Malignant pleural mesothelioma: US-guided histologic core-needle biopsy.

PURPOSE: To assess the clinical use of ultrasonographically (US) guided core-needle biopsy, performed with a one-hand automatic sampling technique, in the diagnosis of malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: The authors reviewed the findings in 70 patients with a tentative diagnosis of MPM who underwent US-guided core-needle biopsy at our institution during the past 10 years. RESULTS: Fifty-two of the 70 patients who underwent automatic high-speed core-needle biopsy at our institution had MPM; 18 had other disorders. The correct diagnosis was made in 56 patients. Twelve of 14 inadequate biopsy specimens were false-negative for MPM. There were no false-positive biopsy results. In the detection of MPM, US-guided core-needle biopsy had a sensitivity of 77%, specificity of 88%, accuracy of 80%, positive predictive value of 100%, and negative predictive value of 57%. There were no serious complications. CONCLUSION: US-guided core-needle biopsy is highly effective in the diagnosis of MPM. Owing to its simplicity, low cost, and few side effects, it could be the biopsy method of choice for detection of this condition.

Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group Phase II Study.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.

Prognostic factors in bone sarcomas.

Based on a literature review and the SSG experience, the most important prognostic factors in high-grade osteosarcoma appear to be the presence of detectable metastases at diagnosis, tumour volume, old age, sex, histologic response, and possibly tumoral P-glycoprotein expression. However, for an adolescent patient with non-metastatic extremity disease, there is no consensus regarding prognostic factors at initial presentation, and currently there is thus no established method for dividing them into high- and low risk groups for the purpose of treatment differentiation. It should also be remembered that available prognostic factors have been identified only in a retrospective manner, following aggressive treatment of all patients. Thus patients in "favourable" prognostic groups may simply be patients who have had a good effect from aggressive treatment, and how they would have done with reduced treatment remains to be shown. Obviously the best method for prognostication would be the direct demonstration of micrometastatic disease in the lungs or in peripheral blood. In the relatively near future, this may become possible with immunoscintigrapy or immunohistochemistry utilizing monoclonal antibodies [29-31]. In Ewing's sarcoma, the most powerful factors indicating poor prognosis are metastases at diagnosis, poor histologic response, large tumour size and possibly pelvic localisation. There appears to be a somewhat better international consensus regarding prognostic factors in Ewing's sarcoma than in osteosarcoma. Although several studies have implemented intensified treatment for poor prognostic groups [8, 32], the role (if any) of high-dose treatment with stem cell rescue remains to be proven. The same factors are prognostic both for the development of metastases and local recurrence, but in addition, surgical treatment as opposed to radiotherapy appears to reduce local failure rate [12, 17, 33, 34]. As in osteosarcoma, the near future offers promise regarding the detection and quantification of micrometastatses and minimal residual disease, by means of PCR techniques recognizing specific genetic changes in the Ewing family of tumors [35].

Synovial sarcoma: immunohistochemical expression of P-glycoprotein and glutathione S transferase-pi and clinical drug resistance.

Our purpose was to study the role of the expression of P-glycoprotein (Pgp) and glutathione S transferase-pi (GST-pi) in predicting the response to chemotherapy, relapse-free interval, and survival of patients with synovial sarcoma (SS). Thirty-seven cases of primary SS, without regional lymph node or distant metastases, were studied. There were 17 females and 20 males, ranging in age from 7 to 81 years (median, 31 years) with tumors located in the lower extremity (n = 24) upper extremity (n = 5) and trunchus (n = 8). The cases were retrospectively studied without knowledge of clinical course to compare the immunohistochemical expression of Pgp and GST-pi, flow cytometry parameters (ploidy and % of cells in S+G2 phases), and PCNA and Ki-67 labeling of primary tumors before any therapy, with that observed in local recurrences and metastases after chemotherapy. The relationship of the aforementioned parameters with clinicopathological features (gender, age, and histo-blood group of the patients, size, location, histological subtype. TNM stage, and clinical response to chemotherapy of the tumors) was also evaluated. Results revealed that Pgp and GST-pi were expressed in 29.7% and 40.5% of the cases, respectively. In 48.6% of the tumors there was expression of a least one of the drug resistance markers. The markers were coexpressed in 25.0% of the tumors. The prevalence of Pgp expression was lower, but not significantly, in stage I-II (17.6%) than in stage III (40.0%) tumors, and also in cases without clinical progression (16.7%), than in cases with (36.0%). No such differences were observed for GST-pi expression. Pgp and GST-pi expressions were significantly associated with biphasic SS and were particularly noticeable in solid/glandular areas of biphasic SS. The expression of the drug resistance markers was not significantly associated with gender, age, and histo-blood group of the patients, dimension, location, and proliferative activity of the tumors; it was also not significantly related to relapse-free interval and survival of the patients. The expression of Pgp and GST-pi was not significantly associated either to response to chemotherapy or influenced by chemotherapy. We conclude that Pgp and GST-pi expressions are not good predictors response to of the chemotherapy in patients with localized SS. Other drug resistance mechanisms may be active in SS.

Targeted radiotherapy of osteosarcoma using 153 Sm-EDTMP. A new promising approach.

We report a case where targeted radionuclide therapy using 153Sm-EDTMP gave substantial palliative effect. A 35-year-old male with a primary osteosarcoma located in the first lumbar vertebra relapsed with progressive back pain after conventional treatment modalities had failed. He became bedridden, and developed paraparesis and impaired bladder function. On a diagnostic bone-scan intense radioactivity was localized in the tumor. He therefore was given 153Sm-EDTMP treatment twice, 8 weeks apart, 35 and 32 MBq/kg body weight respectively. After a few days the pain was significantly relieved and by the second radionuclide treatment the pareses subsided. For six months he was able to be up and about without any neurological signs or detectable metastases. Eventually, however, he experienced increasing local pain, developed paraparesis, was re-operated but died 4 months later. The dramatic transient improvement observed in this case warrants further exploration using 153Sm-EDTMP as a boost technique, supplementary to conventional external radiotherapy.

Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival.

BACKGROUND: A retrospective study of long term outcome after the development of metastases from osteosarcoma was performed, with emphasis on the impact of different treatment strategies and the identification of prognostic factors. METHODS: From 1975 to 1993, a population-based series of 60 patients with distant metastases (relapse) from high grade, extremity-localized osteosarcoma was treated at The Norwegian Radium Hospital. Six patients relapsed after surgery alone, 28 patients relapsed after primary chemotherapy of low potency, and 26 patients after modern, intensive chemotherapy. Lung metastases were present in 88% of the patients, 52% had bilateral lesions, and the median number of lesions was three (range, 1-25 lesions). Forty-seven percent of patients had complete surgical excision of all identifiable metastatic nodules and 54% of these had additional second line chemotherapy defined as adequate. Adequate chemotherapy included further dose escalations of methotrexate in approximately half of the patients, usually from 8 to 12 g. The rest were exposed to novel agents such as cisplatin, etoposide, and ifosfamide. Of the operated patients, 43% had additional thoracotomies after subsequent relapses. RESULTS: The projected 5-year survival rate from the first metastatic event was 24% for all patients and 50% for patients who underwent complete metastasectomy. In a multivariate analysis, the factors with independent predictive value for improved overall survival were the presence of a solitary metastasis, the accomplishment of complete metastasectomy, and the administration of adequate salvage chemotherapy. CONCLUSIONS: Complete metastasectomy is mandatory for long term survival of patients with metastatic osteosarcoma, and repeated lung resections are necessary in nearly half the patients. Second line chemotherapy and following primary treatment with modern intensive chemotherapy protocols may improve survival further.

Treatment of advanced, high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide.

A total of 33 patients (median age, 44 years) with high-grade, adult soft-tissue sarcoma were treated with etoposide given at 600 mg/m2 in a 72-h continuous infusion and ifosfamide given at 1500 mg/m2 per day for 3 days every 3 weeks. Dose escalation/reduction was protocolled depending on the level of hematological toxicity observed in the preceding course. Overall, 90% of patients had metastatic disease, and the most common histologies were malignant fibrous histiocytoma and leiomyosarcoma. A median of 5 (range, 1-9) courses were given. Of 30 patients who were evaluable for response, 12 (40%) obtained a partial remission, and the median time to progression was 8 (range, 4-13) months. Grade 3-4 leukopenia and thrombocytopenia were seen after 89% and 8% of the courses, respectively; neutropenic fever was seen in half of the patients (15% of courses); and 32% of courses had to be postponed by 7 days or more due to myelosuppression. Dose reduction to below the standard had to be performed in 46% of courses, and dose escalation was achieved in only 13%. The reduced toxicity seen after the addition of granulocyte colony-stimulating factor (G-CSF) in five patients indicates that growth-factor support may enhance the dose intensity of the regimen. The results indicate significant activity for this regimen in adult soft-tissue sarcoma, which may in part be a result of the escalated dose and prolonged mode of administration of the phase-specific agent etoposide. As a result of this pilot series, a phase II study with ifosfamide, etoposide, and G-CSF in advanced adult soft-tissue sarcoma has been initiated by the Scandinavian Sarcoma Group.

[Treatment of chondrosarcoma. A retrospective study at the Norwegian Radium Hospital]. / Behandling av kondrosarkom. En retrospektiv undersøkelse ved Det Norske Radiumhospital.

The authors present a retrospective analysis of 59 chondrosarcoma patients treated at the Norwegian Radium Hospital during the period 1981 to 1993. 31 patients were admitted with untouched tumour, seven after fine needle cytology and 20 after open biopsy or partial excision. One patient had recurrent local disease. Only 20% of the tumours were of high grade malignancy. 51 patients were treated by surgery. Reconstructions were performed in 16 patients, using allografts or endoprostheses. Amputations were performed in six cases and wide excision in 12 cases. In these 18 patients local recurrence appeared in one case, and two developed lung metastases. Only one of the 18 patients operated by amputation or wide excision has since died from chondrosarcoma. Marginal excisions were performed in 26 cases. Nine of these patients developed a local recurrence, five developed metastases and three have died. Six patients had partial excisions. Postoperative radiotherapy was given to one patient only. Five of the six are alive. In one case, the quality of the margins could not be evaluated. A total of 45 of the 51 patients treated for the primary tumour by surgery are alive. The median observation time is four years. Treatment of nonmetastatic chondrosarcoma should be surgical. Chondrosarcoma patients show wider variations in age, localization of tumour and tumour growth rate than patients with other bone sarcomas. Although wide excisions provide the best local control of any grade of malignancy, the mutilation or risk involved may be so great that some patients may benefit from marginal or even partial excision.

Immunoscintigraphy of bone sarcomas--results in 5 patients.

The feasibility of using the murine monoclonal antibody, TP-1, for clinical immunoscintigraphy was examined in a pilot study involving 5 patients with bone sarcomas. 131I-labelled F(ab')2 antibody fragments were injected in doses of 0.8-1.0 mg (90-130 MBq), and the accumulation of radioactivity was examined by scintigraphy, and assessed by direct measurements on biopsied tumour and normal tissue. One osteosarcoma patient had a primary tumour in the femur, whereas the other 4 had single lung metastases detected by other diagnostic methods. Immunoscintigraphy of the femoral primary was optimally visualised after 22 h. In 2 patients, the method failed to detect lung metastasis, in 1 of the cases possibly related to less than optimal methodological conditions. In 2 other patients, increased accumulation of radioactivity indicated one and three lung tumours, in addition to the single metastasis observed by X-ray and CT scanning, tumours that were later confirmed and removed surgically. The concentration of radioactivity in tumour and normal tissues 44-72 h after antibody injection could be measured in 4 patients. The tumour to blood ratios were in the range of 1.2-4.2, compared to 0.1-0.8 for various normal tissues. The results indicate that immunoscintigraphy with TP-1 antibody fragments have a potential for early detection of lung metastases in patients with bone sarcoma.

[Diagnostic aspects of subacute osteomyelitis in children and adolescents. Clinical and radiographic resemblance to primary malignant tumors]. / Diagnostiske aspekter ved subakutt osteomyelitt hos barn og ungdom. Klinisk og røntgenologisk likhet med primaer malign beintumor.

During a six-year period, 17 patients younger than 20 years of age, with a final diagnosis of subacute osteomyelitis, were admitted to the Norwegian Radium Hospital because of an initial suspicion of primary malignant bone tumour. The most common localizations were the metaphyses of long bones (eight patients) and the clavicle (four patients). Pain was the dominating symptom. Common radiological findings were localized osteolysis and/or sclerosis, cortical bone destruction, periosteal reaction and an adjacent, often palpable soft tissue mass. Clinical signs of infection were generally absent, and a positive bacterial culture was obtained from the biopsy material in only one patient. Following extensive investigations, a malignant bone tumour (especially Ewing's sarcoma) remained a differential diagnosis, and open biopsy was indicated in all cases. The patient material illustrates the difficulty in distinguishing between subacute osteomyelitis and malignant bone tumours, and it is stressed that diagnostic investigations for this type of patients should be performed in an oncological centre with experience of bone tumours.

High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study.

From 1984 to 1989, 63 patients with diffuse, malignant mesothelioma of the pleura were treated with 4-8 courses of high-dose methotrexate (HDMTX, 3 g total dose) and citrovorum factor rescue. There were 61 male and two female patients of median age 60 years. CT scan was performed before and after treatment and used for response evaluation. Of 60 patients evaluable for response, 37% showed partial or complete remission, 32% showed no change and 32% showed progressive disease. Median survival from start of treatment for all patients was 11 months, for 42 patients with the epithelial type 12 months, and for 20 patients with sarcomatous or mixed types only 5 months. Toxicity was acceptable, with only five patients (8%) terminating therapy due to toxicity. One toxic death occurred. We conclude that HDMTX is an active regimen in malignant pleural mesothelioma. The significantly shorter survival for patients with the sarcomatous or mixed subtypes indicates that further investigations on the activity of HDMTX in mesothelioma should be limited to patients with the epithelial subtype.

The treatment of osteosarcoma: present trends. The Scandinavian Sarcoma Group experience.

The study comprised 97 patients treated by the Scandinavian Sarcoma Group for high-grade, extremity-localized osteosarcoma. Chemotherapy was according to the T-10 protocol, with four courses of high-dose methotrexate (HDMTX) given preoperatively at weekly intervals. Seventeen percent of the patients obtained a good (grade III or IV) histologic response, 62% a moderate (grade II) response and 21% a poor (grade I) response. Grade II-IV responders had significantly higher serum MTX levels than grade I responders. Good responders had significantly better survival than moderate/poor responders, and had a trend towards both lower recurrence rate and longer time to recurrence. Five-year overall and relapse-free survival for all patients was 63% and 53%, respectively. Within a group of patients with similar primary tumour response, there was a trend for better survival with increasing serum MTX levels, indicating that individualization of MTX doses according to renal excretion rates may be indicated. The present results underline the importance of introducing effective chemotherapy from the start of osteosarcoma treatment, and that HDMTX alone seems to be insufficient preoperative therapy. The toxicity of HDMTX is generally mild, but we have by cerebral MRI found signal changes in white matter in 14/22 patients; changes that may represent subclinical MTX CNS toxicity. In the subsequent SSG osteosarcoma protocol, cisplatin and doxorubicin has been added to HDMTX from the start of treatment. Our data also suggest that an aggressive approach involving second-line chemotherapy and surgery is indicated for metastatic disease and that such an approach may lead to long-term survival in up to 30% of patients.

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

Alterations of blood analyses at relapse of osteosarcoma and Ewing's sarcoma.

Alterations of blood analyses have been studied at relapse of patients with osteosarcoma and Ewing's sarcoma. The tests included erythrocyte sedimentation rate (ESR), haemoglobin (Hb), leukocyte and thrombocyte counts, gamma glutamyltransferase (GT), lactate dehydrogenase (LD) and alkaline phosphatase (ALP). Sixteen relapsing patients diagnosed from 1970 to 1987 were eligible in each sarcoma group. Median age was 16 years (range 9-30) at diagnosis. The blood tests seemed to be of no help in detecting relapse of osteosarcoma, while ESR, LD and GT rose significantly in relapsing patients with Ewing's sarcoma. ESR was best correlated to disease activity.

A longitudinal study of the hyaluronan level in the serum of patients with malignant mesothelioma under treatment. Hyaluronan as an indicator of progressive disease.

The serum hyaluronan levels of 37 patients with malignant mesothelioma were followed during the course of treatment (high doses of methotrexate were given to 32 of these patients). The patients could be divided into the following two groups: (1) those with progressive disease (n = 17) or (2) those showing improvement during therapy (complete remission [n = 2], partial remission, or no change [n = 18]). On admission to the hospital, the patients with progressive disease showed significantly higher initial serum hyaluronan levels (median value, 250 micrograms/l) than those in the second group (median value, 97 micrograms/l) (P less than 0.005, Wilcoxon). Serum hyaluronan as a predictor of progressive disease has a sensitivity of 65% and a specificity of 85%. There was a significant increase in serum hyaluronan levels during treatment in patients with progression (P less than 0.01). In three patients with initially high levels there was a clear decrease in parallel with the reduction in tumor burden. In the remaining patients of the responder group, the values were constantly low. There was no significant correlation between the hyaluronan level and any other laboratory test performed on blood samples. Pleural fluid was removed for medical reasons from 13 patients. Neither the presence of pleural fluid nor its hyaluronan level were correlated to the progression of the disease. However, there was an interesting negative correlation between serum and pleural hyaluronan levels, indicating that an elevated serum hyaluronan level does not reflect high production in the pleural cavity.

Characteristics of a cell line established from a patient with multiple osteosarcoma, appearing 13 years after treatment for bilateral retinoblastoma.

An osteosarcoma cell line, OHS, was established from a patient with multiple skeletal manifestations of osteosarcoma, developing after bilateral retinoblastoma. The tumor cells expressed sarcoma-associated antigens and showed rapid growth in monolayers and as multicellular spheroids. They formed distinct colonies in soft agar, and subcutaneous tumors in nude mice. Morphological studies indicated that OHS cells had retained important characteristics of the cells of origin. No deletion of the retinoblastoma genes on chromosome 13q14 could be demonstrated with the banding techniques used. However, cytogenetic studies revealed double minute chromosomes, as evidence of gene amplification, as well as translocations involving chromosomes 1,6,11 and 13. The OHS line can be used to study the genetic basis of tumor initiation and growth, and to elucidate factors predisposing for second primary cancers in retinoblastoma patients.

Primary retroperitoneal sarcomas. A review of 36 cases.

A retrospective study of 36 patients with primary retroperitoneal sarcomas treated at The Norwegian Radium Hospital is presented. The median age at presentation was 57 years. The most common presenting symptom was abdominal pain. Leiomyosarcoma and liposarcoma were the most common histologic subtypes. The median survival in the whole series was 25 months. Patients with completely resected tumors had a longer median survival (59 months) than patients with incomplete resection (16 months) but the difference was not statistically significant. The malignancy grade seemed to be the most important prognostic factor and patients with low grade tumors had a significantly better outlook than those with high grade tumors.