Treatment of advanced dermatofibrosarcoma protuberans with imatinib mesylate with or without surgical resection.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma of the skin characterized by the presence of specific COL1A1-PDGFB fusion protein, which appears as a consequence of the t(17;22) (q22;q13) translocation. OBJECTIVE: The aim of the study was to perform an analysis of patients with advanced DFSP treated with imatinib, with or without surgery, in clinical practice outside trials. PATIENTS AND METHODS: We analysed the data of 15 patients (6 male, 9 female; median age 56 years) with locally advanced/initially inoperable and/or metastatic DFSP treated with imatinib 400-800 mg daily between 12/2004 and 06/2009. All diagnoses were ascertained cytogenetically (fluorescent in situ hybridization). Median follow-up time was 16 months (range: 4-81). RESULTS: Metastases were present in six cases (two lungs, two soft tissue, two lymph nodes). Fibrosarcomatous transformation (FS-DFSP) was confirmed in seven patients (47%). A 2-year progression-free survival (PFS) rate was 60%, and a 2-year overall survival (OS) rate was 78% (median time for PFS/OS was not reached). The best overall responses were: 10 partial responses (67%, including 5 FS-DFSP-1 progressed during the follow-up), 2 stable diseases (13%) and 3 progressive diseases (20%). Seven patients (47%) underwent resection of residual disease and remained free of disease. CONCLUSIONS: We have confirmed the profound anti-tumour effect of imatinib in DFSP harbouring t(17;22) with long-term responses. Imatinib therapy may in some cases lead to tumour resectability of lesser disfiguration.

Diagnostic yield and safety of endoscopic ultrasound-guided trucut [corrected] biopsy in patients with gastric submucosal tumors: a prospective study.

BACKGROUND AND STUDY AIMS: Endoscopic-ultrasound-guided trucut needle biopsy (EUS-TCB) has not been adequately evaluated in patients with submucosal tumors (SMTs). PATIENTS AND METHODS: This prospective, uncontrolled study involving 49 consecutive patients with hypoechoic gastric SMTs (> or = 20 mm) evaluated diagnostic yield and 30-day morbidity of EUS-TCB, factors related to the success of EUS-TCB, and agreement between EUS-TCB and the surgical pathology diagnosis. Seventy-three percent of tumors were gastrointestinal stromal tumors (GIST). RESULTS: Tumor tissue adequate for diagnosis was obtained by EUS-TCB in 31 patients (63 %; 95 %CI 49 % to 75 %). In the remaining cases, EUS-TCB provided no tissue (n = 11) or an insufficient amount (n = 7). Logistic regression analysis showed that tumor location on the lesser curvature of the stomach was the only independent predictor of obtaining diagnostic material [odds ratio (OR) 7.4; 95 %CI 1.9 to 28; P = 0.004]. The experience of the endosonographer, the size of the tumor, and the location of the tumor relative to the long axis of the stomach were not related to the success of the biopsy. Agreement between EUS-TCB and surgical pathology specimens in respect of the diagnosis and CD117 status was high (0.9, standard error 0.31; and 0.95, standard error 0.16, respectively); however, there was no correlation between the mitotic index as determined on EUS-TCB and that determined on the surgical pathology specimen (correlation coefficient, 0.08). There were two severe septic complications in 52 procedures (3.9 %; 95 %CI 0.3 % to 14 %). CONCLUSIONS: The diagnostic yield of EUS-TCB in patients with gastric SMTs was moderate. Tissue samples were too small to reliably determine the mitotic index. Antibiotic prophylaxis should be considered because of possible septic complications.

Surgical resection of residual disease in initially inoperable imatinib-resistant/intolerant gastrointestinal stromal tumor treated with sunitinib.

AIM: Sunitinib malate therapy in inoperable and/or metastatic gastrointestinal stromal tumor (GIST) resistant to imatinib mesylate may facilitate surgical removal of residual disease. We explored this possibility in the course of treating patients as part of a treatment-use trial, the objective of which was to provide access to sunitinib treatment. METHODS: Four patients with inoperable and/or metastatic GIST resistant to imatinib who had responded to sunitinib therapy administered at a starting dose of 50 mg daily in 6-week cycles of 4 weeks on treatment followed by 2 weeks off underwent surgical removal of residual disease. Disease progression on or clinical response to treatment was defined based on Response Evaluation Criteria in Solid Tumors. RESULTS: In three of four cases it was possible to perform macroscopically complete resection of residual disease, resulting in surgical complete clinical responses, two with durations of 13 months. The fourth patient achieved a dramatic partial response to sunitinib that required emergency surgical resection of the necrotic tumor mass, with the partial response having been maintained for 15 months. In all cases, viable GIST cells were detected histologically in the resection specimens, and sunitinib treatment was resumed post-surgery. None of the patients experienced any postoperative complications during 13-16 months of follow-up. CONCLUSIONS: Combining sunitinib treatment with surgical removal of residual disease may allow selected imatinib-resistant GIST patients who have shown a favorable response to sunitinib to achieve complete and sustained remission or durable control of previously progressive disease beyond that expected for sunitinib treatment alone.

Molecular and biochemical testing in stage III melanoma: multimarker reverse transcriptase-polymerase chain reaction assay of lymph fluid after lymph node dissection and preoperative serum lactate dehydrogenase level.

BACKGROUND: There is a need for biomarkers to identify patients at risk for disease progression after resection of melanoma regional lymph node metastasis. OBJECTIVES: This study assessed the prognostic value of multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) assay in lymphatic drainage (LY) after lymph node dissection (LND) and of preoperative serum lactate dehydrogenase (LDH) levels in American Joint Committee on Cancer (AJCC) stage III melanoma patients. METHODS: We collected 24-h LY from 255 stage III melanoma patients after radical LND [114, completion LND after positive sentinel node biopsy (CLND); 141, therapeutic LND for clinically/cytologically detected regional nodal metastases (TLND)]. For detection of melanoma cells, RT-PCR assays with primers specific for tyrosinase, MART1 (MelanA) and uMAGE mRNA were conducted. The LY sample was deemed positive if at least one marker was detected. In 244 patients, the preoperative serum LDH level was available. Median follow-up time was 25 months (range 5-60). RESULTS: The LY multimarker RT-PCR assay results were positive in 82 of 255 patients (32%). A significantly higher rate of melanoma recurrence was observed in patients with positive LY multimarker RT-PCR results (P = 0.01). Significant relationships were observed between positive LY multimarker RT-PCR results and shorter 3-year overall survival (OS) and disease-free survival (DFS), both in univariate and multivariate analyses (P = 0.007). Preoperative serum LDH level was increased in 79 of 244 patients (32%) [40.5% in TLND group and 23.0% in CLND group (P = 0.003)]. There were significant differences in OS between patients with normal and high preoperative LDH levels (P = 0.007), and these differences were seen mainly in patients in the TLND group. CONCLUSIONS: The multimarker RT-PCR assay detected melanoma cells in approximately 32% of LY after LND, which correlated significantly with early melanoma recurrence and shorter survival. Increased pre-LND serum LDH level had an additional negative impact on OS of melanoma patients with palpable nodal metastases after TLND.

In transit/local recurrences in melanoma patients after sentinel node biopsy and therapeutic lymph node dissection.

This study has analyzed the incidence of in transit/local recurrences (IT/LR) in melanoma patients after sentinel node (SLN) biopsy; completion lymph node dissection (CLND) that was performed due to positive node; and therapeutic LND (TLND) due to clinically detected node metastases and factors influencing IT/LR. Between May 1995 and May 2004, 1187 consecutive patients underwent SLN biopsy (median Breslow thickness 2.5 mm) and 224 of them had subsequent CLND. During the same time period, 306 patients had TLND (median Breslow 3.9 mm). The excision margin of primaries was > or =1cm. At median follow-up time of 37.5 months, we analyzed the incidence of IT/LR as the first site of relapse and clinicopathological parameters affecting these recurrences. In SLN-negative cases, IT/LR as the site of the first recurrence were rare (46/963; 4.8%) and; in SLN+/-CLND IT/LR were detected in 45/224 cases (20.1%). IT/LR in SLNB group correlated with presence of SLN metastases (P<0.0001), higher Breslow thickness (P<0.001) and lower extremity localization (P=0.03). In TLND group, IT/LR were observed in 52/306 patients (17%), which is similar to all CLND patients (P=0.3), but less common when analyzing only patients who relapsed (TLND: 52/209 (24.9%) vs. CLND: 45/121 (37.2%); P=0.02). Estimated 3-year overall survival (from the date of relapse) in IT/LR only patients was better than in other types of relapses after LND (29% vs. 8%; P<0.0001). IT/LR incidence in the entire group of SLN+/-CLND patients was similar to that observed in TLND patients and it was affected by presence of nodal metastases, Breslow thickness and lower extremity location.

The clinical characteristics and the role of surgery and imatinib treatment in patients with liver metastases from c-Kit positive gastrointestinal stromal tumors (GIST).

The purpose of this study was to analyze the clinical features of the group of c-KIT positive GIST patients with liver metastases evaluated and treated in two referral institutions as well as to attempt to define the role of surgery in the management of GIST given the emergence to imatinib as an important part of treatment strategy in GIST patients. Between August 2001 and December 2002, 90 patients with c-KIT positive GIST were referred to our institutions. In 50 patients metastatic disease were disclosed. Of these, 35 patients (35/50; 70%) were rendered to have liver metastases and therefore offered imatinib or surgical therapy depend on CT assessment. The median follow-up of these 35 patients calculated from the time of first operation was 23 months (range 3-246 months). Male patients comprised the majority of patients (70%) with liver metastases. In 14 patients (40%) the metastases were confined only to the liver, in the others 21 patients (60%) the liver metastases were accompanied by intraperitoneal dissemination (17; 48.6%) or local recurrences (4; 11.4%). The period of time between the diagnosis of primary lesion and occurring liver metastases ranged from 0 to 164 months (median time of liver metastases presentation was 16 months for patients undergone primary curative surgery). The liver metastases were estimated as resectable in 3 cases (8.6%) and hepatic resection of all gross lesions was possible. Group of 32 patients with unresectable liver involvement was considered to treatment with imatinib. The median time of imatinib treatment for survivors is 7.5 months (range: 3.5-18.5 months). Twelve patients (37.5%) demonstrated partial response (PR) and 16 patients (50%) stable disease (SD) according to RECIST criteria. We did not observe any complete response (CR). At median follow-up 7 months, 32 of 35 patients (91.4%) were alive, 3 patients (8.6%)remained free of disease and 28 patients (87.5%) remained on imatinib treatment and have maintained disease although with partial response or stabilization only. Radical surgical resection remains the only possibility of cure for GIST patients because the complete response after imatinib therapy is restricted to a few patients only. However, despite the advanced metastatic disease, approximately 90% of patients are alive and continue imatinib treatment with median follow-up time more than 7 months. Surgery in combination with adjuvant imatinib treatment may result in improved survival with patients with advanced GIST.

Lymph node status and survival in cutaneous malignant melanoma--sentinel lymph node biopsy impact.

AIM: The survival benefit of sentinel lymph node biopsy (SLB) with lymphadenectomy for microscopic melanoma metastases to regional lymph nodes (SLND) is uncertain. The aim of the study was to analyse the factors influencing clinical outcome (overall survival (OS) and disease free survival (DFS)) of patients undergone lymph node dissection (LND) as result of positive sentinel lymph node disease (SLND) or as consequence of clinically detected metastases (CLND). PATIENTS AND METHODS: This was a single-institution retrospective analysis of survival data of 350 consecutive, prospectively collected, melanoma patients who underwent radical LND in 1995-2001. One hundred and forty-five patients underwent SLND and 205 underwent CLND. RESULTS: The median OS and DFS times of the entire group of melanoma patients, computed from the date of primary lesion excision, were 46.3 months and 26.5 months (5-year OS ratio 41.8% and 5-year DFS ratio 31.5%). The factors which correlated with poor OS by multivariate analysis were: primary tumour Breslow thickness >4 mm (p=0.001), extracapsular extension of lymph node metastases (p=0.004), male sex (p=0.001) and metastases to more than one regional lymph node (p=0.04). The negative factors for DFS were: nodal extracapsular invasion (p=0.00002) and primary tumour Breslow thickness >4 mm (p=0.004). There were no significant differences in OS and DFS between SLND and CLND groups, when calculated from the date of primary tumour excision. However, if OS and DFS were estimated from the date of LND, the SLND group demonstrated significantly better survival in comparison with CLND. CONCLUSION: The study demonstrates no survival benefit from SLB with subsequent radical regional LND in malignant melanoma patients with lymph node metastases.

Detection of circulating melanoma cells in peripheral blood by a two-marker RT-PCR assay.

The aim of this study was to develop a highly sensitive two-marker assay for the detection of circulating melanoma cells in patients' blood using a reverse transcriptase-polymerase chain reaction (RT-PCR). We analysed the usefulness of two different sets of markers: tyrosinase and MUC-18 (TYR/MUC-18), and tyrosinase and MART 1 (TYR/MART 1). Total cellular RNA was isolated from 337 blood samples from 80 melanoma patients at different stages of the disease. All patients had undergone primary surgery. Assay sensitivity and specificity were confirmed using three different melanoma cell lines and two different fibroblast lines. In addition, blood from 47 healthy subjects and 10 patients with non-melanoma cancer was used as a negative control. We found that two-marker analysis is more accurate than the single tyrosinase assay. The frequency of melanoma cell detection in patients' blood was about 10% higher when the TYR/MART 1 two-marker assay was used. Using this assay we did not find any statistical correlation between the molecular markers and the UICC stage of disease or the Breslow thickness or Clark level of the primary melanoma. The frequency of melanoma cell detection with the TYR/MUC-18 two-marker assay was even higher than the TYR/MART 1 assay, but unfortunately the MUC-18 transcript was also present in about 20% of healthy subjects. Therefore we do not recommend the use of MUC-18 as a standard value marker.

Fluorescence in situ detection of human cutaneous melanoma: study of diagnostic parameters of the method.

Multicenter study of the diagnostic parameters was conducted by three groups in Poland to determine if in situ fluorescence detection of human cutaneous melanoma based on digital imaging of spectrally resolved autofluorescence can be used as a tool for a preliminary selection of patients at increased risk of the disease. Fluorescence examinations were performed for 7228 pigmented lesions in 4079 subjects. Histopathologic examinations showed 56 cases of melanoma. A sensitivity of fluorescence detection of melanoma was 82.7% in agreement with 82.5% found in earlier work. Using as a reference only the results of histopathologic examinations obtained for 568 cases we found a specificity of 59.9% and a positive predictive value of 17.5% (melanomas versus all pigmented lesions) or 24% (melanomas versus common and dysplastic naevi). The specificity and positive predictive value found in this work are significantly lower than reported earlier but still comparable with those reported for typical screening programs. In conclusion, the fluorescence method of in situ detection of melanoma can be used in screening large populations of patients for a selection of patients who should be examined by specialists.

Alterations of routine blood tests in adult patients with soft tissue sarcomas: relationships to cytokine serum levels and prognostic significance.

BACKGROUND: It has been reported that malignancy is often accompanied by hematological alterations and that such alterations may correlate with poor prognosis. It has also been demonstrated that several cytokines may be synthesized by many malignant tumors and that elevated serum levels of some cytokines are associated with changes in blood cell counts in cancer patients. However, so far little is known about the prognostic significance and mechanism of hematological changes in soft tissue sarcomas. The aim of the study was to evaluate the routine blood tests of disturbances in patients with malignant soft-tissue tumors prior to treatment and to correlate these results with selected cytokine serum levels, clinicopathological features of the tumors and patient survival. PATIENTS AND METHODS: 145 patients (75 males, 70 females; mean age 49.97 +/- 16.9 yrs) with histologically confirmed soft tissue sarcomas before treatment were enrolled into the study. In all these patients we evaluated routine blood tests (hemoglobin level HGB, white blood cell count WBC, platelet count PLT, white blood cell differential count-neutrocyte count NE, lymphocyte count LY, monocyte count MN, eosinophile count EO) and serum levels of 13 cytokines and soluble cytokine receptors (IL-6, IL-8, IL-10, TNFalpha, G-CSF, M-CSF, bFGF, VEGF, IL-1ra, sIL-2R. sIL-6R. TNF RI, TNF RII)--ELISA method. Peripheral blood samples from 50 healthy volunteers served as control. Statistical analysis was performed using Kolmogorov-Smirnov and Mann-Whitney U-tests, chi2 test (P < 0.05), where appropriate. For survival analysis the Kaplan-Meier method, log-rank test and multivariate Cox analysis were applied. RESULTS: Alterations of at least one of the standard blood tests were found in 43.4% of all cases. The most frequent alterations were: neutrophilia (28.3% of cases), leukocytosis (27.6%), decreased HGB (25.5%), monocytosis (19.3%) and thrombocytosis (14.5%); they correlated strongly with elevated serum levels of several cytokines and soluble cytokine receptors (particularly: sIL-2R, IL-6, IL-8, M-CSF, VEGF, TNF RI, TNF RII) (P < 0.001). Lymphocytopenia (LY < 1.0) found in 10.3% of patients correlated strongly with increased serum levels of IL-6, sIL-2R, TNF RI. In parallel, we found a significant difference in serum levels of 11 of 13 cytokines (IL-1ra. sIL-2R, IL-6, IL-8, IL-10, TNF RI, TNF RII, TNFalpha, M-CSF, bFGF, VEGF) (P < 0.001) in soft tissue sarcoma patients compared to healthy controls. Hematological alterations were significantly more frequent in patients with advanced tumors. In multivariate analysis we found no prognostic significance of any of the routine blood tests in soft tissue sarcoma patients. CONCLUSION: The results of this study demonstrate that hematological alterations, which occur in over 40% of soft tissue sarcoma cases, are found more frequently in patients with advanced tumors. Strong correlations between the occurrence of hematological abnormalities and elevated serum levels of several cytokines and soluble cytokine receptors, suggest that the former may develop as a result of cytokine misbalance frequently detected in soft tissue sarcoma patients. However, the results of routine blood tests alone are no independent prognostic factor for survival of soft-tissue sarcoma patients.

Sentinel lymph node biopsy in cutaneous melanoma: the WHO Melanoma Program experience.

BACKGROUND: We report the experience of the World Health Organization (WHO) Melanoma Program concerning sentinel lymph node (SLN) biopsy for detecting patients with occult regional nodal metastases to submit to selective regional node dissection. METHODS: From February 1994 to August 1998, in 12 centers of the WHO Melanoma Program, 892 SLN biopsies were performed in 829 patients with clinical stage I melanoma (male: 370; female: 459; median age: 50 years old). The location of the primary melanoma was as follows: trunk 35%; lower limbs, 45%; upper limbs, 18%; and head and neck, 2%. Blue dye injection for SLN identification was performed in all cases; preoperative lymphoscintigraphy was done in 440 patients, and an intra-operative probe for a radio-guided biopsy was used in 141 cases. Overall, the SLN identification rate was 88%. In 68% of the patients, only one SLN was identified, whereas two and three or more SLN were detected in 24% and 8% of the remaining cases, respectively. RESULTS: Overall SLN positivity rate was 18%. Intra-operative frozen section examination was performed in 39% of the cases and was helpful in detecting occult localizations only in 47% of the positive SLNs. Distribution of positive cases by primary thickness was as follows: < 1mm: 2%; 1-1.99 mm: 7%; 2-2.99 mm: 13%; and > or = 3 mm: 31%. Positive nonsentinel lymph nodes were found in 22% of cases with positive SLN submitted for selective dissection. No complications due to the procedure were registered. Of 710 patients who were evaluated, 40 (6%) presented a regional nodal relapse after a negative SLN biopsy and underwent a delayed therapeutic dissection. From the 710 enrolled cases, 638 (88.5%) were alive without evidence of disease at the time of this writing. A multivariate analysis showed SLN status as one of the most significant prognostic factors (P = .000) along with thickness (P = .001) and ulceration (P = .015) of primary tumor. CONCLUSIONS: These data confirm the feasibility and safety of the SLN technique for selecting patients to submit to a radical node dissection. The data represent the basis for a future trial by the WHO Melanoma Program in this field to evaluate the most appropriate surgical approach for treating patients with occult regional nodal metastases.

Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group.

PURPOSE: To assess antitumor response and time to progression (TTP) with docetaxel compared with doxorubicin in first-line treatment of advanced and/or metastatic soft tissue sarcoma. PATIENTS AND METHODS: Patients with measurable soft tissue sarcoma lesions and adequate bone marrow, liver, and renal function were entered onto the study. They were randomized to either docetaxel 100 mg/m(2) given as a 1-hour intravenous infusion every 3 weeks or doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks. A maximum of seven cycles of treatment were scheduled. The study was designed as a randomized phase III study evaluating TTP by log-rank model. There was a clause for premature closure of the trial if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm. RESULTS: Eighty-six patients were entered onto the study; 85 were assessable for toxicity and 83 for response. The rate of severe granulocytopenia was not significantly different between the two arms. Nausea (P =.001), vomiting (P <.001), and stomatitis (P =.005) were more common with doxorubicin therapy, whereas neurotoxicity was more frequent with docetaxel treatment. The response rate to doxorubicin therapy was 30% (95% confidence interval, 17% to 46%), whereas no responses to docetaxel therapy were seen (P <.001). In view of this, the trial was closed prematurely and the phase III study part was not conducted. CONCLUSION: Docetaxel is inactive in soft tissue sarcomas and cannot be recommended for further use in treatment of this disease.

Comparison between the in vitro intrinsic radiation sensitivity of human soft tissue sarcoma and breast cancer cell lines.

The purpose of this study is to evaluate the radiation sensitivity of human soft tissue sarcoma cell lines in vitro and to compare with that of human breast carcinoma and glioblastoma cell lines. The intrinsic radiation sensitivity parameters of seven human soft tissue sarcomas and eight breast carcinoma cell lines were investigated in vitro by clonogenic assays for single-dose irradiation under aerobic conditions on cells in exponential phase of growth. The results for sarcoma cell lines showed that the mean surviving fraction at 2 Gy (SF2) was 0.39 (SD +/- 0.09) with a range of 0.24 to 0.53, and the average mean inactivation dose (MID) was 1.92 (SD +/- 0.35) range from 1.36 Gy to 2.49 Gy. These values were not different from that of breast cell lines examined concurrently and using the same experimental methods (mean SF2 0.38, SD +/- 0.09; MID 1.9 Gy, SD +/- 0.37). However radiobiological parameters of nine karyotyped human malignant glioma cell lines determined earlier in this laboratory were significantly higher (mean SF2 0.50 +/- 0.14; mean MID 2.61 +/- 0.60). In conclusion, the data presented here do not support the view that cells of sarcomas show unusual radiation resistance. To the extent that the in vitro determined cellular radiation sensitivity reflects the tumor response in vivo, the success rate for radiation applied against sarcoma and breast carcinoma of comparable size could be similar.

Quantitative comparison of xenotransplantation of a human soft tissue sarcoma into the subcutaneous tissue of normal, postincision, and postincision plus indomethacin-treated nude mice.

The purpose of this study was to test the hypotheses that (1) surgical wounding can enhance the xenotransplantability of a human soft tissue sarcoma (HSTS26T) into subcutaneous (s.c.) tissue of nude mice, and (2) Indomethacin may reduce the xenotransplantability of this human tumor in the surgical wounding animal model by suppressing angiogenesis. The experimental method was to employ the quantitative transplantation assays (TD50, the number of tumor cells that, on average, would be expected to induce a tumor in 50% of the recipients). After an incisional wound (1.0-1.2 cm long) was made on the right leg of each experimental mouse, tumor cells were inoculated into the surgical wound, or into the contralateral leg at 24 and 72 hr postincision, and in another group tumor cells were inoculated into the wound at 72 hr postincision, plus daily s.c. injection of indomethacin, 2 mg/kg body weight for 8 consecutive days in a separate experiment. Nonincisional mice received the same inoculation as the control groups. The TD50s of surgically wounded groups were 3.5-10.7 times lower than that of the control groups. Significantly lower TD50 values were found in groups of cells inoculated into the surgical wound at 72 hr postincision (P < 0.05 or P < 0.01) and into the contralateral leg at 24 hr postincision (P = 0.05). No significant difference was found between the TD50 values in mice that received cells inoculated at 72 hr postincision plus indomethacin treatment, and those with no wound controls. Our conclusion is that the surgical wound can enhance the xenotransplantability of HSTS26T in nude mice. Indomethacin can decrease this enhancing effect level similar to that in no-wound controls and may prevent tumor recurrence in a surgical wound.

Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

PURPOSE: To evaluate the benefit of adjuvant chemotherapy in adult patients with soft tissue sarcomas. The principal end points were freedom from local recurrence and/or metastases and overall survival. PATIENTS AND METHODS: Between January 1977 and June 1988, 468 patients entered this randomized study and 317 were considered eligible. Following complete surgical resection with or without radiotherapy, outcome in 145 eligible patients receiving cyclophosphamide 500 mg/m2 intravenously (IV) bolus on day 1, vincristine 1.4 mg/m2 IV bolus on day 1, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) 50 mg/m2 IV bolus on day 1, and dacarbazine (DTIC) 400 mg/m2 by 1-hour infusion on days 1 to 3 (CYVADIC) cycles repeated every 28 days for eight courses was compared with that in 172 control patients. RESULTS: With a median follow-up duration of 80 months (range, 39 to 165), actuarial percentage survival figures at 7 years were compared. Relapse-free survival rates were higher for CYVADIC, 56% versus 43% (P = .007), and local recurrence was significantly reduced in the CYVADIC arm at 17% versus 31% (P = .004). In contrast, distant metastases occurred with similar frequency in both arms, 32% for CYVADIC versus 36% for control patients (P = .42), and overall survival rates were not significantly different at 63% versus 56% (P = .64). A reduction in local recurrence was only apparent in the group of head, neck, and trunk sarcomas (P = .002), but not in limb tumors (P = .31). CONCLUSION: Adjuvant chemotherapy with CYVADIC cannot be recommended outside the context of a clinical trial. Experience from this study has been used to plan a trial of neoadjuvant chemotherapy with doxorubicin/ifosfamide, which is currently in progress.

Quantitative comparison between the transplantability of human and murine tumors into the subcutaneous tissue of NCr/Sed-nu/nu nude and severe combined immunodeficient mice.

In previous reports, nude mice have demonstrated residual immunoreactivity against xenografts. Severe combined immunodeficient (SCID) mice lack functional T- and B-cells. These animals are expected to be better hosts in which to perform preclinical studies on human tumors. The purpose of this study is to quantitate the advantage of SCID mice over nude mice in terms of transplantability of human and murine tumors and the importance of residual immunity in SCID mice. The transplantation assays are described by an assay based on the number of tumor cells required to transplant tumor into 50% of recipients (TD50). Seven human tumors of different histology and four murine tumor cell lines were used. Serial 2-10-fold dilutions of cells were injected (0.1 ml) into the flanks of normal and whole-body irradiated WBI nude and SCID mice. The results showed that in 6 of 6 human tumor cell lines studied, TD50S for SCID mice were 2.4 to 200 times lower than that of nude mice (significant in 5 cell lines). In contrast, in 2 of 3 murine tumors, TD50S in WBI SCID mice were significantly higher than that found in nude mice. When SCID and nude mice received WBI, TD50S were lower than those of nonirradiated animals in 5 of 5 xenografts (significant in 2 cell lines for nude mice and in 5 cell lines for SCID mice). We concluded that WBI SCID mice are significantly better recipients of human tumor xenografts than nude mice. There is a factor of 10-1625 gain in TD50S in favor of the WBI SCID mice when compared to nonirradiated nude mice. WBI has, however, an important effect on SCID mice which may suggest a detectable residual immunoreactivity, perhaps due to natural killer cells. These data demonstrate that WBI SCID mice are better models for human tumor transplantation that nude mice and, although WBI at 6 Gy suppressed significantly the immune system of nude mice, a certain level of immunoreactivity against xenografts is still maintained.

Induced soft tissue sarcomas following radiation treatment for uterine carcinomas.

Twenty-two cases of sarcomas arising from irradiated soft tissues were observed in 531 patients operated on for soft tissue sarcomas over 38 years in our Department. Eleven women were initially irradiated for cervical cancer (ce-ca), two for endometrial cancers. The remaining nine patients were irradiated for other lesions, malignant or benign. The median interval between the radiation for uterine cancer and the outcome of clinical symptoms of a sarcoma was 18 years. Sarcomas more frequently arose in the posterior fields (buttock or sacral region in nine patients) than in the anterior (pubis, hypogastrium-four patients). The infiltration of skin was almost always present (10/13), in seven cases with an ulceration (7/13). Histologically, four hemangiosarcomas, four fibrosarcomas, three malignant fibrous histiocytomas and two neurofibrosarcomas were found. The irradiation administered to ce-ca patients consisted of radium (22.0 mcd to 58.0 mcd) and an external radiation from X-ray units (except in one case) from two pairs of two anterior and posterior fields, with skin doses of 3200 cGy to 4200 cGy directly on one field plus several hundreds cGy from the opposite field. Three-year overall survival rate was low (30%) similar to that observed in patients with primary high-grade (G-3) sarcomas. We observed more cases subjected to radiotherapy for cervical cancer than might be expected.

Clinical factors and treatment parameters affecting prognosis in adult high-grade soft tissue sarcomas: a retrospective review of 267 cases.

Data on 267 adults with high-grade soft tissue sarcomas were reviewed. Male sex, large tumor size, Stage IIIC, IV A and sarcomatous skin invasion, as well as marginal excision, amputation, postoperative fever and wound infection, were found to be associated with shorter survival time. Head and neck location, multifocal growth of sarcoma. Stage IIIC, malignant skin infiltration, locally recurrent tumor as well as marginal excision and limb-sparing resection, were found to influence local control unfavorably in single factor analyses. Each of the significant variables were entered into a multivariate proportional hazards model in a stepwise manner. Stage, postoperative fever, the surgical margin and type of surgery, and sarcomatous skin changes significantly affected survival time. Local recurrence was significantly affected by the surgical margin and type of surgery, the status of tumor (primary or recurrent), stage and malignant skin infiltration.

[Value of adjuvant treatment applying the "CYVDIC" program after surgical treatment of soft tissue sarcomas. Preliminary communication]. / Wartosc leczenia uzupelniajacego programem--"cyvadic" po operacji miesaków tkanek miekkich doniesienie wstepne.

The EORTC Soft Tissue and Bone Sarcoma Cooperative Group carries out since 1978, prospective study of the "CYVADIC" (Cyclophosphamide, Doxorubicin , Vincristine and Dacarbazine) programme applied in the postoperative course in patients with soft tissue sarcomas. The group of 24 patients treated in the Oncology Center-Institute in Warsaw entering this international programme is presented. Results so far obtained by the EORTC Cooperative Group concerning 358 patients introduced from over 15 oncologic centers from various European countries are discussed. Neither the improved survival nor extension of the free of metastases period in patients treated with chemotherapy have been observed in comparison with the control groups. The authors conclude that at present time there is not any evidence indicating the favourable results of treatment applying the "Cyvadic" programme as adjuvant therapy in the postoperative course of treatment of soft tissue sarcomas.