Therapeutic use of carminomycin in soft tissue sarcomas

Under endoscopic control, biopsy specimens were taken from the oxyntic gland area of the stomach before and after administration of pentagastrin, synthetic secretin, and 13-norleucine motilin (13-nle-motilin), respectively. In 29 volunteers, the basal rate of 14C-leucine incorporation into mucosal protein averaged 41.2 +/- 7.7 X 103 cpm/mg protein (mean +/- S.D.). One and 4 hours after s.c. administration of pentagastrin (6 mug/kg body weight), values were significantly increased (p less than 0.05) by 18.9 and 21.8%, respectively, with respect to the basal level. One hour after an intravenous shot of 2 CU per kg body weight of secretin, gastric mucosal protein synthetis was not substantially inhibited, whereas a 1-hour continuous i.v. infusion of 13-nle-motilin (0.4 mug/kg body weight, hr) significantly decreased 14C-leucine incorporation rates by 17.5% (p less than 0.05). In contrast to rats, 1 hour after s.c. pentagastrin, protein synthesis in human duodenal mucosa was not altered. From these results it may be concluded that pentagastrin has a trophic influence on gastric mucosa in man. Moreover, the data presented are compatible with the hypothesis that gastrin and motilin may be involved in the regulation of human gastric mucosal protein synthesis.     

Combined modality treatment of extremity soft tissue sarcomas

Various aspects of epilepsy, including its evolution, were studied in 78 children with mental retardation in a prospective 5-year (1989-1994) follow-up study. Level of mental retardation was moderate or even more severe (IQ < 50) in 83% of children, and 56% suffered from significant cerebral palsy. Epilepsy remained uncontrolled in 28% of cases, 2-year remission was achieved by 26%, and mortality was 12% during the study period. Associated cerebral palsy was the most important single risk factor for severe epilepsy, and several handicaps seemed to have a strong multiplicative effect. Complexity of epilepsy in children with mental retardation was reflected by the evolutionary features described.     

Surgical aspects in the multidisciplinary treatment of soft tissue sarcomas

Sarcomas are rare malignant tumors with a large variety of histologic subtypes. The surgical approach depends more on the histologic grade, the size and the site of the tumor. Radiologic diagnosis relies predominantly on MR-imaging. Discernible improvements have taken place in soft tissue sarcoma patient survivorship and quality of life over the past 20 years, with overall 5-year survival currently at approximately 50-80%. The place of surgery in the treatment of soft-tissue sarcoma is defined in the light of a review of the recent literature. Radical surgical resection is the mainstay of therapy. Local recurrence is the most common type of failure. Local recurrence is resectable and limb preservations possible in the majority of patients. Survival after treatment of local recurrence is determined mainly by the grade and secondarily by the size of the tumor. The essential risk factor for local recurrence is the quality of surgical resection, defined by the definitive resection margins. A lateral safety margin of 5 cm and of 2 cm to the depth should be respected. In sarcoma of the extremity the compartment is defined based on clinical, radiographic, histopathologic and operative findings. The use of muscle flaps to fill the surgical defects can improve the functional result and reduce the complication rate. Only about 5% of the patients need amputation. Evaluation of functional results must be based on objective criteria. In retroperitoneal sarcoma the significant factors for determining prognosis are grade and completeness of exzision. Multidisciplinary treatment according to common protocols is essential. Shifts in treatment have taken place over the past decade, from single-modality treatment involving radical surgery with compartment resection to sophisticated limb-salvage strategies combined with radiation therapy. In case of inadequate surgery e.g. in a large tumor with positive margins in high-grade soft tissue sarcomas the addition of radiotherapy can improve local control, but cannot ensure that obtained by adequate surgery. Patients with large (greater than 5 cm), high grade soft tissue sarcoma are at high risk for distant recurrence and disease-related mortality. Investigations of combined modality therapy with newer chemotherapy agents and dose intensification treatment strategies are warranted.     

Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: a study of the Spanish Group for Research on Sarcomas (GEIS)

BACKGROUND: The agent Ifosfamide (IFOS) is active against soft tissue sarcomas (STS), and patients who progress to IFOS at doses < or = 10 g/m2 show remissions when exposed to high-dose ifosfamide (HDI) (i.e., doses > 10 g/m2), which supports a dose-response relationship for this drug. Because of a lack of first-line studies in adult STS patients, we decided to test the activity and toxicity of HDI in a phase II trial. PATIENTS AND METHODS: Forty-eight patients were enrolled in the study. IFOS was administered at a dose of 14 g/m2 by continuous infusion over six days every four weeks. Granulocyte-macrophage colony-stimulating factor (GM-CSF) at 5 micrograms/kg/day for 10 consecutive days was systematically administered after an episode of neutropenic fever or a delay in hematologic recovery. Patients were treated until progression or the occurrence of severe toxicity, and surgical rescue was attempted when possible. RESULTS: Six pathology-established complete remissions and 11 partial remissions were observed in 45 assessable patients with a response rate of 37.7% (95% CI: 25.5%-50%). Grade 3-4 toxicity (% of cycles) was noted by hemoglobin (17%), leukocyte (75%), granulocyte (75%) and platelet (13%) counts in 158 evaluable cycles. GM-CSF was administered to 28 patients, and 25 suffered one or more episodes of neutropenic fever. Renal toxicity was mild and reversible with some degree of tubular and glomerular dysfunction detected in up to 60% of patients. Grade 3 CNS toxicity was observed in 32% of patients but only one required interruption of therapy. Sixty-four per cent of the patients had asthenia grade 2-3 and 20% were excluded from the study due to excessive toxicity. There was one treatment-related death. CONCLUSIONS: HDI is an active drug in first-line therapy against adult STS. Different administration schedules should be evaluated in an attempt to improve its therapeutic index.     

Morphology and molecular biology of malignant soft tissue sarcomas

Malignant soft tissue tumors are classified and named according to cellular differentiation and thus the non-neoplastic soft tissue they imitate. The topical WHO classification already comprises more than 140 entities and tumor subtypes, but the process of defining new tumor variants will go on. Questions of nomenclature are discussed briefly with laying special emphasis on the non-undisputed concept of malignant fibrous histiocytomas. Without doubt, this diagnosis is made too frequently by which it has become to a collective name for unclassifiable pleomorphic sarcomas. For the time being nobody is able to say whether or not the malignant fibrous histiocytoma will remain an entity. Likely, fibrosarcomas and hemangiopericytomas are defined as exclusion diagnosis, as well. The diagnosis of malignant soft tissue tumors is based on recognizing the cellular line of differentiation. This is frequently possible at light microscopic level, sometimes additional diagnostic methods are required. The most important adjunct method is immunohistochemistry. Because aberrant differentiations and unexpected immunohistochemical reactions are known the use of a panel of antibodies is necessary. In the last years soft tissue tumors has increasingly been characterized by molecular biological methods. The results are of significance for understanding sarcoma pathogenesis and may be used for diagnosis, as well. Chromosome translocations are explained and rhabdomyosarcomas are taken as example for demonstrating the diagnostic significance of molecular biological/cytogenetic findings. Molecular biology may also aid in defining the histopathologic features of an entity as shown for intraabdominal desmoplastic small cell tumors. Eventually, heterogeneity in soft tissue sarcomas is addressed and discussed in view of its importance for diagnosis, classification and therapy as well as for development of sarcoma progression.     

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer

Melatonin production in the chick pineal gland is high at night and low during the day. This rhythm reflects circadian changes in the activity of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT; EC 2.3.1.87), the penultimate enzyme in melatonin synthesis. In contrast to the external regulation of pineal rhythms in mammals by the suprachiasmatic nucleus, rhythmic changes in AA-NAT activity in cultured chick pineal cells are controlled by an oscillator located in the pineal cells themselves. Here we present evidence that the chick pineal clock generates a rhythm in the abundance of AA-NAT mRNA in cultured cells that parallels the rhythm in AA-NAT activity. In contrast, elevating cAMP by forskolin treatment markedly increases AA-NAT activity without producing strong changes in AA-NAT mRNA levels, and lowering cAMP by norepinephrine treatment decreases enzyme activity without markedly decreasing mRNA. These results suggest that clock-controlled changes in AA-NAT activity occur primarily through changes at the mRNA level, whereas cAMP-controlled changes occur primarily through changes at the protein level. Related studies indicate that the clock-dependent nocturnal increase in AA-NAT mRNA requires gene expression but not de novo protein synthesis, and that AA-NAT mRNA levels are suppressed at all times of the day by a rapidly turning over protein. Further analysis of the regulation of chick pineal AA-NAT mRNA is likely to enhance our understanding of the molecular basis of vertebrate circadian rhythms.     

Phase II study of recombinant interleukin 1alpha and etoposide in patients with relapsed osteosarcoma

A Phase II trial using interleukin 1alpha (IL-1alpha) and etoposide for patients with relapsed osteosarcoma (OS) was undertaken to assess the feasibility and tolerability of combination therapy with biotherapy and chemotherapy. Nine patients with histologically proven relapsed OS were treated with IL-1alpha immediately followed by etoposide daily for 5 days every 3 weeks. Surgical resection of lung metastasis or peripheral tumor was performed after two or three cycles. We observed three partial responses; disease was stable in another case. One case could not be evaluated. The side effects associated with combination therapy were as predicted from known side effects of the individual agents; however, more profound neutropenia was observed. Four patients exhibited clinical signs of capillary leak syndrome, i.e., hypotension, edema, and weight gain. The etiology of the capillary leak was unclear, because serum IL-1alpha, IL-2, tumor necrosis factor, and nitric oxide levels could not be used to predict which patients would develop capillary leak. Histological analysis of tumor specimens obtained after two or more courses of therapy showed changes consistent with a response to a biological response modifier: peripheral fibrosis surrounded the metastasis with infiltration of chronic and acute inflammatory cells. Because the response of relapsed OS to any type of salvage regimen has been poor, we interpret the clinical response of this therapy as good. However, the significant side effects associated with this therapy must also be taken into consideration before deciding to use this combination therapy. It is unfortunate that the study was stopped early due to halted production of IL-1alpha. If this agent is again manufactured for clinical use, we conclude that additional evaluation in patients with relapsed OS is warranted.     

Skeletal and soft tissue sarcomas. Treatment with adjuvant immunotherapy

Because there is evidence for an active immunologic response against sarcoma, a clinical trial of adjuvant immunotherapy using bacillus Calmette-Guérin (BCG) and tumor cell vaccine was begun. Eleven of 18 patients with localized soft tissue sarcoma who received immunotherapy are free of disease, compared to only 5 of 15 treated by operation alone who are free of disease. Furthermore, immunotherapy also prolonged the median disease-free interval from 7.3 months to 15 months in the patients who experienced recurrence of their disease.     

Operative management of soft tissue sarcomas: impact of anatomic site

Operative management of soft tissue sarcomas begins with the surgical biopsy. Incisional biopsy of an undiagnosed soft tissue mass allows optimal later definitive resection, this resection including the entire biopsy wound, as well as accomplishing an "adequate" margin around the sarcoma. The principles employed for this resection are those that lead to adequate gross and microscopic margins of normal tissue around the sarcoma while considering the limitations, in terms of physical disability, from the procedure itself. This operative strategy is described for various anatomic locations, such as the extremities, trunk, retroperitoneum, and head and neck; special problems with each of these primary sites are discussed.     

The role of adjuvant chemotherapy in the treatment of adult soft tissue sarcomas

The influence of the postantibiotic effects (PAEs) of ciprofloxacin, pefloxacin, imipenem, meropenem and amikacin in the suprainhibitory concentrations (2 x and 4 x MIC) on the metabolic processes of P. aeruginosa was studied. The synthesis of macromolecules was expressed by influencing of the incorporation rate of [14C] adenine and [14C] leucine. Remarkable affecting of both biosynthetic processes evoked the suprainhibitory concentration 4 x MIC of meropenem by inhibition of the nucleic acids synthesis to 76.1% and proteins synthesis to 61.1% against the control. The suprainhibitory concentration 4 x MIC of both pefloxacin and ciprofloxacin affected the highest suppression of the endogenous respiration to 16.5% and to 20.3%, respectively. The respiration was influenced the least after the effect of meropenem in the both suprainhibitory concentrations tested. According to our knowledge, this is first report about the evaluation of the endogenous respiration after PAE. In this study we demonstrated the inhibitory effects of 4 x MIC concentration of antibiotics studied on the metabolic processes of P. aeruginosa. The results suggest a multiple mechanism for the PAE.     

Pulmonary metastasectomy for soft tissue sarcomas: is it justified?

beta-blocker therapy for mitral stenosis is controversial. This study compares right and left heart hemodynamics at rest and supine submaximal exercise in patients (n = 7) receiving chronic beta-antagonists with untreated patients (n = 17) matched for age (mean +/- SD = 51 +/- 12 years) and valve area (0.7 +/- 0.2 cm2/m2). Little benefit was observed with treatment at rest. Although pulmonary capillary wedge pressures (PCWP) were lower during exercise in the beta-blocker group (22 +/- 4 vs. 31 +/- 9 mmHg; P < 0.05), exercise performance was not enhanced and cardiac output response during exercise was reduced (control = 41% increase vs. 12% for beta-blockade). PCWP rose rapidly when diastolic filling periods were < 300 msec in both groups. Pulmonary capillary wedge pressure was found to be a nonlinear functions (P < 0.001) of diastolic filling period (PCWP = 15.9 + 5.84 x 10(5)/dfp2). These data suggest that there is a critical heart rate in patients with mitral stenosis above which hemodynamic compromise rapidly occurs.     

S-phase fraction of 155 soft tissue sarcomas: correlation with clinical outcome

BACKGROUND: Traditionally, grade is considered the most important prognostic factor for soft tissue sarcomas (STS). However, because of the alleged difficulties in reproducibility of grading, new, objectively determined prognostic factors would be of value. The aim of our study was to establish if S-phase fraction (SPF) measured with flow cytometry was of prognostic significance for STS. METHODS: In this study, we included all 193 adult STS patients with superficial trunk or limb tumors who were treated by the Helsinki University Central Hospital (HUCH) STS group between January 1987 and May 1993. One hundred and seventy-two formalin fixed paraffin embedded tumor samples were available. SPF measurement was successful in 155 cases. RESULTS: Eighty-six cases were diploid. Ploidy was found to have no effect on overall survival. The median SPF was 6.8% (diploid tumors, 4% and nondiploid tumors, 12.9%). A high SPF predicted a shorter survival in patients with diploid tumors (P=0.003). The prognostic value was even stronger when we studied disease specific survival and excluded from analysis samples that contained less than 50% tumor cells (P=0.011). However, no prognostic value could be detected in nondiploid tumors or in the material as a whole. CONCLUSIONS: Our results suggest that high SPF is an adverse prognostic factor for survival of patients with diploid STS. However, further studies are needed to confirm these results.     

Cyclin-dependent kinase inhibitor p57KIP2 in soft tissue sarcomas and Wilms'tumors

Mammalian cyclin-dependent kinase inhibitors fall into two families, the INK4 and the CIP/KIP. The CIP/KIP family comprises three structurally related members, including p21CiP1/WAF1, p27KIP1, and p57KIP2. These proteins are all capable of inhibiting the progression of the cell cycle by binding and inhibiting G(1) cyclin/cyclin-dependent kinase complexes. In humans, p57KIP2 is expressed specifically in skeletal muscle, heart, brain, kidney, and lung. Human KIP2 resides in 11p15.5, a chromosomal region that is a common site for loss of heterozygosity in certain sarcomas, Wilms' tumors, and tumors associated with the Beckwith-Wiedemann syndrome. Because of the function, selective expression, and chromosomal location of p57KIP2, we undertook the present study to search for potential mutations of KIP2 in a cohort of 126 tumors composed of 75 soft tissue sarcomas and 51 Wilms' tumors. The KIP2 gene was characterized by Southern blot, comparative multiplex PCR, PCR -single-strand conformational polymorphism, and DNA sequencing assays in these neoplasms. Deletions of the KIP2 gene or point mutations at the region encoding the cyclin-dependent kinase inhibitory domain were not found in the tumors analyzed. The absence of KIP2 mutations might indicate that these tumors arise due to defects at a closely linked but separate locus. Alternatively, similarly to the mouse homologue, inactivation of KIP2 could occur via genomic imprinting.     

High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group

The activity and toxicity of single-agent standard-dose doxorubicin were compared with that of two schedules of high-dose epirubicin. A total of 334 chemonaive patients with histologically confirmed advanced soft-tissue sarcomas received (A) doxorubicin 75 mg m(-2) on day 1 (112 patients), (B) epirubicin 150 mg m(-2) on day 1 (111 patients) or (C) epirubicin 50 mg m(-2) day(-1) on days 1, 2 and 3 (111 patients); all given as bolus injection at 3-week intervals. A median of four treatment cycles was given. Median age was 52 years (19-70 years) and performance score 1 (0-2). Of 314 evaluable patients, 45 (14%) had an objective tumour response (eight complete response, 35 partial response). There were no differences among the three groups. Median time to progression for groups A, B and C was 16, 14 and 12 weeks, and median survival 45, 47 and 45 weeks respectively. Neither progression-free (P = 0.93) nor overall survival (P = 0.89) differed among the three groups. After the first cycle of therapy, two patients died of infection and one owing to cardiovascular disease, all on epirubicin. Both dose schedules of epirubicin were more myelotoxic than doxorubicin. Cardiotoxicity (> or = grade 3) occurred in 1%, 0% and 2% respectively. Regardless of the schedule, high-dose epirubicin is not a preferred alternative to standard-dose doxorubicin in the treatment of patients with advanced soft-tissue sarcomas.