Ewing Sarcoma tumor cells express CD34: implications for autologous stem cell transplantation.

The significance of tumor cell contamination in marrow and peripheral blood stem cell (PBSC) collections of patients with solid tumors remains controversial. Various methods have been developed to purge tumor cells from autologous stem cell products, including CD34+ selection. PBSC harvests from patients with Ewing family of tumors (EFT) were analyzed for contaminating tumor cells prior and after CD34+ selection using reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC) analyzes. The expression of CD34 was studied by RT-PCR and FC in 14 primary tumors and 13 PBSC harvests, respectively. Tumor cells were identified in the harvests by both methods. In two patients, contaminating tumor cells were evident by RT-PCR only after positive selection. FC analysis confirmed a higher level of tumor cells in the CD34+ fraction. In an attempt to explore this finding, expression of CD34 was detected in 93% of primary tumors and 67% of contaminated harvests. As CD34 is expressed on EFT cells, these cells may be enriched following CD34+ selection of harvests, although the total number of tumor cells is reduced. Other methods of purging, rather than CD34+ selection, should be explored in patients with EFT undergoing autologous stem cell transplantation.

Synovial sarcoma of the extremities and trunk: a long-lasting disease.

Synovial sarcoma (SS) of an extremity or trunk is relatively rare and is approached by limb sparing surgery (LSS), radiation therapy (RT) and chemotherapy. We conducted a retrospective analysis of the clinical and histopathological data of 73 patients with proven SS. At a median follow-up time of 6 years, local recurrence was seen in 17.8 and systemic recurrence 35.6% of patients (local-only, 6.8; systemic-only, 24.6; combined, 11%). The 10-year local recurrence-free survival (LRFS), systemic recurrence-free survival (SRFS) and overall survival (OS) rates were 78, 68 and 61%, respectively. LRFS was significantly better in patients treated with isolated limb perfusion (ILP); SRFS was influenced by the delay until diagnosis. The practical aspects of our observations are the need for long-term follow-up in order to diagnose recurrences, the fact that not all local or distant recurrences are necessarily associated with a shortening of OS time and the important role of induction ILP with TNF in cases of extremity SS.

Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy.

Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumour, the type of liposarcoma and the quality of resection. Our results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma.

Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors.

PURPOSE: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT). PATIENTS AND METHODS: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated. RESULTS: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P <.0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P =.0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery. CONCLUSION: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.

ErbB-4 expression in limb soft-tissue sarcoma: correlation with the results of neoadjuvant chemotherapy.

ErbB-4 is a recently described growth factor receptor. Relatively little is known about its expression in human tumours. In this study, we assessed the possible role of erbB-4 as a tissue marker for soft-tissue sarcomas (STS) and its correlation with the response to chemotherapy. The histological specimen of 29 patients with STS of a limb who had received preoperative doxorubicin (ADR)-based chemotherapy were studied for the degree of necrosis and the expression of erbB-4 (by an avidin-biotin-peroxidase technique). ErbB-4 expression in the preoperative tissue samples was compared with the expression in the postchemotherapy resected tumour. The true objective response rate to preoperative chemotherapy was 34%. Wide resection of the tumour was done in 12 patients, marginal in 14, amputation in 2 and no surgery in 1. The tumour necrosis was above 90% in 9 patients, 60-90% in 12, and less than 60% in 7 patients. An increase in erbB-4 expression was more common in cases with no response to chemotherapy, while no change or a decrease in erbB-4 was more common in responsive tumours (P=0.004). No correlation could be found between the degree of necrosis or the chemotherapeutic regimen and the change in expression of erbB-4. The median disease-free survival (DFS) was longer for patients with a decrease or no change in expression of erbB-4 than for patients with increased expression. It is believed that postchemotherapy new expression or no downregulation of the erbB-4 molecule represents tumour aggressiveness and increased capability of growth and spread.

Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

BACKGROUND: The management of extensive, recurrent limb desmoid tumors is extremely difficult. The failure of multimodality treatments, such as repeated resections, radiotherapy, systemic chemotherapy, or endocrine manipulations, can end up with multilating surgery or even amputation, similar problems sometimes encountered in soft tissue sarcoma of the limbs. The high rate of limb salvage achieved by isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan for extensive, high-grade soft tissue sarcoma led us to implement this modality in difficult cases of limb desmoids. METHODS: During a 4-year period, 6 patients aged 14 to 52 years were treated. All were significantly symptomatic and candidates for amputation or mutilating surgery. Five had lower and one had upper limb lesions. Two had multifocal disease. At ILP, 3 to 4 mg TNF and 1 to 1.5 mg/kg melphalan were delivered during a 90-minute period. One patient had a double perfusion. All patients underwent definitive resective operation 6 to 8 weeks after perfusion. RESULTS: No systemic complications were observed, and local complications included reversible skin redness and blisters. Response rate was 83% with 33% (2 of 6) complete response and 50% (3 of 6) partial response. In 1 patient less than 50% regression was observed. Limb salvage rate was 100%; even the patient with stabilization of disease could be locally resected. Local recurrence during a follow-up period of 7 to 55 months (median 45 months) occurred in 2 patients at 8 and 24 months, respectively; the first underwent amputation, whereas for the second a wide excision was possible. CONCLUSIONS: ILP with TNF and melphalan can be used as a limb preservation modality in patients with recurrent desmoids and significant symptoms who would otherwise require multilating surgery to control their neoplasm.

Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study.

PURPOSE: To assess the efficacy of gemcitabine in patients with a variety of sarcomas that have failed to respond or escaped Adriamycin- and ifosfamide-based chemotherapy. PATIENTS AND METHODS: A group of 18 symptomatic heavily pretreated patients with sarcomas of bone or soft tissue received one induction course of gemcitabine at a dose of 1000 mg/m(2) per week for 7 consecutive weeks, followed by 1 week rest. Response to the induction course was assessed by interview and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000 mg/m(2) per week for 3 weeks every 28 days was given until failure was clinically or radiologically evident. RESULTS: A total of 51 cycles of gemcitabine were given including 18 cycles of induction. A mean of 3.6 postinduction cycles were given to nine patients. The treatment was well tolerated by the patients. One partial response (leiomyosarcoma) and one minimal response (angiosarcoma) were observed, yielding a true objective response rate of 5.5%. An additional six patients achieved stabilization of disease (chondrosarcoma and osteosarcoma), yielding an overall progression-free rate of 44%. The median time to progression was more than 27 weeks. Clinical benefit response was observed only in those who also achieved a progression-free state. CONCLUSION: Gemcitabine was found to be effective in achieving stabilization and even a minimal response of soft tissue or bone sarcoma refractory to standard chemotherapy.

Adriamycin-ifosfamide induction chemotherapy for extremity soft tissue sarcoma: comparison of two non-randomized protocols.

Chemotherapeutic cytoreduction of soft tissue sarcomas may permit less radical operation. In cases of large or multi-compartmental masses, deeply seated tumors or involvement of a neurovascular bundle, down-sizing of the mass is required before limb sparing surgery can be considered. We have applied a combination chemotherapy consisting of intravenous adriamycin and ifosfamide with intra-arterial cisplatin for patients with soft tissue sarcomas of the extremity as induction treatment, and switched to an intravenous-only protocol due to toxicity and management difficulties. Adjuvant chemotherapy and radiation therapy were given after limb-sparing surgery in both regimens. Fresh tumor specimens were obtained and were examined for tumor size, surgical margins, percent of necrosis, evidence of vascular or perineural invasion, and the presence of Pgp, Ki-67, p53, PCNA and bcl-2-oncoprotein. Our results in terms of percentage of tumor necrosis were comparable and even better in favor of the second regimen [38% good histological response with intravenous (i.v.)-only versus 12.5% for combined i.v. + intra-arterial (i.a.]. The clinical and radiological responses were also better for the second (i.v. only) regimen (45%) than for the first (i.v. + i.a.) regimen (12.5%). The toxicity and the inconvenience to the patients and to the treating staff were greater in the first regimen that combined intra-arterial and intravenous infusions. In the first group the failure rate is 75% within 32 months of follow-up, while it is 33% within 12 months follow-up in the second group. The immunohistochemical markers did not correlate with disease control nor with the patient outcome. Intravenous administration of ADR-IFX induction chemotherapy was more feasible than combined i.v. ADR-IFX plus i.a. cisplatin and achieved better results.

Carcinoid tumor of the coccyx: case report and review of the literature.

STUDY DESIGN: Report of a patient with a carcinoid tumor of the coccyx. OBJECTIVES: To describe the clinical presentation, diagnosis, and treatment of a patient with a carcinoid tumor of the coccyx and to review the relevant medical literature in English. SUMMARY OF BACKGROUND DATA: No reports of a carcinoid tumor of the coccyx were found in the literature. Seven reports of carcinoid of the sacrum are described. METHODS: Clinical history, magnetic resonance imaging studies, and light and electronic microscope micrographs are reviewed. RESULTS: A coccygeal mass was detected during evaluation of coccygodynia in a 40-year-old woman. Four years after extended coccygectomy, there are no signs of local tumor recurrence. CONCLUSIONS: Carcinoid tumor of the coccyx is extremely rare. An extended coccygectomy may lead to a cure or at least to a prolonged disease-free interval.

Primary chronic sclerosing (Garré's) osteomyelitis in children.

Three children with unifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were located at the metaphyseal region of long bones. Three was progressive sclerosis and hyperostosis in the tibia or femur, such as the changes described in Garré's osteomyelitis. No pus was released by exploration of the lesions. Tissue and blood cultures were negative. The histology was typical of chronic osteomyelitis: the symptoms returned intermittently over several years, together with the development of sclerosis but without disturbance of bone growth. It is not clear whether Garré's chronic sclerosing osteomyelitis is a different entity from chronic recurrent multifocal osteomyelitis.

Chondrosarcoma of the larynx: a therapeutic challenge.

The diagnosis of laryngeal chondrosarcoma is likely to be missed because of its infrequent occurrence and its indolent pattern of growth. A 53-year-old woman came to our service with an 18-year history of hoarseness and increasing dyspnea. She had been previously documented as having left vocal fold paralysis and a bulging laryngeal mass. Computed tomography revealed the presence of a large calcified tumor that had caused a deformity of the larynx and an erosion of the arytenoid and cricoid cartilages. Direct laryngoscopy detected a large supraglottic mass with a normal-appearing mucosa. Total excision of the tumor was achieved through a lateral neck incision that spared the larynx. This case emphasizes the importance of a high index of suspicion for laryngeal chondrosarcoma in a patient who has unexplained vocal fold paralysis and a submucosal subglottic mass. Every effort should be made to take a conservative surgical approach that preserves laryngeal function when possible.

Is it important to maintain high-dose intensity chemotherapy in the treatment of adults with osteosarcoma?

Neoadjuvant chemotherapy for osteosarcoma is the standard of care, but there is still confusion regarding the best chemotherapy regimen and the optimal intensity. This retrospective study intends to evaluate whether there is a clear correlation between the chemotherapy dose intensity (DI) and the percentage of tumor necrosis, the risk of tumor recurrence after surgery and patient survival. The medical records of all adult patients with localized osteosarcoma that received treatment between the years of 1998 and 2009 at the Tel Aviv Sourasky Medical Center were analyzed. We used multiple logistic/linear regression models to test the effect of the neoadjuvant chemotherapy relative DI (RDI) on histological response, recurrence and time to recurrence. A Cox regression analysis was conducted for the effects of neoadjuvant chemotherapy RDI, histological response, tumor location, gender and age on patient survival. Thirty medical records were analyzed. Survival, histological response, recurrence and time to recurrence were not affected by the chemotherapy RDI. The 5-year overall survival of the patient's population was found to be 63% with a median survival of 9.4 years. Patients with a good histological response had a longer survival than those with a bad response (mean survival times 11.0 vs. 6.6 years, log-rank test, P = 0.046). High DI is not a prognostic factor in osteosarcoma and maintaining it should not be a prime priority. Histological response is a prognostic but possibly not a reliable predictive factor, and further research is needed in order to find other reliable factors.

Hypofractionated adjuvant radiation therapy of soft-tissue sarcoma achieves excellent results in elderly patients.

OBJECTIVE: Adjuvant radiation therapy (RT) is an essential part of combined limb-sparing treatment of soft-tissue sarcoma (STS). Elderly or medically unfit patients often have difficulty in completing 6-7 weeks of standard fractionated daily treatment. Our aim was to evaluate the efficacy of a hypofractionated adjuvant approach with RT for STS in elderly and debilitated patients. METHODS: 21 elderly patients were treated with a short course of adjuvant RT (39-48 Gy, 3 Gy per fraction) for STS. The medical records of the patients were retrospectively reviewed for local or distant recurrence and side effects of RT. RESULTS: At a mean 26 months of follow-up, three local recurrences (14%) were detected. Eight patients (38%) had lung metastases during the observed period. Three of them died from metastatic disease. The hypofractionated radiation was well tolerated with minimum long-term side effects. CONCLUSION: Hypofractionated adjuvant radiation appears to be an effective treatment in terms of local control in elderly and debilitated patients. ADVANCES IN KNOWLEDGE: The results of this study might provide an alternative to commonly used standard fractionation of radiotherapy in sarcoma patients.

Fifteen years of bone tumor cryosurgery: a single-center experience of 440 procedures and long-term follow-up.

BACKGROUND: This summary of a single center's extensive cumulative experience in bone tumor cryosurgery assesses the long-term outcome of bone conservation surgery in which adjuvant cryosurgery plays a pivotal role. MATERIALS AND METHODS: We performed 440 cryosurgical procedures between January 1988 and December 2002. Two-thirds of the series comprised a variety of primary benign-aggressive and low-grade malignant lesions, and one-third were primary high-grade and metastatic bone tumors. The anatomical locations included almost every bone of the skeleton. Two methods of bone cryosurgery were used: Marcove's "open" direct-pour system using liquid nitrogen (1988-1997) and Meller's "closed" argon-based system (1998 to the present). RESULTS: The study cohort consisted of 214 males and 191 females (age range 5-82 years). The median follow-up was 7 years (range 3-18). The overall local recurrence rate was 8%: fractures=1%, infections=2% and skin burns=1.3%. There were three cases of transient nerve palsies in areas other than the sacrum, and four cases of late osteoarthritis of an adjacent joint. The functional outcome for the 372 patients with no evidence of disease was almost 100% "good" and "excellent" (American Musculo-skeletal Tumor Society System). Only two patients needed secondary amputations. CONCLUSIONS: Bone cryosurgery is a safe and effective limb-, joint- and even epiphysis-sparing surgical technique in suitable types of bone tumors, temporarily or permanently obviating the need for resection surgery.

The effect of pneumoperitoneum on dissemination and scar implantation of intra-abdominal tumor cells.

PURPOSE: The role of laparoscopy for the treatment of cancer remains controversial, and a particular concern is port site metastases after laparoscopic surgery. Since laparoscopy is being performed with increasing frequency, the question arises as to whether it is a safe oncological procedure. After intraperitoneal inoculation of renal cell carcinoma cells in a mouse model, we compare abdominal wall scar implantation following laparoscopic trocar insertion and pneumoperitoneum with standard laparotomy, and examine the effects on tumor dissemination in the peritoneal cavity. MATERIALS AND METHODS: Following intra-abdominal RENCA cell inoculation, Balb/c mice were randomized into group 1-20 mice that underwent carbon dioxide pneumoperitoneum and telescope trocar insertion, group 2-20 subjected to laparotomy and group 3-10 anesthetized only. All animals were sacrificed 2 weeks after inoculation, and abdominal wall metastases and intraperitoneal tumor distribution were evaluated. RESULTS: Overall, intra-abdominal implantation of inoculated RENCA tumor cells was detected in 15 of 20 animals (75%) in group 1, 14 of 20 (70%) in group 2 and 10 of 10 (100%) in group 3. Wound metastases developed in 46.7% of the mice in group 1 and 50% in group 2. CONCLUSIONS: There was no difference among the groups in the pattern of intraperitoneal tumor implants and scar seeding incidence. Pneumoperitoneum does not facilitate port site metastases.

Cellular and molecular properties associated with osteosarcoma cells.

Osteosarcoma cells are recognized by abnormal function that causes a primary bone tumor. Osteosarcoma cells U(2)OS and SAOS-2 were analyzed for the expression of cell surface markers. High expression was quantified for hyaloronidase receptor (CD-44) > moderate for integrins (CD-51 and -61), > and lower for selectins (CD-62). High mitotic capacity were demonstrated by gene expression (measured by RT-PCR) and the protein level (measured by FACS) for cFOS, cMYC, and cJUN. The basic definition of osteosarcoma is excessive production of pathological osteoid. Expression of mRNA for matrix genes osteocalcin, osteonectin, and biglycan was studied. Osteocalcin and osteonectin were detected in RNA from primary cultured marrow stromal, trabecular bone cells, and osteosarcoma cell lines (U(2)OS, SAOS-2). mRNA for biglycan was detected only in primary cells and MG-63 cell line and was undetectable in RNA from U(2)OS, SAOS-2 osteosarcoma cell lines and by RNA extracted from bone biopsies of osteosarcoma patients. The absence of biglycan message observed in osteosarcoma samples provides evidence for the alterations in the extra cellular matrix which result with non-mineralized osteoid produced by the osteosarcoma cells.

Gemcitabine in bone sarcoma resistant to Doxorubicin-based chemotherapy.

SUBJECTS AND METHODS: Seven patients with progressive localized or metastatic chemo-resistant osteosarcoma were treated by gemcitabine.The protocol included gemcitabine 1000 mg/m2/w for 7 consecutive weeks, followed by 1 week rest. If no progression was observed,maintenance by gemcitabine 1000 mg/m2/w for 3 weeks every 28 days was given until failure was clinically or radiologically evident.Results. The true objective response rate was 0%. However, disease stabilization and clinical benefit response were observed in five patients (70%) for 13-96 weeks.Discussion. Postponing the inevitable death with a relatively non-toxic treatment, is, in our opinion, an important issue especially in young patients.Thus it may be justified and warranted to investigate the activity of gemcitabine in a larger group of patients with bone sarcomas.

Periosteal Ewing's Sarcoma: Report of Two New Cases and Review of the Literature.

Background. The origin of Ewing's sarcoma in a periosteal location is rare and not clearly documented. Other malignant bone tumors appear to have a somewhat better prognosis when confined between periosteum and bone. Is it the same for periosteal Ewing's sarcoma?Methods. We describe two new cases and comprehensively review the literature consisting of 18 documented cases since the condition was first described in 1986 (S.M. Bator.Cancer 58:1781- 4).Results. Periosteal Ewing's sarcoma differs from the other forms of Ewing's sarcoma in terms of sex predominance, location of tumor, surgical stage at presentation and typical imaging studies. Eighteen out of the 20 patients were reported to be alive with no evidence of disease.Conclusions. It seems that the prognosis of this rare variant of Ewing's sarcoma family of tumors might be better but the small number of cases precludes such a firm conclusion.