Search

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (HILP-TM) with or without IFN-gamma is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-gamma; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6-8 weeks after HILP-TM with (n = 15) or without (n = 22) IFN-gamma, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-gamma to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment.

Purpose: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection., Methods and Materials: Between 1991 and 1995, 34 patients--16 males and 18 females, median age 50 (range 18-80) years--underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvant 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvant EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases were scored., Results: During a median follow-up of 34 months (range 8-54), limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p < 0.05). Regional metastases were observed in one patient from the HILP + EBRT group (7%) and in two patients from the HILP-only group who were treated with curative intent (14%). Distant metastases occurred in four patients after HILP + EBRT (27%) and in four patients after HILP only with curative intent (29%). The mean morbidity (subjective, objective, medical management, and analytical evaluation) score in both groups was, respectively, 0.33 for skin and subcutaneous tissue and for muscle and soft tissue, 0.34 (HILP + EBRT group) and 0.33 (HILP-only group)., Conclusion: Adjuvant EBRT after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed tumor resection of locally advanced extremity STS is feasible and may increase local tumor control without increasing treatment morbidity.

In patients with disseminated nonseminomatous testicular germ cell tumors (NSTGCT), a retroperitoneal residual tumor mass (RRTM) and/or a pulmonary residual tumor mass (PRTM) are often present after successful treatment with cisplatin-based polychemotherapy. Results and complications of postchemotherapy resection of PRTM were studied and survival was calculated. In the period 1979 to 1996, 31 patients with a median age of 28 years (range, 17 to 44 years) underwent 32 thoracotomies for the resection of a PRTM. A solitary lesion was encountered nine times (28.1%) and multiple lesions were encountered 23 times (71.9%). The median size was 15 mm (range, 2 to 60 mm). There were only three major postoperative complications (9.6%): prolonged ventilation, pneumothorax, and pneumonia. In 16 patients (51.6%), the resected PRTM showed mature teratoma, while in four patients (12.9%) it showed viable cancer. In 11 patients only necrosis and/or fibrosis were found (35.5%). Resection of an RRTM had been performed prior to thoracotomy in 20 patients. There was dissimilarity between the histologic features of the resected RRTM and PRTM in 10 of the 20 patients (50%). During a median follow-up of 80 months (range, 2.5 to 203 months), five patients died from metastatic disease (16.1%). The 5-year survival rate was 86.8% and the 10-year survival rate was 82.2%. Owing to the dissimilarity between the histologic features of the postchemotherapy resected RRTM and PRTM in 50% of the patients, all sites of pulmonary residual disease must be resected in patients with disseminated NSTGCT, irrespective of the histologic features of previously resected retroperitoneal residual disease. This approach offers minimal morbidity and a high 10-year survival rate.

Objective: To evaluate the resection of the retroperitoneal residual tumour mass (RRTM) for histological examination after chemotherapy in patients with disseminated non-seminomatous testicular germ cell tumours (NSTGCTs), with particular attention to surgical morbidity., Patients and Methods: From 1979 to 1995, 112 patients (mean age 28 years, range 16-53) with NSTGCT had residual disease after chemotherapy for which surgical evaluation was indicated; the histology of the residual tumour and the surgical complications were assessed. Possible associations between the occurrence of surgical complications and the age of the patient, size of the residual tumour, operative duration, previous laparotomy and pathological findings were evaluated., Results: The median size of the residual tumour was 4 cm (range 0-18); histological examination revealed viable tumour in 9%, mature teratoma in 44% and necrosis/fibrosis in 44% of the patients. In three patients (2.8%) no residual tumour mass was found at laparotomy. There were 26 complications in 20 patients (18%); urinary tract infection was the most common, occurring in nine patients (8%). One patient died during the induction of anaesthesia. There were no significant relationships between the occurrence of complications and age, size of the residual tumour, operative duration, previous laparotomy or pathological findings., Conclusion: The resection of RRTM after polychemotherapy treatment for disseminated NSTGCT is a safe surgical procedure, with low treatment morbidity consisting mainly of urinary tract infection. Knowledge of the potential complications may help to prevent morbidity. However, the surgical evaluation of the ultimate effect of polychemotherapy remains the gold standard.

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target. The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma., Patients and Methods: Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18-80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4-14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined. The changes in tumor vascularization after treatment were scored and compared with the pathological response., Results: All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with > 90% necrosis of the tumor. Of seven patients with an AA, pathological examination showed a pCR in one patient, 10-50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p < 0.001)., Conclusion: An angiography performed after hyperthermic isolated limb perfusion with TNF-alpha and melphalan provides a good indication, regardless of whether a good pathological response is expected.

Unlabelled: We investigated FDG-PET in patients undergoing hyperthermic isolated limb perfusion (HILP) with rTNF-alpha, rIFN-gamma and melphalan for locally advanced soft-tissue sarcoma of the extremities., Methods: Twenty patients (11 women, 9 men; aged 18-80 yr, mean age 49 yr) were studied. FDG-PET studies were performed before, 2 and 8 wk after HILP. After the final PET study, the tumor was resected and pathologically graded. Patients with pathologically complete response (pCR) showed no viable tumor after treatment. Those with pathologically partial response (pPR) showed various amounts of viable tumor in the resected specimens., Results: Seven patients showed a pCR (35%) and 12 patients showed a pPR (60%). In one patient, pathological examination was not performed (5%). The pre-perfusion glucose consumption in the pCR group was significantly higher than in the pPR group (p<0.05). Visual analysis of the PET images after perfusion showed a rim of increased FDG uptake around the core of absent FDG uptake in 12 patients. The rim signal contained a fibrous pseudocapsule with inflammatory tissue in the pCR group, viable tumor was seen in the pPR group. The glucose consumption in the pCR group at 2 and 8 wk after perfusion had decreased significantly (p<0.05) in comparison to the glucose consumption in the pPR., Conclusion: Based on the pretreatment glucose consumption in soft-tissue sarcomas, one could predict the probability of a patient achieving complete pathological response after HILP. FDG-PET indicated the pathological tumor response to HILP, although the lack of specificity of FDG, in terms of differentiation between an inflammatory response and viable tumor tissue, hampered the discrimination between pCR and pPR.

The effectiveness of polychemotherapy in young patients with rhabdomyosarcomas has been well established. The morphologic alterations in the tumor tissue, however, have not been widely reported. Therefore, in a group of 15 patients from 1 to 24 years of age, specimens of tumor tissue obtained before and after polychemotherapeutic treatment were compared. No morphologic changes, other than fibrosis and necrosis, occurred in patients who initially had virtually undifferentiated tumors. When moderately or well-differentiated areas were present in the initial specimens, these areas showed proportionate increases in the follow-up specimens. Moreover, the cellular characteristics of round rhabdomyoblasts and strap cells with or without cross-striations became more distinct after treatment. However, cell types that were not present in the initial specimens were never found in follow-up specimens. It was concluded that the major role of polychemotherapy is the selective destruction of undifferentiated tumor cells; further differentiated cells are stimulated either directly or indirectly to reach their maximal inherent differentiation levels, but it does not appear that transitions from one cell type to the other occur.

In children with Wilms' tumours the length of survival is greatly influenced by success in preventing or controlling metastatic disease. The current study focuses on the morphological aspects of metastases when compared with the primary tumour. In 8 patients it appeared that blastema is the most likely component to metastasize, whereas epithelial and stromal components were hardly, if at all, represented in metastases. Furthermore, flow cytometric DNA ploidy determinations on 4 cases showed that both the primary tumours and the metastases had stemlines in the diploid and low aneuploid (hyperdiploid) range. Finally, in four cases the influence of therapy on morphology of the primary tumours was analyzed. In these cases blastema seemed to be the component most sensitive to therapy. Thus, blastema seems to play a central role in prognosis of Wilms' tumours; either reacting to therapy or, if insensitive, by metastasizing.

A 3 year old boy presented with a presumably incurable form of rhabdomyosarcoma. Conventional treatment for advanced stage rhabdomyosarcoma (chemotherapy plus radiotherapy) was not used and intensive chemotherapy alone was given, resulting in an apparent cure. Our treatment rationale is discussed.