Antoine Thyss

Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group

BACKGROUNDnThere are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS).nnnPATIENTS AND METHODSnData from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors.nnnRESULTSnThe median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS.nnnCONCLUSIONnAs for other high-grade soft-tissue sarcomas, well-planned wide surgical excision with adjuvant radiotherapy remains the cornerstone of treatment for SS. Neo-adjuvant or adjuvant chemotherapy should not be delivered outside a clinical trial setting.

Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer.

SummaryTwenty-nine previously untreated patients with head and neck carcinoma received a total of 63 cycles of an initial chemotherapy protocol combining cis-platinum (100 mg/m2 on day 1) and continuous 5-day infusion of 5-FU (1000 mg/m2/24 h) from day 2 to day 6. This protocol was repeated on day 16 and day 31. Two daily blood samples obtained from all patients every day during 5-FU administration were analyzed by HPLC to determine the 5-FU concentrations. In the majority of cases a constant elevation was observed in total 5-FU cycle exposure (CxT) from cycle to cycle. A close relationship was demonstrated between elevated 5-FU CxT values (over 30 000 ng h ml-1) and the frequency of cycles in which signs of toxicity (myelosuppression, mucositis, diarrhea) were observed. By contrast, no obvious association was noted between response to treatment and systemic 5-FU exposure.

Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG)

BACKGROUNDnData regarding the role of chemotherapy (CT) in patients with recurrent and/or unresectable desmoid tumors (DTs) are scarce.nnnPATIENTS AND METHODSnRecords of patients with DT who were treated with CT in centers from the French Sarcoma Group were reviewed.nnnRESULTSnSixty-two patients entered the study. The two most common locations were extremities (35.5%) and internal trunk (32.5%). Twelve patients (19.5%) were diagnosed with Gardner syndrome. Thirty-seven patients (54.7%) received previously one or more lines of systemic therapies (nonsteroidal anti-inflammatory drugs: 43.5%, antiestrogens: 43.5% and imatinib: 30.5%). Combination CT was delivered in 44 cases (71%) and single agent in 18 patients (29%), respectively. Thirteen patients (21%) received an anthracycline-containing regimen. The most frequent nonanthracycline regimen was the methotrexate-vinblastine combination (n = 27). Complete response, partial response, stable disease and progressive disease were observed in 1 (1.6%), 12 (19.4%), 37 (59.6%) and 12 (19.4%) patients, respectively. The response rate was higher with anthracycline-containing regimens: 54% versus 12%, P = 0.0011. Median progression-free survival (PFS) was 40.8 months. The sole factor associated with improved PFS was the nonlimb location: 12.1 months (95% confidence interval 5.6-18.7) versus not reached, P = 0.03.nnnCONCLUSIONSnCT has significant activity in DT. Anthracycline-containing regimens appear to be associated with a higher response rate.BACKGROUNDnData regarding the role of chemotherapy (CT) in patients with recurrent and/or unresectable desmoid tumors (DTs) are scarce.nnnPATIENTS AND METHODSnRecords of patients with DT who were treated with CT in centers from the French Sarcoma Group were reviewed.nnnRESULTSnSixty-two patients entered the study. The two most common locations were extremities (35.5%) and internal trunk (32.5%). Twelve patients (19.5%) were diagnosed with Gardner syndrome. Thirty-seven patients (54.7%) received previously one or more lines of systemic therapies (nonsteroidal anti-inflammatory drugs: 43.5%, antiestrogens: 43.5% and imatinib: 30.5%). Combination CT was delivered in 44 cases (71%) and single agent in 18 patients (29%), respectively. Thirteen patients (21%) received an anthracycline-containing regimen. The most frequent nonanthracycline regimen was the methotrexate-vinblastine combination (n=27). Complete response, partial response, stable disease and progressive disease were observed in 1 (1.6%), 12 (19.4%), 37 (59.6%) and 12 (19.4%) patients, respectively. The response rate was higher with anthracycline-containing regimens: 54% versus 12%, P=0.0011. Median progression-free survival (PFS) was 40.8 months. The sole factor associated with improved PFS was the nonlimb location: 12.1 months (95% confidence interval 5.6-18.7) versus not reached, P=0.03.nnnCONCLUSIONSnCT has significant activity in DT. Anthracycline-containing regimens appear to be associated with a higher response rate.

Response to chemotherapy as justification for modification of the therapeutic strategy for pharyngolaryngeal carcinomas

From September 1983 to September 1987, 238 patients with squamous cell carcinoma of the upper aerodigestive tract were given 3 cycles of chemotherapy [cisplatinum (cis‐DDP), 100 mg/m2 on day 1; 5‐fluorouracil (5‐FU), 1,000 mg/m2 on days 2‐6] before any local treatment. Eighty‐one of these patients had pharyngolaryngeal cancer. Of the 45 of 50 laryngeal cancers and 26 of 31 hypopharyngeal cancers suitable for evaluation, complete responses (CR) were obtained in 51.1% and 53.8%, respectively. These response rates led to changes in the postchemotherapy protocols. For CRs, mutilating surgical protocols were replaced by definitive radiotherapy: one local recurrence has been observed among the 9 laryngeal cancers, and 3 of 10 hypopharyngeal cancer patients, who had an initial indication of total laryngectomy or total pharyngolaryngectomy replaced by radiotherapy. In the group of CR, survival rates at 2 years were 93% and 69%, respectively, for the larynx and hypopharynx vs 65.6% and 40% for non‐CR patients. The possibility of conservative treatment sparing vocal function with a high degree of reliability would in itself appear to be justification for induction chemotherapy in pharyngolaryngeal cancers, even though its long‐term effects remain controversial.

Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation.

Hairy-cell leukemia (HCL) is a lymphoproliferative disorder characterized by the presence of CD103-positive circulating B cells, pancytopenia and splenomegaly.[1][1] HCL cases were recently shown to harbor a mutation at codon 600 of BRAF ( V600E ), suggesting that this genetic event represents a key

High expression of the antigen recognized by the monoclonal antibody GB24 on human breast carcinomas: A preventive mechanism of malignant tumor cells against complement attack?

SummaryGB24 is a mouse monoclonal antibody raised against a common trophoblast-lymphocyte cross-reactive antigen. GB24 detects the membrane cofactor protein (MCP, CD46), a member of the complement regulatory protein family, which serves as a cofactor for factor 1 mediated cleavage of C3b. This study investigated the reactivity of GB24 on 38 breast carcinomas and 34 normal/benign breast tissues by immunochemistry as well as the reactivity of F2B7-2, an antibody specific to the decay accelerating factor (DAF, CD55) of the complement. GB24 staining was present on both normal tissue and benign lesions, but very strong diffuse reactivity was observed on carcinomas. This reactivity increased with the tumor grade. By contrast, malignant tumor cells lacked DAF expression. F2B7-2 antibody reacted weakly with benign epithelial cells. Results were studied by computer assisted image analysis to accurately define the mean optical densities. The densitometric analysis of MCP positive carcinomas showed a high intensity of the staining. Expression of MCP and DAF on MCF-7 cell lines was analyzed by flow cytometry. MCF-7 cell lines were strongly stained by mAb GB24 only. These data suggest that selectively enhanced expression of the antigen recognized by GB24 is associated with malignant breast disorders. This high expression, which may reflect a protective mechanism by which tumor cells survive complement activation, may prove useful as a marker of malignant transformation.

Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies

This pharmacokinetic study examined the relationship between methotrexate (MTX) dose and drug concentrations in blood and cerebrospinal fluid (CSF) during repeated 24 hr infusions. Two regimens were used: an intermediate dose (ID) of 0.5 g/m2 (7 patients, 23 cycles) and a high dose (HD) of 2.5 g/m2 (8 patients, 39 cycles). Inter-patient variability in the drug concentration was apparent in serum and CSF for both doses. The dispersion was particularly wide in CSF for HD MTX. Considering median values, serum and CSF MTX were linked to dose escalation. Individual CSF/serum drug ratios were not modified by the dose (1.1% for ID MTX versus 1.4% for HD MTX). A potentially cytotoxic drug level in CSF (10(-6) M) was never obtained for ID MTX cycles, but was achieved in 44% of HD MTX cycles: for HD MTX, this corresponded to 88% of patients (7/8). Total body clearance did not modify the degree of CSF MTX passage. A positive, significant correlation (r = 0.62, P less than 0.05) was observed for ID MTX between individual serum and CSF MTX; no such relationship was seen with HD MTX. Individual cycle-to-cycle variations in the MTX concentration were particularly marked in CSF and for HD MTX, without strict concordance with blood levels.

Thyroid spindle epithelial tumor with thymus-like differentiation (the “settle” tumor)

An intrathyroid primary epithelial spindle-cell tumor with mucous cysts is described in a 9-year-old child. Histologically, this well-circumscribed tumor exhibited a nodular pattern, a prominent spindle cell component with minimal pleomorphism, and well-differentiated mucinous glands within fibrous bands. The spindle cells demonstrated diffuse immunopositivity for cytokeratin and vimentin. Electron microscopy of tissue sections demonstrated that cells contained bundles of cytoplasmic tonofilaments and numerous desmosomes. The light and electron microscopic features and immunohistochemical profile of this tumor were similar to those of recently described thyroid tumors that have been called “SETTLE” tumors (i.e., spindle epithelial tumor with thymus-like differentiation). These uncommon tumors can be considered intrathyroid thymoblastomas and must be regarded as potentially malignant lesions.

Osteosarcomas of the mandible: Are they different from other tumor sites?

BACKGROUNDnOsteosarcomas of the mandible (MOS) affect 1/10 million persons/year, mostly the young adult. Due to lack of specific data, the treatment of MOS is extrapolated from that of extragnathic OS but varies widely between institutions.nnnMATERIALS AND METHODSnWe aimed at providing a focused description of MOS histologies and grades through the English literature, at determining the evidence-based role of chemotherapy, of adjuvant radiation therapy and the potential of reconstructive surgery tailored through modern pre-operative multi-modal imaging.nnnRESULTSnThe estimated proportion of high grade MOS was 58%. However, low-grade MOS may be underestimated as they are mostly reported as case reports. The intermediate grade was hardly found in the literature. Estimated weighted-mean proportions of chondroblastic and osteoblastic MOS were 37% and 46%, respectively. Multimodal imaging modalities including MRI has a great potential for accurate pre-operative assessment of tumor extensions into bone and soft tissues. Surgery is the mainstay of treatment and margins the most important factor. The role of neoadjuvant chemotherapy in treating occult systemic metastases and in increasing the probability of clear margins is controversial, as well as the histology-dependent response to chemotherapy. The role of adjuvant radiotherapy (mostly proposed for positive margins) and/or adjuvant chemotherapy is still controversial. Crude survival is around 77% and local control around 67%. Local failure is the main cause of death in MOS compared to extragnathic sites.

High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial

BACKGROUNDnMetastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients.nnnPATIENTS AND METHODSnAdvanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7.nnnRESULTSnFrom 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity.nnnCONCLUSIONnThis study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.BACKGROUNDnMetastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients.nnnPATIENTS AND METHODSnAdvanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m2, day 1-5), ifosfamide (2.5 g/m2, day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m2, day 1-4) with PBSC reinjection at day 7.nnnRESULTSnFrom 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity.nnnCONCLUSIONnThis study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.