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Hyperthermia in cancer treatment: current and future prospects.

The renewed interest in the possible use of localized hyperthermia in cancer therapy is prompted by two major realizations. The first is the radiobiological evidence indicating that there may be a significant advantage in the use of heat alone or combined with radiation therapy or chemotherapy to enhance the inactivation of tumor cells The second is that early clinical investigation with refractory malignant tumors at temperatures between 41 degrees C and 45 degrees C have shown tumor regression response rate over 70% without increasing normal tissue complication. A phase I/II study using electromagnetic hyperthermia immediately following administration of ionizing radiation was begun at Duke in the fall of 1976 to evaluate the response of normal tissues, the regression of cutaneous and subcutaneous tumors, and the feasibility of such combined modalities in therapeutic radiology. Each hyperthermia session consisted of 45 minutes at 42-43.5 degrees C 2-3 times per week immediately following radiotherapy. The radiation therapy fraction size was usually 2-3 Gy 3-5 times per week with a maximum total of 48 Gy. The 60+ patients treated to date have had squamous cell carcinoma, adenocarcinoma, malignant melanoma, plasmacytoma, liposarcoma, epithelioid sarcoma, and undifferentiated carcinoma. After more than 600 hyperthermia sessions, we have found: (1) local hyperthermia with microwave alone or in combination with ionizing radiation can be used with excellent normal tissue tolerance provided local tissue temperatures are carefully monitored and controlled; (2) a significantly higher level of preferential heat induction into tumor tissue is possible as compared to surrounding normal tissues; (3) repeated hyperthermia at 42-43.5 degrees C for 45 minutes per session immediately following radiation therapy yields favorable therapeutic results. Tumor regression response rate of over 70% was achieved without concomitant increase of normal tissue complication. Therefore, the potentially significant impact on clinical cancer therapy, whether of curative or palliative intent, by moderate thermotherapy is evident. Technical advances to optimize such treatment methods including R & D for delivering a known localized quantity of heat to tumors in any location in the body are expected to progress rapidly. The methods with most promising potential for inducing local thermotherapy are those involving the use of electromagnetic waves, e.g., radiofrequency energy, microwave energy, and ultrasound energy.

Aged↗

Primary retroperitoneal tumours a 25 year study.

Primary retroperitoneal neoplasia is not a common condition. Out of the 34 tumours analysed in the present study 15 were germ cell tumours, 10 were soft tissue tumours and 9 were tumours of the sympathetic nervous system. Among the 15 germ cell tumours, 9 were mature teratomas while there were 2 each of immature teratoma, embrayonal carcinoma and dysgerminoma. Out of the 10 soft tissue tumours 9 were sarcomas with 5 liposarcomas, 3 leiomyosarcomas and 1 neurogenic sarcoma. The only benign soft tissue tumour was a lipoma. The 9 tumours of the sympathetic nervous system included 7 neuroblastomas and 2 ganglioneuroblastomas. Overall, in the present series majority of the primary retroperitoneal tumours (22 out of 34 i.e. 70.6%) were malignant tumours.

Child↗

Reassessment and clinicopathological prognostic factors of malignant fibrous histiocytoma of soft parts.

Recently, the category of malignant fibrous histiocytoma (MFH) has been under discussion and new entities resembling MFH have appeared. To clarify the recent situation regarding MFH, we reassessed previously diagnosed MFH cases in accordance with the most up-to-date diagnostic criteria, which included allied tumors. We carefully reassessed 428 cases that had been diagnosed in our institute during the past 28 years. Moreover, we searched for clinicopathological prognostic factors among the cases that were finally diagnosed as MFH. Among the 428 cases, 138 cases had their diagnoses changed. The revised cases included 78 leiomyosarcomas (57%; ordinary leiomyosarcoma, 45 cases; pleomorphic leiomyosarcoma, 23 cases; myxoid leiomyosarcoma, 10 cases), 12 liposarcomas (9%; pleomorphic liposarcoma, 11 cases; dedifferentiated liposarcoma, one case), seven dermatofibrosarcoma protuberans (5%), six unclassified sarcomas (4%), five primary or metastatic carcinomas (4%), four low-grade fibromyxoid sarcomas (3%), four inflammatory myofibroblastic tumors (3%), three rhabdomyosarcomas (2%), three malignant peripheral nerve sheath tumors (2%), three acral myxoinflammatory fibroblastic sarcomas (2%) and two atypical fibroxanthomas (1.5%). Among the 1974 soft tissue sarcomas registered in our institute, MFH (428 cases) had been the most common sarcoma, followed by liposarcoma, leiomyosarcoma and rhabdomyosarcoma. However, after reassessment, leiomyosarcoma proved to be the most common soft tissue sarcoma (322 cases), followed by 290 MFH, 273 liposarcomas and 202 rhabdomyosarcomas. Among these 290 cases finally diagnosed as MFH, survival data were available in 189 cases. Tumor location in the abdominal cavity, the retroperitoneum or the head and neck (P = 0.0024), tumor size of 5 cm or more (P < 0.0001), deep tumor location (P < 0.0001), high histological grade (grade 3) based on the French Federation of Cancer Centers' grading system (P = 0.0007), and high stage (stage III or IV) based on the American Joint Committee on Cancer (AJCC) staging system (P < 0.0001) were significantly worse prognostic factors by univariate analysis. In multivariate analysis, deep tumor location and high AJCC stage were independent adverse prognostic factors. We conclude that leiomyosarcoma is the most important differential diagnosis for MFH, especially pleomorphic leiomyosarcoma from storiform-pleomorphic type and myxoid leiomyosarcoma from myxoid type. Tumor depth and AJCC stage are the most important predictive prognostic factors in MFH.

Data Interpretation, Statistical↗

Sarcomas of the breast: a multicenter series of 70 cases.

A multicenter retrospective series of 70 breast sarcomas (malignant cystosarcoma phyllodes (25), osteosarcoma (12), liposarcoma (10), stromal sarcoma (8), angiosarcoma (7), mixed types sarcoma (4), malignant histiocytoma (3), leiomyosarcoma (1)) was reviewed. The average follow-up was 5.9 years. Diagnostic tests (palpation, mammography, sonography and cytology) were poorly sensitive, and a large proportion of cases, appearing as regular, sharp bordered, rounded masses were diagnosed as benign fibroadenomas. Surgery (limited (29), mastectomy (41)) was the treatment of choice. Axillary nodes were rarely involved (2 of 31) at pathologic staging. No significant predictors of local recurrences (12 cases) were observed although recurrences were more frequent in larger lesions (0-20 mm = 1.1%, 21-50 mm = 1.7%, > 50 mm = 6.1% women-year) and in cases treated with limited surgery (limited surgery 4.6%, mastectomy 2.0% women-year). Distant metastases (16 cases) were less frequent in malignant cystosarcoma phyllodes or liposarcoma patients, but no other significant predictors of distant metastases were evidenced. Five-year disease-free or overall survival was 50% or 66%, respectively. The study confirms that breast sarcomas are rare, difficult to diagnose, but can be cured by surgical treatment in a considerable proportion of cases.

Adult↗

[An analysis of autopsy cases of malignant soft tissue and bone tumors].

Clinicopathologically we studied the autopsy cases including 110 soft tissue sarcoma (28 malignant fibrous histiocytomas, 23 rhabdomyosarcomas, 18 leiomyosarcomas, 11 liposarcomas, 7 synovial sarcomas, 4 angiosarcomas, 3 malignant schwannomas, and 16 others) and 29 malignant bone tumors (19 osteosarcomas, 3 Ewing's sarcomas, 3 chondrosarcomas, and 4 others). We may summarize as follows: (1) In autopsy cases sarcomas occurring in the retroperitoneum outnumbered those in surgical cases in frequency, probably because most retroperitoneal tumors could not be removed and were difficult to diagnose without the help of autopsy findings. (2) Metastases were disclosed most often in the lungs, followed by the bones and liver. Lymph-node metastases were also encountered more frequently than expected, particularly in rhabdomyosarcoma (48%) and synovial sarcoma (57%). (3) Transition in histologic features, including cellular differentiation, nuclear grade and cellularity, from the surgically resected tumors to the tumors at autopsy in the same case, occurred not infrequently.

Autopsy↗

Angiography in soft tissue sarcomas.

Angiography was performed in 41 patients with histologically proven soft tissue sarcomas that included tumors derived from a variety of cell types and locations. The leiomyosarcomas and sarcomas of uncertain or mixed origin showed extensive neovascularity. Liposarcomas, synovial cell sarcomas, and fibrous histiocytic sarcomas were moderately vascularized. Sarcomas originating from vascular, fibrous, neural, and osseous tissues had variable degrees of vascularity. In nearly all of the cases studied, angiography revealed tumor size, extent, source, and degree of vascularity and helped to determine the degree of malignancy. While angiography does not provide a histologic diagnosis, it plays an important role in patient management when a conservative therapy plan that uses several modalities is followed.

Adolescent↗

Histologic grading of adult soft tissue sarcomas.

Histologic grading is currently the most important prognostic factor for adult soft-tissue sarcomas. The French grading system is based on a score generated by evaluating three parameters: tumor differentiation, mitotic rate and amount of tumor necrosis. This system has been compared to the National Cancer Institute System. Histologic grade particularly indicates the probability of distant metastasis and overall survival, but not the probability of local recurrence. In our experience, it is an independent prognostic factor for the whole group of adult soft-tissue sarcomas, but also for malignant fibrous histiocytomas, liposarcomas, leiomyosarcomas, synovial sarcomas and unclassified sarcomas. It is also a useful tool for deciding which patients should receive chemotherapy.

Adult↗

Caffeine-potentiated chemotherapy and conservative surgery for high-grade soft-tissue sarcoma.

We report here the results of preoperative and postoperative caffeine-potentiated chemotherapy and limb-sparing surgery for soft-tissue sarcomas. Thirty-six patients with histologically high-grade soft-tissue sarcomas were treated with caffeine-potentiated chemotherapy and conservative surgery (25 cases of limb-sparing surgery and 11 of local tumor excision). There were 13 patients with malignant fibrous histiocytoma (MFH), eight with synovial sarcoma, five with liposarcoma, four with malignant schwannoma, four with epithelioid sarcoma, one with leiomyosarcoma and one with extraskeletal chondrosarcoma. Nine patients were at stage III with lung metastasis and the other 27 at stage IIB without metastasis; 22 were male and 14 female with a mean age of 48 years, ranging from 16 to 77. For intra-arterial preoperative chemotherapy, we administered 2-5 courses of cisplatin (120 mg/m2), doxorubicin (30 mg/m2 x 2 days), and caffeine (1.5 g/m2 x 3 days) to 18 patients, and cisplatin and caffeine to the other 18. Although 15 patients had already undergone unplanned tumor excision at other hospitals before preoperative chemotherapy, all patients underwent definitive limb-sparing surgery after the preoperative chemotherapy. Surgical margins were wide for 28 patients, marginal for three and intralesional for five. Local tumor recurrence was seen in one patient with MFH and one with epithelioid sarcoma. Of the 27 stage IIB patients, lung metastasis newly developed in one with MFH, three with synovial sarcoma, two with malignant schwannoma and one with leiomyosarcoma. As for the effects of preoperative chemotherapy in the 33 eligible cases, radiographically confirmed complete response was seen in two patients, partial response in 20 and no response in 11. Histological response to this preoperative chemotherapy consisted of grade I (no response) in 14, grade II (50-90% necrosis) in four, grade III (> 90% necrosis) in eight, and grade IV (no viable cells) in seven cases. An overall objective response rate of 73% was obtained. With the mean follow-up period of 58 months (5-101 months), the overall 5-year cumulative survival rate ascertained with the Kaplan-Meier method was 63% and that of stage II patients 81%. Eight of the nine stage III patients died of metastatic disease within two and a half years from the beginning of the treatment. In conclusion, caffeine-potentiated chemotherapy and limb-sparing surgery brought good results for stage II nonmetastatic soft-tissue sarcomas. The problem of treatment for stage III metastatic soft-tissue sarcomas, however, remains unsolved.

Adolescent↗

The management of retroperitoneal liposarcoma with synchronous intra-duodenal sarcoma.

Intra-abdominal (as opposed to extremity or limb and limb-girdle) soft tissue sarcomas (STS) are rare and account for less than 1% of all diagnosed neoplasms. These tumours are usually associated with a poor prognosis and are often locally invasive and metastatic at the time of presentation. Retroperitoneal sarcomas with synchronous or metachronous different histological types are rare and intra-duodenal sarcomas extremely unusual. A case of a giant retroperitoneal STS weighing approximately 15 kg consisting of two histologically different types is presented. Intra-duodenal involvement with sarcoma was found intra-operatively. We discuss the management of this condition in the context of an illustrative case in our recent experience.

Adult↗

Classification and subtype prediction of adult soft tissue sarcoma by functional genomics.

Adult soft tissue sarcomas are a heterogeneous group of tumors, including well-described subtypes by histological and genotypic criteria, and pleomorphic tumors typically characterized by non-recurrent genetic aberrations and karyotypic heterogeneity. The latter pose a diagnostic challenge, even to experienced pathologists. We proposed that gene expression profiling in soft tissue sarcoma would identify a genomic-based classification scheme that is useful in diagnosis. RNA samples from 51 pathologically confirmed cases, representing nine different histological subtypes of adult soft tissue sarcoma, were examined using the Affymetrix U95A GeneChip. Statistical tests were performed on experimental groups identified by cluster analysis, to find discriminating genes that could subsequently be applied in a support vector machine algorithm. Synovial sarcomas, round-cell/myxoid liposarcomas, clear-cell sarcomas and gastrointestinal stromal tumors displayed remarkably distinct and homogenous gene expression profiles. Pleomorphic tumors were heterogeneous. Notably, a subset of malignant fibrous histiocytomas, a controversialhistological subtype, was identified as a distinct genomic group. The support vector machine algorithm supported a genomic basis for diagnosis, with both high sensitivity and specificity. In conclusion, we showed gene expression profiling to be useful in classification and diagnosis, providing insights into pathogenesis and pointing to potential new therapeutic targets of soft tissue sarcoma.

Adult↗

Reconstructive treatment following resection of high-grade soft-tissue sarcomas of the lower limb.

PURPOSE: To review the role of free tissue transfer in reconstructive surgery following resection of high-grade soft-tissue sarcomas of the lower limb. METHODS: Medical records of all consecutive patients with high-grade soft-tissue sarcomas of the lower limbs between August 1997 and September 2003 were reviewed. RESULTS: Of 8 patients (6 women and 2 men) aged between 19 and 65 years, 4 had malignant fibrous histiocytoma, one had malignant peripheral nerve sheath tumour, one had synovial sarcoma, one had recurrent liposarcoma, and one had epitheloid sarcoma. The tumour sizes ranged from 132 cm(2) to 483 cm(2). The soft-tissue defects following tumour extirpation ranged from 153 cm(2) to 896 cm(2). The flaps used were 3 free latissimus dorsi flaps, 2 free osteoseptocutaneous fibula flaps (one vascularised fibula flap and one 'double barrel' fibula flap), one free rectus abdominis flap, 2 free mini-transverse rectus abdominis flaps, and one pedicled rectus abdominis flap. Five patients did not have local recurrence and systemic metastases. CONCLUSION: Tissue transfer allows early adjuvant therapy facilitating the multimodal approach for the high-grade soft-tissue sarcomas of the lower extremity.

Adult↗

[From cytogenetics to cytogenomics of adipose tissue tumors: 2. Malignant adipose tissue tumors].

Malignant adipose tissue tumors, also called liposarcomas, are the most common sarcoma of adult life. They may be hard to distinguish from benign adipose tissue tumors as well as from other types of sarcomas. Well-differentiated liposarcomas and myxoid liposarcomas are the two histological subtypes that have been best characterized at the genetic level. The defining genetic features of well-differentiated liposarcoma cells are supernumerary circular ("ring") and giant linear rod chromosomes. These rings and giant chromosomes contain amplification of the 12q14-15 region, including the MDM2 gene, associated with coamplification of various other chromosomal regions. In addition, they most often lack alpha-satellite centromeric sequences. The detection of MDM2 amplification is a valuable tool for the differential diagnosis between well-differentiated liposarcomas and lipomas. Dedifferentiated liposarcomas usually present with patterns of MDM2 amplification similar to those observed in well-differentiated liposarcomas. In addition, recent CGH-array studies suggest that co-amplification of MDM2 with the 6q23-25 region might be a specific feature. Myxoid and round-cell liposarcomas are characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. A rare variant translocation t(12;22) that fuses DDIT3 with EWS has also been described. The genetics of pleomorphic liposarcoma is still obscure. Pleomorphic liposarcomas show complex karyotypes with many numerical and structural chromosomal aberrations. To date, no specific molecular abnormality has been identified.

Chromosomes, Human, Pair 12↗

Comparative 99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-furifosmin uptake in human soft tissue sarcoma cell lines.

The uptake characteristics of technetium-99m hexakis-2-methoxyisobutylisonitrile (MIBI), 99mTc-tetrofosmin and 99mTc-furifosmin in human soft tissue sarcoma cell lines were investigated and compared. After 10-120 min of incubation at 37 degrees C, 32 degrees C and 22 degrees C with 99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-furifosmin, the kinetics of cellular uptake of these tracers in human soft tissue sarcoma cells SW 684 (fibrosarcoma), SW 872 (liposarcoma), SW 982 (synovial sarcoma) and SW 1353 (chondrosarcoma) was assessed. The uptake of 99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-furifosmin was temperature dependent. The kinetics of uptake of 99mTc-MIBI and of 99mTc-tetrofosmin was similar between fibrosarcoma and liposarcoma cells, as well as between synovial sarcoma and chondrosarcoma cells. 99mTc-furifosmin showed similar uptake kinetics in all cell lines. The uptake of 99mTc-furifosmin was, however, significantly higher in liposarcoma than in the other cells. The data indicate that the cellular uptake of 99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-furifosmin is dependent on cellular metabolic activity.

Cell Survival↗

Giant retroperitoneal liposarcoma.

Liposarcomas are one of the most common soft tissue sarcomas of adulthood. Liposarcomas are remarkable because of their frequently large size. We report a case with an extremely large dedifferentiated liposarcoma that weighed 18 kg. Although it was capsulated and could be excised en bloc, the patient suffered a relapse 9 months later and died 1 year after the operation.

Abdominal Neoplasms↗

Sarcoma and thyroid disorders: a common etiology?

We have recently observed that many of our sarcoma patients presented also with thyroid disorders. Literature data are almost unavailable on this topic. The relationship between the sarcoma and thyroid disorders is examined. Retrospective analysis of files of patients with sarcoma and clinically overt thyroid disorders was carried out. Of the 375 patients with soft tissue sarcomas (STS) and 235 with bone sarcoma (BS) including small blue round cell tumors (SBRC), 28 patients (4.6%) had an associated significant thyroid disorder. The types of sarcoma were mainly liposarcoma followed by malignant fibrous histiocytoma, leiomyosarcoma and bone sarcoma. The primary sites were mainly limb and trunk. The interval between the diagnosis of the thyroid disorder and the sarcoma varied between -14 years (thyroid first) and +16.5 years (thyroid later) with a median of -0.2 years. Thyroid disorders included goiter, thyroiditis and carcinoma. There are both basic-science and clinical evidence to a possible common pathway that leads to the association between overt thyroid disorders and sarcomas of bone or soft tissues. Oncogene erbA activity is related to thyroid receptors to T3 and to development of sarcoma. Cross talk of the sarcoma oncogene and the erbA might contribute to the development of sarcoma. The thyroid hormone receptor and the highly related viral oncoprotein v-erbA are found exclusively in the nucleus as stable constituents of chromatin. It has been shown that v-erbA can block the spontaneous differentiation in erythroid cells transformed by various retroviral oncogenes. V-erbA can alter the spectrum of neoplasia induced by the v-src oncogene, which causes predominantly sarcomas and erythroblastosis in chicks. The erbA can cooperate with other oncogenes such as v-erbB or with v-fms, v-ras, and c-kit. Cooperation with v-myc may play a role in the development of rhabdomyosarcoma especially in thyroid hormone deficiency state. The possible clinical implications are the need to screen patients with sarcoma to thyroid disorders, and patients with thyroid disorders for malignant diseases.

Adult↗

Reverse transcriptase-polymerase chain reaction amplification of MDR1 gene expression in adult soft tissue sarcomas.

Expression of the multidrug resistance gene MDR1 is reported to be an important determinant of the response to chemotherapy and survival in some cancers. We compared three methods for determining the intrinsic MDR1 expression in soft tissue sarcomas. We studied MDR1 gene expression in 39 samples from 33 cases of soft tissue sarcomas comprising 11 liposarcomas, nine malignant fibrous histiocytomas, six leiomyosarcomas, four malignant schwannomas, three fibrosarcomas, three synovial sarcomas, and three epithelioid sarcomas, and seven cases of benign soft tissue tumors in adult patients. To detect MDR1 mRNA, reverse transcriptase-polymerase chain reaction (RT-PCR) was performed in all samples. Furthermore, RNA dot-blot analysis with digoxigenin-labeled RNA probe and immunohistochemistry with JSB-1 and C-219 antibodies for P-glycoprotein were employed in 34 and 37 samples in soft tissue sarcomas, respectively. We compared these three detection techniques. Of the 39 specimens, 18 (46%) showed MDR1 PCR products. Liposarcomas (six of 11), malignant fibrous histiocytomas (six of nine), leiomyosarcomas (four of six), fibrosarcomas (two of three) revealed high or intermediate MDR1 expression at high frequency. No MDR1 expression was detectable in malignant schwannomas, synovial sarcomas, or epithelioid sarcomas. Of seven benign soft tissue tumors, one ganglioneuroma and one lipomatosis showed low levels of MDR1 expression. By RNA dot-blot analysis, MDR1 transcripts were detectable in 12 of 34 specimens (35%). Four samples were negative by dot blot despite positivity with RT-PCR. Concordance between MDR1 expression by RNA level with RT-PCR and dot blot and at the protein level with immunohistochemistry using C-219 was found in 16 (47%) of the 34 comparable specimens. Eight samples showed positive immunoreactivity for C-219 despite negative results in RT-PCR and dot-blot analysis. The intrinsic MDR1 expression in soft tissue sarcoma seemed to depend on certain tumor types, such as liposarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and fibrosarcoma. For the evaluation of MDR1 expression, RT-PCR is useful because of its relative simplicity and sensitivity. However, the clinical significance of such low levels of MDR1 expression detected only by RT-PCR must be discussed within systematically treated patient groups.

ATP Binding Cassette Transporter, Subfamily B, Mem↗