Isaac Meller

Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas: The cumulative multicenter European experience

OBJECTIVEnThe objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible.nnnSUMMARY BACKGROUND DATAnTo increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation.nnnMETHODSnIn 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP.nnnRESULTSnA major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths.nnnCONCLUSIONSnIn the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

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 1000u2009mg/m2 per week for 7 consecutive weeks, followed by 1u2009week rest. Response to the induction course was assessed by interview and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000u2009mg/m2 per week for 3u2009weeks every 28u2009days 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 27u2009weeks. 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.

The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors

Tumors in the Ewing family (EFTs) are the second most common bone tumors in children and adolescents. Despite aggressive chemotherapy, one‐third of patients with localized tumor still may develop recurrences. This implies that not all tumor cells are eradicated and that the patients may have a level of residual disease. EFTs are characterized by specific chromosomal translocations that result in chimeric transcripts that can be detected with reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis.

The role and biology of cryosurgery in the treatment of bone tumors: A review

The application of liquid nitrogen as a local adjuvant to curettage in the treatment of bone tumors was introduced three decades ago. This technique, termed cryosurgery, was shown to achieve excellent local control in a variety of benign-aggressive and malignant bone tumors. However, early reports showed that cryosurgery was associated with a significant injury to the adjacent rim of bone and soft-tissue, resulting in high rates of fractures and infections. These results reflected an initial failure to appreciate the potentially destructive effects of liquid nitrogen and establish appropriate guidelines for its use. We review the biological effect of cryosurgery on bone, surgical technique, and current indications for its use.

A new surgical classification system for shoulder-girdle resections. Analysis of 38 patients.

A new, six-stage surgical classification system is described for shoulder-girdle resections for patients being treated by limb-sparing procedures for bone and soft-tissue tumors. The classification is based upon current concepts of oncological surgery, the structures removed, the type of resection performed, and the relationship of the resection to the glenohumeral joint, and it indicates the increasing surgical magnitude of the procedure. Data from 38 patients with an average follow-up period of 4.6 years (range, two to 8.4 years) were analyzed. Thirty-two tumors were in bone and six in soft tissue. Eighty-seven percent (33 of the 38 tumors) were malignant. Twenty-four lesions were located in the proximal humerus and 14 in the scapula. The system permitted classification of all shoulder girdle resections done in this studys institutions. The classification is proposed as a means of establishing a uniform terminology in the comparison of such data.

Unacceptable Complications Following Intra-Articular Injection of Yttrium 90 in the Ankle Joint for Diffuse Pigmented Villonodular Synovitis

BACKGROUNDnSimple resection of diffuse pigmented villonodular synovitis of the ankle joint is associated with local recurrence rates as high as 50%. Thus, adjuvant treatment modalities, such as radiation or intra-articular isotope injection, are sometimes used after tumor resection. Our initial and highly satisfactory experience with the injection of radioactive yttrium 90 to treat pigmented villonodular synovitis of the ankle joint eroded with time so much so that we discontinued its use in the ankle and believe that it is important to alert our colleagues to the complications that we observed.nnnMETHODSnBetween 1989 and 2006, we treated seven patients who had diffuse pigmented villonodular synovitis of the ankle joint with subtotal synovectomy followed by intra-articular injection of 15 mCi of yttrium 90.nnnRESULTSnTwo of the study patients had full-thickness skin necrosis develop around the injection site, necessitating free muscle flap transfer within three months of treatment, and a third patient had development of a draining sinus that was associated with chronic severe pain. The other four patients reported pain after the injection that was reasonably controlled by the use of nonsteroidal anti-inflammatory drugs. At the most recent follow-up evaluation, no study patient had recurrent disease.nnnCONCLUSIONSnBecause of the unacceptably high rate of serious complications associated with the injection of yttrium 90 into the ankle joint following subtotal synovectomy, we discontinued its use as a local adjuvant in the management of diffuse pigmented villonodular synovitis of the ankle.

Palliative Major Amputation and Quality of Life in Cancer Patients

Limb sparing surgery has replaced the amputation surgery in the treatment of limb sarcomas. Recurrent or persistent disease constitutes a major problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patients quality of life. In this clinical set-up palliative amputation should be considered. Eighteen patients with soft-tissue or bone sarcomas and 3 patients with metastatic carcinoma underwent palliative major amputation. Hemipelvectomy was performed in 3 patients, hip disarticulation in 10, knee disarticulation or below-knee amputation in 3 patients, shoulder disarticulation in one patient and forequarter amputation in 4 patients. Local control of the disease and pain and improvement of the performance status were observed in 19 evaluable patients. The mobility was restored in 15 patients with lower limb surgery. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. To conclude, we have, found palliative major amputation surgery worth performing in low-performance status cancer patients with locally advanced disease.

Is forequarter amputation justified for palliation of intractable cancer symptoms

Background: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. Methods: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. Results: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90–100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3–24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. Conclusions: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.

Pre-clinical and clinical significance of heparanase in Ewing’s sarcoma

Heparanase is an endoglycosidase that specifically cleaves heparan sulphate side chains of heparan sulphate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumour metastasis, angiogenesis and inflammation. Heparanase up‐regulation was documented in an increasing number of human carcinomas, correlating with reduced post‐operative survival rate and enhanced tumour angiogenesis. Expression and significance of heparanase in human sarcomas has not been so far reported. Here, we applied the Ewing’s sarcoma cell line TC71 and demonstrated a potent inhibition of cell invasionu2002in vitrou2002and tumour xenograft growthu2002in vivou2002upon treatment with a specific inhibitor of heparanase enzymatic activity (compound SST0001, non‐anticoagulant N‐acetylated, glycol split heparin). Next, we examined heparanase expression and cellular localization by immunostaining of a cohort of 69 patients diagnosed with Ewing’s sarcoma. Heparanase staining was noted in all patients. Notably, heparanase staining intensity correlated with increased tumour size (Pu2002= 0.04) and with patients’ age (Pu2002= 0.03), two prognostic factors associated with a worse outcome. Our study indicates that heparanase expression is induced in Ewing’s sarcoma and associates with poor prognosis. Moreover, it encourages the inclusion of heparanase inhibitors (i.e.u2002SST0001) in newly developed therapeutic modalities directed against Ewing’s sarcoma and likely other malignancies.

Limb-sparing resections of the shoulder girdle

BACKGROUNDnLimb-sparing surgeries around the shoulder girdle pose a surgical difficulty, because tumors arising in this location are frequently large at presentation, are juxtaposed to the neurovascular bundle, require en bloc resection of proportionally large amounts of bone and soft tissues, and necessitate complex resection and reconstruction.nnnSTUDY DESIGNnBetween 1980 and 1997, we treated 134 patients who presented with 110 primary malignant, 12 metastatic, and 12 benign aggressive bone and soft tissue tumors of the shoulder girdle and subsequently underwent a limb-sparing resection. Reconstruction of the bone defect included 92 proximal humerus and 9 scapular prostheses. All patients were followed up for a minimum of 2 years. We summarize the principles of limb-sparing resections of the shoulder girdle, with emphasis on the surgical anatomy of the shoulder girdle, principles of resection and reconstruction, and functional outcomes.nnnRESULTSnFunction was estimated to be good or excellent in 101 patients (75.4%), moderate in 23 patients (17.1%), and poor in 10 patients (7.5%). Complications included 13 transient nerve palsies, 2 deep wound infections, and 1 prosthetic loosening. Local tumor recurrence occurred in 5 of 103 (4.9%) patients with primary sarcomas of the shoulder girdle.nnnCONCLUSIONSnDetailed preoperative evaluation and surgical planning are essential for performing a limb-sparing resection around the shoulder girdle. Local tumor control, associated with good functional outcomes, is achieved in the majority of patients.