDIFO) in recurrent or advanced Ewing sarcoma family tumors (EFT). METHODS: Thirty-seven EFT patients [median age 17 years (6-45 years)] previously treated with chemotherapy regimens including standard dose ifosfamide were enrolled. HDIFO was administered for metastatic recurrent disease in 33 patients and for progression during neoadjuvant chemotherapy in 4 patients. All patients who received two courses of 15 g/m(2) ifosfamide were evaluable for radiographic response assessed according to RECIST criteria. RESULTS: Transient Grade 4 neutropenia and thrombocytopenia in 97% and 54% HDIFO courses respectively and severe CNS toxicity in one patient were observed. Thirty-five patients were evaluable: 12 (34%) had complete (2) or partial (10) response, 11 (32%) had stable disease, and 12 (34%) had progression. CONCLUSIONS: In patients with relapsed or advanced EFT previously treated with standard dose ifosfamide HDIFO is active and it should be considered a treatment option.

CAD-CAM construction of a provisional nasal prosthesis after ablative tumour surgery of the nose: a pilot case report.

The computer-aided design of a nasal prosthesis based on pre-operative virtual laser scanning of the affected site was virtually adapted to the post-operative laser-scanned surface. The designed volume of the nose was rapidly prototyped and used to fabricate a provisional prosthesis and a computed tomography diagnostic template to check the available premaxilla bone for implants. The mould for the nasal prosthesis was prototyped using a computer-aided design and manufacturing (CAD-CAM) procedure. In addition, the mesiostructure of an eyeglasses-supported provisional prosthesis was also designed and prototyped using CAD-CAM procedures.

Clinical impact of the methotrexate resistance-associated genes C-MYC and dihydrofolate reductase (DHFR) in high-grade osteosarcoma.

BACKGROUND: Aims of this study were the validation of C-MYC involvement in methotrexate (MTX) resistance and the assessment of clinical impact of C-MYC and dihydrofolate reductase (DHFR) in osteosarcoma (OS). MATERIALS AND METHODS: The involvement of C-MYC in MTX resistance was validated with an antisense approach. C-MYC and DHFR protein levels at diagnosis were assessed by immunohistochemistry on series of patients treated with either a MTX-based protocol (IOR/OS-1; 72 patients) or with a standard four-drug regimen (ISG/SSG 1; 61 patients). RESULTS: Down-regulation of C-MYC significantly decreased the MTX resistance level of OS cells, demonstrating its causal involvement in this phenomenon. In clinical samples, a worse outcome was associated with increased levels of DHFR and C-MYC at diagnosis in the IOR/OS-1 patients and of C-MYC in the ISG/SSG 1 patients. CONCLUSIONS: Meanwhile the adverse clinical impact of DHFR overexpression appeared to be closely related to the relevance of MTX in the chemotherapeutic protocol, that of C-MYC overexpression was more general and not strictly MTX related. The assessment of C-MYC and DHFR at diagnosis, together with that of other known prognostic markers, can be considered for an early identification of subgroups of OS patients with higher risk of adverse outcome.

Adjuvant and neo-adjuvant chemotherapy for Ewing's sarcoma family tumors and osteosarcoma of the extremity: further outcome for patients event-free survivors 5 years from the beginning of treatment.

BACKGROUND: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarcoma (OS) treated with adjuvant and neo-adjuvant chemotherapy and event-free survivors 5 years from the beginning of treatment we evaluated outcome in the following years. Post 5-year follow-up for these patients was 9.7 years (5.5-29 years). PATIENTS AND METHODS: Adverse events observed after 5-year follow-up were 73 (7.6%): 38 late relapses, nine leukemia, 14 second solid tumor, seven radioinduced sarcoma, three severe adriamycin-related cardiomyopathy, one suicide and one death by car crash. RESULTS: Of the patients who developed late events, 16 (22.5%) are alive and event free after 8 years from the last treatment (2-22 years). CONCLUSION: We conclude that the high rate of late adverse events after 5 years in patients with OS and ESFT is noteworthy and indicates that these patients should be followed for >5 years.

Ewing's sarcoma family tumours. Differences in clinicopathological characteristics at presentation between localised and metastatic tumours.

Despite local treatment with systemic chemotherapy in Ewing's sarcoma family tumours (ESFT), patients with detectable metastases at presentation have a markedly worse prognosis than those with apparently localised disease. We investigated the clinical, pathological and laboratory differences in 888 patients with ESFT, 702 with localised disease and 186 with overt metastases at presentation, seen at our institution between 1983 and 2006. Multivariate analyses showed that location in the pelvis, a high level of serum lactic dehydrogenase, the presence of fever and a short interval between the onset of symptoms and diagnosis were indicative of metastatic disease. The rate of overt metastases at presentation was 10% without these four risk factors, 22.7% with one, 31.4% with two, and 50% for those with three or four factors. We concluded that in ESFT the site, the serum level of lactic dehydrogenase, fever, and the interval between the onset of symptoms and diagnosis are indicators of tumours having a particularly aggressive metastatic behaviour.

Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999.

AIMS: Evaluation of pattern of recurrences of 290 patients with an Ewing's sarcoma family tumor (ESFT), who relapsed after adjuvant or neoadjuvant chemotherapy. METHODS: Retrospective analysis at a median follow-up of 16.6 years (range: 5-32) from the primary therapy. RESULTS: There were 378 recurrences, treated by surgery, and/or chemotherapy, radiotherapy, or only palliative treatments. At the last control 18 patients were alive and free of disease 2.5 to 20 years (median 12.1 year) from the last treatment, 4 were alive with uncontrolled disease, 2 died of second line chemotherapy-related toxicity, and 266 died of the tumor 4 months to 20.5 years from the first relapse (median 3.2 years). The 5-year event free survival after the last relapse and overall survival were 5.1 and 7.9%, respectively, and resulted significantly correlated with the time of first relapse, the site of first metastases, the treatment performed after relapse (all patients presently free of disease had been treated by surgery alone or combined with a second line chemotherapy) and for patients treated with neoadjuvant chemotherapy and locally by surgery, with the histologic response to preoperative chemotherapy. CONCLUSIONS: We confirm that the post-relapse outcome of patients with ESFT who relapse after conventional treatment is very poor. Nonetheless specific subgroups of patients may be cured even after 2 or 3 relapses: patients who relapse 2 or more years after primary treatment, patients who relapse with only lung metastases, and patients whose recurrences can be surgically treated.

Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients.

Between 1986 and 2002, 42 patients with synchronous multifocal osteosarcoma were treated with two different protocols of neoadjuvant chemotherapy. When feasible, the primary and secondary tumours were excised as a combined procedure. After initial chemotherapy 26 patients were excluded from simultaneous excision of all their secondary bone lesions as their disease was too advanced. In 12 patients only isolated excision of the primary lesion was possible. For 16 patients simultaneous operations were conducted to excise the primary and secondary lesions. This involved two supplementary sites in 15 patients and four additional sites in one patient. Of these, 15 attained remission but 12 relapsed and died (11 within two years). Three patients remained disease-free at five, six and 17 years. The histological response to pre-operative chemotherapy of the primary and secondary lesions was concordant in 13 of the 16 patients who underwent simultaneous operations at more than one site. The prognosis for synchronous multifocal osteosarcoma remains poor despite combined chemotherapy and surgery. The homogeneous histological responses in a large proportion of the primary and secondary lesions implies that synchronous multifocal osteosarcoma tumours are not multicentric in origin, but probably represent bone-to-bone metastases from a single tumour.

Multidrug resistance and malignancy in human osteosarcoma.

In osteosarcoma, resistance to chemotherapy and metastatic spread are the most important mechanisms responsible for the failure of current multimodal therapeutic programs. We have shown previously that overexpression of the MDR1 gene product P-glycoprotein is the most important predictor of an adverse clinical course in patients with osteosarcoma. treated with chemotherapy. In this study, we analyzed the relationship between P-glycoprotein expression and local aggressiveness and systemic dissemination of multidrug-resistant (MDR) human osteosarcoma cells. Compared to parental sensitive cells, MDR cells showed a decreased tumorigenicity,and metastatic ability in athymic mice, together with a reduced migratory and invasive ability and a lower homotypic adhesion ability in vitro, suggesting that P-glycoprotein overexpression is associated with a less malignant phenotype. These experimental observations were confirmed by clinical data. In fact, the time of appearance of lung metastases in a series of osteosarcoma patients treated with chemotherapy was significantly shorter in the group of cases with no expression of P-glycoprotein in the primary lesion compared to the group with P-glycoprotein overexpression. Moreover, the incidence of P-glycoprotein overexpression was found to be higher among patients with localized disease at the clinical onset than in patients with evidence of metastasis at the time of diagnosis. These data indicate that, in osteosarcoma, the MDR phenotype is not associated with a more aggressive behavior both in vitro and in clinical settings, suggesting that the previously shown association of the MDR phenotype with a worse outcome in osteosarcoma is not related to a higher metastatic ability of cells with P-glycoprotein overexpression but is more likely due to their lack of responsiveness to cytotoxic drugs.

Neoadjuvant chemotherapy for peripheral malignant neuroectodermal tumor of bone: recent experience at the istituto rizzoli.

PURPOSE: The results achieved in 44 patients with nonmetastatic peripheral neuroectodermal tumor (PNET) of bone treated with neoadjuvant chemotherapy are reported. PATIENTS AND METHODS: A six-drug regimen of chemotherapy (vincristine, doxorubicin, dactinomycin, cyclophosphamide, ifosfamide, and etoposide) was administered to all patients. Local treatment consisted of surgery in 20 patients, surgery followed by radiotherapy in 13, and radiotherapy only in 11. RESULTS: At a mean follow-up of 4.5 years (range, 2 to 7 years), 23 patients (52%) remain event-free, 20 have relapsed (45%), and one has died of chemotherapy-related toxicity. The 5-year event-free survival and overall survival were 54.2% and 62.7%, respectively. To assess the prognostic significance of neural differentiation in the family of Ewing's sarcoma, these results have been compared with the outcomes of 138 concomitant patients with typical Ewing's sarcoma (TES) who were treated according to the same protocol. Of these, 103 (75%) remained continuously event-free, 34 (24%) relapsed, and one died of chemotherapy-related toxicity. It follows that PNET patients treated with this chemotherapy regimen have a significantly worse prognosis than typical ES patients (5-year event-free survival, 54.2% v 70.6%, P <.012; 5-year overall survival, 62.7% v 78.3%, P <.002). CONCLUSION: The authors conclude that studies into new adjuvant therapy for Ewing's sarcoma modulated according to risk of relapse should also consider neural differentiation as a risk factor.

A randomized trial for the treatment of high-grade soft-tissue sarcomas of the extremities: preliminary observations.

A new trial for evaluating the effectiveness of adjuvant chemotherapy in high-grade soft-tissue sarcomas of the extremities in adult patients is presented. All patients after local treatment were randomized into two arms, one without further therapy and the other to receive adjuvant chemotherapy (Adriamycin [Farmitalia-Carlo Erba, Milan, Italy], 450 mg/m2). The preliminary results of the study are reported at a median observation period of 27.6 months. Of the 59 patients who entered the study, 79.1% in the chemotherapy group are without sign of disease, whereas the corresponding figure in the nonadjuvant chemotherapy group is 54.3%. The difference between the two groups is statistically significant (P less than .005, log rank test). These preliminary observations encourage continuation of the study.

Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report.

PURPOSE: To provide an estimate of long-term prognosis for patients with osteosarcoma of the extremity treated in a single institution with neoadjuvant chemotherapy and observed for at least 10 years. PATIENTS AND METHODS: Patients with nonmetastatic osteosarcoma of the extremity were preoperatively treated with high-dose methotrexate, cisplatin, and doxorubicin (ADM). Postoperatively, good responders (90% or more tumor necrosis) received the same three drugs used before surgery, whereas poor responders (less than 90% tumor necrosis) received ifosfamide and etoposide in addition to those three drugs. RESULTS: For the 164 patients who entered the study between September 1986 and December 1989, surgery was a limb salvage in 136 cases (82%) and a good histologic response was observed in 117 patients (71%). At a follow-up ranging from 10 to 13 years (median, 11.5 years), 101 patients (61%) remained continuously free of disease, 61 relapsed, and two died of ADM-induced cardiotoxicity. There were no differences in prognosis between good and poor responding patients. ADM-induced cardiotoxicity (six patients), male infertility (10 of the 12 assessable patients), and second malignancies (seven patients) were the major complications of chemotherapy. Despite the large number of limb salvages performed, only four local recurrences (2.4%) were registered. CONCLUSION: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with nonmetastatic osteosarcoma of the extremity and amputation may be avoided in more than 80% of them. Because local or systemic relapses, myocardiopathies, and second malignancies are possible even 5 years or more after the beginning of treatment, a long-term follow-up is recommended for these patients.

Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing's sarcoma of the extremities.

PURPOSE: To evaluate more accurately the effectiveness of preoperative chemotherapy in the treatment of patients with Ewing's sarcoma, we studied histopathologically the chemotherapeutic response and correlated it to oncologic outcome. PATIENTS AND METHODS: Between June 1983 and December 1989, 68 patients with nonmetastatic Ewing's sarcoma of the extremities were treated at our institute with preoperative chemotherapy (without radiation therapy) and surgery. The specimens were retrospectively evaluated for areas of viable tumor cells and graded from I to III (macroscopic, microscopic, or no residual disease, respectively) in a blinded fashion. Clinical follow-up data were available on all patients for a mean of 60 months (range, 32 to 111). RESULTS: This histopathologic analysis was strongly correlated with oncologic outcome (P = .004). Patients who demonstrated grade III response (no identifiable viable tumor nodules present) had improved 5-year disease-free survival rates as compared with patients with grade II (microscopic nodes present; P = .023; 90% v 53%) and grade I responses (macroscopic nodules present; P = .0003; 90% v 32%). Patients with grade II necrosis had statistically improved survival rates over those with grade I necrosis (53% v 32%; P = .074). CONCLUSION: This new histopathologic analysis technique for the evaluation of neoadjuvant chemotherapy effectiveness (which does not rely on tumor volume for its assessment) is a valuable prognostic indicator for patients with Ewing's sarcoma treated with surgery. Based on this preliminary report, cases of grade I or II chemotherapeutic tumor response should be considered clinical failures and a different, more aggressive postoperative chemotherapy regimen should be considered.

Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli.

PURPOSE: The identification of prognostic factors in patients with nonmetastatic Ewing's sarcoma could allow the use of risk-adapted therapeutic strategies of treatment. PATIENTS AND METHODS: Data on 359 patients with nonmetastatic Ewing's sarcoma of bone treated at a single institution between January 1979 and April 1995 were retrospectively considered. The influence of clinical, hematologic, therapeutic, and histologic parameters on event-free survival was assessed. RESULTS: By univariate analysis, the following features were found to be associated with a poor prognosis: male sex (P <.02), age older than 12 years (P <.006), fever (P <.0001), anemia (P <.0025), high serum lactate dehydrogenase (LDH) level (P <.0001), axial location (P <.04), radiation therapy only for local control (P <.009), type of chemotherapy regimen (P <.0001), and poor chemotherapy-induced necrosis (P <.001). After multivariate analysis, the adverse independent prognostic factors were male sex (P <.04), age older than 12 years (P <.001), fever (P <.0002), anemia (P <.02), high serum LDH level (P <.0003), axial location (P <.02), and type of chemotherapy regimen (P <.0003). When the multivariate analysis was restricted to surgically treated patients, the adverse independent prognostic factors were poor chemotherapy-induced necrosis (P <.0001), fever (P <.015), anemia (P <.02), and high serum LDH level (P <.025). CONCLUSION: The prognosis in cases of nonmetastatic Ewing's sarcoma is influenced by many different clinical and hematologic variables, all of which are to be considered when patients are being stratified according to the risk of relapse. In surgically treated patients, the most important prognostic factor is chemotherapy-induced necrosis.

High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study.

PURPOSE: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse. PATIENTS AND METHODS: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT. RESULTS: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%. CONCLUSION: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.

Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin.

PURPOSE: In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy. PATIENTS AND METHODS: In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response. RESULTS: Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). CONCLUSION: Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.