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OBJECTIVE: The aim of the study is to review the available literature on the use of Extracorporeal Shock Wave Therapy (ESWT) for the treatment of osteonecrosis (ON) and bone vascular disease (BVD), to understand its therapeutic potential and compare it with other therapies. MATERIALS AND METHODS: A systematic review was performed on the PubMed, Scopus, Science Direct, and Research Gate databases with the following inclusion criteria: 1) randomized controlled trials (RCTs); 2) written in English; 3) published in indexed journals within the last 25 years (1995-2020); and 4) dealing with the use of ESWT for the treatment of BVD or ON. The risk of bias was assessed by the Cochrane Risk of Bias tool for RCTs. RESULTS: Five studies involving 199 patients in total (68 female and 131 male) were included. Patients in the control groups received different treatments, like surgery, bisphosphonates in combination with prostacyclin or ESWT, and hyperbaric oxygen therapy. Looking at the quality of the available literature, none of the studies included could be considered a "good quality" study; only one was ranked as "fair" and the remaining were marked "poor" quality studies. No major complications or serious adverse events were reported in any of the included studies. Based on the available data, ESWT can produce rapid pain relief and functional improvement. CONCLUSIONS: Overall, a substandard quality of method emerged from the analysis of the literature, with most studies flawed by relevant bias. Ultimately, ESWT has the potential to be a useful conservative treatment in bone degeneration due to vascular and tissue turnover impairment. [ABSTRACT FROM AUTHOR]

In the Taiwan EFL context particularly, little attention has been given to investigating the effects of wikis on EFL writing performance. Therefore, this study suggests a wiki-based collaborative writing activity in the writing process of creative English writing. In addition, the students’ perceptions of wiki collaborative writing were also measured. In this one-group pretest-post-test study, 32 learners at a public university in central Taiwan were invited to participate. The participants were selected using convenience sampling, a non-probability sampling technique. Instruments used to collect the data were online student background questionnaires, writing pre- and post-tests, and a student online questionnaire on wiki collaborative writing. The data from the wiki collaborative writing questionnaire were analyzed using descriptive statistics. The result of the study is expected to be able to enhance students’ writing performance and to encourage them to have strong motivation and good attitudes toward English writing. The students enjoyed being involved in online collaborative writing and learned to give comments and receive feedback in groups. It is thought to be a useful practice to enable students to socially interact to gain more knowledge, insights, and experience.

Mathewos Anza,1 Milkyas Endale,1 Luz Cardona,2 Diego Cortes,3 Rajalakshmanan Eswaramoorthy,1 Jesus Zueco,4 Hortensia Rico,4 Maria Trelis,5 Belen Abarca2 1Department of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, Adama, Ethiopia; 2Department of Organic Chemistry, Faculty of Chemistry, University of Valencia, Burjassot, Spain; 3Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Burjassot, Spain; 4Department of Microbiology and Ecology, Faculty of Pharmacy, University of Valencia, Burjassot, Spain; 5Parasites and Health Research Group, Department of Pharmacy, Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjassot, SpainCorrespondence: Mathewos Anza; Milkyas EndaleDepartment of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, P.O. Box 1888, Adama, EthiopiaEmail mathewosanza@gmail.com; milkyas.endale@astu.edu.etBackground: Uvaria scheffleri (Annonaceae), Clematis burgensis (Ranunculaceae), and Euphorbia schimperiana (Euphorbiaceae) are medicinal plants traditionally used to treat cough, tuberculosis, asthma, sore throat and skin infections.Methods: Silica gel column chromatographic separation was used to isolate compounds. Crude extract and isolated compounds were evaluated for antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans via the broth dilution method. Docking studies were performed with E. coli DNA-Gyrase B and human DNA topoisomerase IIα by using AutoDock Vina. ADMET were predicted by SwissADME, PreADMET, and OSIRIS Property predictions. The optimized structures and molecular electrostatic potential surface of the isolated compounds were predicted by DFT analysis using B3LYP/6-31G basis levels.Results: Silica gel column chromatographic separation afforded five compounds 1– 5 of which N-methyl-2,3-bis(2-hydroxybenzyl)-1Н-indol ( 1) is reported herein for the first time, along with known C-benzylated dihydrochalcone uvaretin ( 2), bis(2-ethylheptyl) phthalate ( 3), lupeol ( 4) and suberosin derivative ( 5). Dichloromethane roots extract of U. scheffleri showed potent antibacterial activity against S. aureus (MIC = 6.25 μg/mL) compared to gentamicin (MIC=5 μg/mL). In silico, molecular docking analysis of compounds ( 1and 3– 5) showed strong interaction with E. coli DNA gyrase B with a binding energy value ranging from − 6.9 to − 6.0 kcal/mol compared to ciprofloxacin − 7.2 kcal/mol, whereas analysis against human topoisomerase IIα showed binding energy value ranging from − 5.9 to − 5.3 kcal/mol compared to vosaroxin (− 6.2 kcal/mol).Conclusion: The results obtained suggest that N-methyl-2,3-bis(2-hydroxybenzyl)-1Н-indol ( 1) and coumarin ( 5) are potential topoisomerase II α inhibitors and might be used as anticancer agents. The ADMET studies showed the highest drug-likeness properties for studied compounds other than bis(2-ethylheptyl) phthalate ( 3). DFT calculations suggested that studied compounds showed the lowest gap energy and were chemically reactive, and isolated compounds may serve as potential drug candidates that corroborate with the traditional uses of studied plants.Keywords: Uvaria scheffleri, Clematis burgensis, Euphorbia schimperiana, antimicrobial, molecular docking, ADMET, DFT analysis

Secondary Parkinson’s disease or subacute Parkinson’s may occur after stroke, drug overdose carbon monoxide or manganese toxicity, and rarely owing to a brain tumor. Loss of dopaminergic neurons in the substansia negra pars compacta (SNc), or presence of the proteinaceous inclusions called Lewy bodies are thought to be the cause of Parkinson’s disease. Notwithstanding, in the past few decades, many case reports have been published describing Parkinson’s symptoms following either stroke, ischemia, toxicity, brain hemorrhage or rarely neoplasm.

To report the results of the DECT trial, a phase II study of locally advanced or operable HER2-positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA-IIIB HER2-positive BC, 18-75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m(2) intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3-weekly cycles of epirubicin 120 mg/m(2) and cyclophosphamide, 600 mg/m(2) , plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8-78). Four-year recurrence-free survival was 74.7% (95%CI, 58.2-91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541-2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc., (© 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.)

Background: In isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and interferon (IFN)-gamma, pioneered by Lienard and Lejenne in 1988, TNFalpha was empirically employed at a dosage (3-4 mg) ten times higher than the systemic maximum tolerable dose (MTD). We previously conducted a phase I/II study in 20 patients with in-transit melanoma metastases, using a combination of melphalan and TNFalpha at dosages ranging from 0.5 to 3.3 mg. The dose of 1 mg of TNFalpha was identified as optimal in terms of both efficacy and toxicity. The aim of the present study was to describe our experience with 113 stage IIIA/IIIAB melanoma patients treated with a TNFalpha-based ILP and identify prognostic factors for response, locoregional control and survival., Patients and Methods: Patients at stage IIIA-IIIAB (presence of in-transit metastases and/or regional node involvement) were considered eligible. The disease was bulky (>or=10 nodules3 cm) in 42.5% of the patients and unresectable in 33% . Forty patients were treated with a TNFalpha dosage of >1 mg and 73 with 1 mg. Patients with tumors in the upper and lower limbs were submitted to ILP via axillary and iliac vessels, respectively. TNFalpha was injected in the arterial line of an extracorporeal circuit at the pre-established dose, followed by melphalan (13 and 10 mg/l of limb volume for the upper and lower limbs, respectively) 30 minutes later., Results: Complete responses (CR) and partial responses (PR) were 63% and 24.5%, respectively, with an objective response (OR) of 87.5%. No change (NC) was observed in only 12.5% of the patients. Upon multivariate analysis, only bulky disease maintained its independent value for tumor response with an odds ratio of 4.07 and a p-value of 0.02. The 5-year locoregional disease-free survival was 42.7%. Upon multivariate analysis, the only prognostic factors were stage, age and bulky disease. The 5-year overall survival was 49%. Multivariate analysis showed that only sex, stage and CR maintained their independent values., Conclusion: TNFalpha-based ILP was proven to be an effective treatment for melanoma patients with in-transit metastases. The TNFalpha dosage of 1 mg was as effective as 3-4 mg, with lower toxicity and cost. We propose that TNFalpha and melphalan-based ILP should be employed for bulky tumors or after failure of melphalan-based ILP.

Background: Tumor necrosis factor-alpha (TNFalpha)-based hyperthermic isolated limb perfusion (HILP) is routinely carried out at most oncological institutions in the treatment of locally advanced soft tissue limb sarcoma (STS), employing high TNFalpha dosages. After a phase I-II study, the SITILO (Italian Society of Integrated Locoregional Therapies in Oncology) centers began to employ the lower dose of 1 mg of TNFalpha. The aim of this paper is to report on the results obtained in 75 patients with limb-threatening STS treated with a low TNFalpha dose and doxorubicin (Dx)., Patients and Methods: HILP with TNFalpha (at a dosage of either 1 mg) and Dx was administered to 75 patients with limb-threatening STS: 37 males and 38 females; median age 50 years; tumor in the lower and upper limbs in 58 and 17 patients, respectively; primary and recurrent tumors in 45 and 30 patients, respectively. Most tumors (77%) were high grade. Tumor resection was carried out 6 to 8 weeks after HILP., Results: The grade of limb toxicity was mild to moderate in the vast majority of patients (76%). Grades IV and V were observed, but only when high muscle temperatures were recorded and high TNFalpha dosages were employed. Systemic toxicity was also mild to moderate and there were no postoperative deaths. Complete and partial tumor responses were 34% and 48%, respectively, with an overall response of 82% . Limb sparing surgery was carried out in 85.3% of patients. At a median follow-up of 28 months, 16 recurrences (21.3%) were recorded, with a 5-year locoregional disease-free survival of 63% . The 5-year disease-free survival and overall survival were 36.7% and 61.6%, respectively., Conclusion: HILP with 1 mg of TNFalpha is an effective neoadjuvant therapy resulting in a high rate of limb sparing in limb-threatening STS, with acceptable local reactions and negligible systemic toxicity.

We report a retrospective analysis carried out on 23,485 subjects submitted to a screening program from 2000 to 2006. Of these subjects, 3,934 had borderline HbA(2) values from 3.1 to 3.9%; 410 samples, analyzed previously using PCR methods and sequencing because all of these were partners of a carrier of classical beta-thalassemia, were selected for statistical analysis. Of 410 subjects, 94 (22.9%) were positive for a molecular defect in the beta-, delta- or alpha-globin genes. The most prevalent molecular defects were beta IVS1 nt 6 (HBB c.92+6T C), co-inheritance of severe beta thalassemia and delta mutations, beta-promoter mutations and triplication of alpha genes were detected; alpha-thalassemia and Hb-variants were also evident. Borderline HbA(2) is not a rare event in a population with a high prevalence of beta-thalassemia carriers. These data support the necessity to investigate these cases at a molecular level, particularly if the partner is a carrier of beta-thalassemia.

This study aims to correlate the most important prognostic factors of primary melanoma with sentinel node (SN) positive for metastases. We have enrolled 84 patients subjected to sentinel node biopsies for cutaneous melanomas of Breslow's thickness > or = 0.75 mm by using an intra-operative gamma probe after lymphoscintigraphy, without blue dye support. SN metastases were reported in 27% of cases (14% by histology and 13% by immunohistochemistry). By chi-square test Breslow's thickness > 2mm (p= 0.004), IV and V Clark's level (p= 0.02), ulceration (p= 0.05) and high mitotic rate (p= 0.05) were statistically significant (p < 0.05) with reference to SN positive for metastases, unlike the site of cutaneous melanoma, vertical growth phase, tumour infiltrating lymphocytes, regression and vascular invasion. Breslow's thickness remains the first prognostic factor to be considered for sentinel node biopsy in cutaneous melanoma, but other markers must be carefully estimated.

Although delta-globin gene (HBD MIM#142000) mutations have no clinical implications, co-inheritance of beta- and delta-thalassemia may lead to misdiagnosis. Among 7,153 samples studied for beta-thalassemia, 205 samples with lower than expected HbA2 levels were selected for our analysis and 183 samples (2.5%) were positive for delta-globin gene mutations. Twelve different mutations were detected, and among these five have not been not previously described (HbA2-Catania HBD c.8A-->T, HbA2-Corleone HBD c.41C-->A, HbA2-Ventimiglia HBD c.212C-->G, HbA2-Montechiaro HBD c.260C-->A, and HbA2-Bagheria HBD c.422C-->T). This study suggests that delta-globin gene defects are very common in Sicily. Thus, these mutations need to be considered during beta-thalassemia screening to avoid false negative results in the detection of at-risk couples.

Background: Hyperthermic isolation limb perfusion (HILP) with tumor necrosis factor alpha (TNFalpha) and IFNgamma was pioneered by Liénard and Lejeune in 1988. The TNFalpha was empirically employed at a dosage of 3-4 mg, that is ten times the systemic maximum tolerated dose (MTD). After eighteen years from its first clinical application, more than 300 patients have been treated. The aim of this study is to clarify two major arguments: the TNFalpha dose and eligibility criteria for patient selection., Patients and Methods: A phase I-II study has previously been conducted in 20 patients with in-transit melanoma metastases using a combination of melphalan and TNFalpha at dosages ranging from 0.5 to 3.3 mg. Twenty patients were treated and a complete pathological response of 70% was recorded, with no correlation between tumor response and TNFalpha. The dose of 1 mg of TNFalpha provided the best results regarding efficacy and toxicity. On the basis of this results a large phase II SITILO study was undertaken. Patients with stage IIIA - IIIAB (presence of in transit metastases and/or regional node involvement) were considered eligible; a total of 113 patients were enrolled in the study. The disease was bulky (> 10 nodules or fewer nodules with a diameter > or = 3 cm) in 42.5% of the patients and unresectable in 33%. Forty patients were treated with a TNFalpha dosage > 1 mg and 73 with 1 mg. All the patients were submitted to HILP via axillary and iliac vessels for tumor of upper and lower limb, respectively. TNFalpha was injected in the extracorporal circuit at the pre-established dose, followed after 30 minutes by melphalan (13 and 10 mg/L of limb volume for upper and lower limbs, respectively)., Results: A grade 1 and 2 limb toxicity was found in 52.9% and 30.1% of the patients, respectively, 5.5% of patients exhibited a grade 3 and 4, whereas grade 5 limb toxicity was not found. The complete and partial responses were 63% and 24.5%, respectively, with an objective response of 87.5%. We tried to correlate the typed tumor response (CR or not CR) and the TNFalpha dosage < or = 1 mg or > 1 mg, but no statistically significant difference was found between the two groups. The bulky disease was the only prognostic factor able to influence the tumor response., Conclusion: Only patients with bulky melanoma disease can benefit from HILP with TNFalpha at a low dose of 1 mg.

Background: A combination of doxorubicin and tumor necrosis factor alpha (TNFalpha) has been proven to be very effective in the perfusional treatment of advanced soft tissue limb sarcoma both in terms of tumor necrosis and limb conservative surgery rate. Unfortunately, in some patients a grade IV limb reaction has been recorded. The key solution might be the use of liposomal doxorubicin (Caelyx) because the carrier seems to release the drug preferentially in the tumor rather than in the healthy tissue., Patients and Methods: Twenty patients were treated with Caelyx: 14 with Caelyx alone and 6 in combination with a low TNFalpha dose (1 mg). In the first series of 14 patients a dose escalation study was carried out starting from a dose of 10 mg/L of limb volume. Six patients were treated with Caelyx (16 mg) and TNFalpha (1 mg)., Results: The maximum tolerated dose (MTD) was 16 mg/L as in two patients treated with 18 mg/L a grade IV limb reaction was observed. Tumor response was satisfactory and conservative surgery was carried out in 13 patients. In 6 patients treated with Caelyx and TNFalpha, only a grade I limb reaction was recorded, thus, confirming that TNFalpha did not increase toxicity, at least at a dose of 1 mg. The Caelyx-TNFalpha combination did increase treatment efficacy. Tumor necrosis > or = 70% was observed in 4 out of 6 patients, one with 100% necrosis (pathological complete response). All the patients underwent conservative surgery., Conclusion: The Caelyx-TNFalpha combination was proven to increase the efficacy of Caelyx alone, with a very low toxicity. These preliminary results have to be tested in a larger patient population.

Different antineoplastic drugs have been associated to hyperthermia in the treatment of advanced soft tissue limb sarcoma with a good results in terms of conservative surgery (77%-97%), locoregional control (77%-87%) and overall survival (72%). Two different studies were performed: the first was carried out to analyze the doxorubicin-TNFalpha-hyperthermia association (three different trials) in terms of toxicity and efficacy of the treatment (tumor response, locoregional control, disease free and overall survival). The results showed that the trimodality association (doxorubicin TNFalpha and hyperthermia) is the best regimen able to obtain a 77% of objective response and 77% of limb sparing in patients candidate to amputation but may result in high local toxicity if high temperatures (>41.5 degrees C) were maintained during perfusion. The second study describes the employment of liposomal doxorubicin in hyperthermic antiblastic perfusion (HAP) in terms of tumor response, conservative surgery and toxicity; the maximum tolerable dose (MTD) of doxorubicin was 16 mg/l of perfused limb volume at the temperature of 41.5 degrees C; the conservative surgery was possible in 91% of the cases and mild (grade I and II) toxicity was observed in the perfused limb with high temperature (>41.5 degrees C).

On the basis of personal experience and a review of the literature, the authors have evaluated the results obtained with hyperthermic antiblastic perfusion (HAP) for the treatment of stage II, III and IIIAB limb melanoma. The evaluation showed that today HAP may be considered a safe and effective treatment, with a major complication rate ranging between 1% and 4%. In terms of tumor response, locoregional control and survival, this treatment has provided better results than other regional chemotherapeutic modalities and undoubtedly better results than those obtained with conventional, even radical, surgery. The multivariate analysis showed that, of the treatment-related prognostic factors, the minimum tumor temperature influenced the percentage of complete response (CR) to the greatest extent (P<0.03), with a positive trend also with regard to the dosage of the antiblastic drug employed (P<0.08). In turn, the complete response rate was a determinant as far as locoregional control (50%; P<0.0009) and disease-free (51.4%; P=0.0009) and overall survival (63%; P<0.009) rates were concerned. Of the tumor-related prognostic factors, the number of lesions (P<0.0014), sex (P<0.04), and the number of disease recurrences (P<0.01) appear to influence overall survival.

Hyperthermic antiblastic perfusion (HAP) has been proven to be an effective treatment of loco-regional spreading limb melanoma. The mean complete response (CR) rate obtained is 54%, with an objective responses (OR) rate ranging between 70% and 100%. Recently, Tumor Necrosis Factor (TNFalpha) has been employed at high dosages (3-4 mg) in association to Melphalan and hyperthermia. This trimodality combination increased the percentage of CR (70%-90%), but systemic toxicity was also reported due to high TNF doses. A phase I - II study was undertaken in order to assess the MTD of TNFalpha in association to true hyperthermia (41.5 degrees C) and Melphalan. Twenty patients affected with stages IIIA (9 patients), IIIAB (10 patients), and IV (1 patient) were enrolled in this study. The trimodality treatment did not increase the local and systemic toxicity. CR was observed in 70% of the patients, PR in 20% with on OR rate of 90%. These figures are overlapping those obtained with high TNF dosages. No correlation was observed between tumor responses and TNF doses. Taking into account that 70% of our patients have been treated with TNF dosages between 0.5 mg on 1.6 mg, we conclude that 1 mg is the best dosage to be applied during HAP. Patients with bulky tumor are the best candidate to TNF perfusion, because no differences have been observed in terms of CR in patients with low tumor burden treated with TNF-Melphalan-hyperthermia or Melphalan-hyperthermia.

Hyperthermic antiblastic perfusion/HAP) has been proven to be an effective neoadjuvant treatment in the treatment of advanced soft tissue limb sarcoma. As a matter of fact high percentage of limb sparing surgery, local control and functional results have been obtained wide this technique. Many antineoplastic drugs have been associated to hyperthermia by isolation limb perfusion, the aim of this paper was to describe the results obtained with doxorubicin in association to hyperthermia with or without Tumor Necrosis Factor (TNF) alpha in order to identify the most effective regimen in the multidisciplinary treatment of soft tissue limb sarcoma. A total of 106 patients have been evaluated. Three different study were performed: the first was a phase I study carried out in order to assess the maximum tolerable dose (MTD) of doxorubicin during HAP; the second was a phase II study with doxorubicin, and the third was a phase I - II study aimed at evaluating the MTD and tumor response of TNF alpha in association to doxorubicin and hyperthermia. Grade IV limb toxicity was recorded in 11 patients ( 4 in trial A, 3 in trial B, and 4 in trial C). The grade of limb reaction was strictly related to TNF dosage (> 1 mg) and temperature level (> 41.5 degrees C), therefore the best regimen is represented by temperature level not exceeding 41.5 degrees C and 1 mg of TNFalpha. The trimodality association (TNF, doxorubicin and hyperthermia) was proven to be the best regimen able to obtain a 77% of objective response (complete response, 22%) and a 77% of limb sparing in patients candidate to amputation. The results above mentioned showed the HAP with doxorubicin and TNFalpha (1 mg) is a very effective neoadjuvant treatment in the multidisciplinary treatment of advanced soft tissue limb sarcoma.

Hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor-a (TNFalpha) and cytotoxic drugs is currently used for treatment of melanoma and sarcoma of the limbs. Tumor necrosis factor-alpha is involved in the systemic inflammatory response syndrome as a result of activation of inflammatory cells and production of bioactive substances. The goal of this study was to determine the circulating levels of proinflammatory cytokines and soluble adhesion molecules in 19 patients with limb melanoma or sarcoma undergoing ILP with (n = 9) or without TNFalpha (n = 10). The results obtained demonstrated that ILP with TNFalpha was responsible for a leakage of TNFalpha in the systemic circulation, followed by a rise in interleukin (IL)-6 and IL-8 levels within I h. Elevated soluble (s)P-selectin levels were found 1-3 h after ILP. Plasma sE-selectin peaked 6-9 h after ILP, and soluble vascular cell adhesion molecule (sVCAM) levels reached a maximum after 24 h. Significant correlations were observed among these variables, confirming the interdependence of all changes observed. On the other hand, ILP with cytotoxic drugs alone induced only a modest release of TNFalpha, which was not followed by an immediate rise in IL-6 and IL-8. Four of the 9 patients undergoing ILP with TNF had severe systemic toxicity. No association was found between systemic TNF levels and the clinical outcome, whereas elevated TNF perfusion levels as well as systemic IL-6 and IL-8 levels were constantly elevated in patients with severe toxicity. These results are suggestive of an important role of TNFalpha levels in the perfusion system (more than leakage of perfusate) in causing postoperative toxicity, although other ILP-related factors should not be excluded.

To improve the therapeutic effectiveness of hyperthermic antiblastic perfusion (HAP), the association of recombinant tumor necrosis factor alpha (rTNF alpha), doxorubicin, and true hyperthermia (41 degrees C) was employed for the treatment of soft tissue limb sarcoma. A dose-escalation study according to Fibonacci's modified scheme was conducted, starting with a rTNF alpha dose of 0.5-3.3 mg. The doxorubicin doses (0.7 and 1.4 mg for the upper and lower limbs, respectively) and temperature level (41 degrees C) remained unchanged. Eighteen patients have been treated thus far: 9 males and 9 females of a mean age of 33 years (range: 24-71 years). The tumor was located in the upper limb in one patient and in the lower limbs in seventeen. Only 16 patients were evaluable, as 2 refused further treatment after the perfusion. In terms of local toxicity, a grade I limb reaction was observed in 3 patients, a grade II or III in 10 patients, and a grade IV in 5 patients, showing a strict correlation between the TNF dose and the grade of limb reaction. In fact, a grade III-IV limb reaction was observed in 66.6% of the patients treated with > 1 mg of rTNF alpha. The maximum tolerable dose in association with doxorubicin and true hyperthermia (41 degrees C) was 2.4 mg. Eleven patients showed a good pathological response (> 75%) and five patients showed a partial response (> 25%-< 75%). In no case was stable or progressive disease observed. The postperfusional tumor shrinkage permitted limb-sparing surgery in 75% of the patients, all of whom were candidates for amputation before HAP. No recurrences have been observed thus far. Two patients developed regional disease: one presented with a skip femur metastasis that disappeared after radiotherapy and systemic chemotherapy; the second developed regional node involvement, requiring a radical node dissection. Another patient had pulmonary metastases, 2 months after the HAP, which were resected. At a median follow-up of 12 months, all the patients are living without disease. The results of this phase I study suggest that the association of rTNF alpha, doxorubicin, and true HAP (41 degrees C) by regional perfusion is feasible and safe at a maximum tolerable rTNF alpha dose of 2.4 mg. However, because no correlation was found between the amount of rTNF alpha and the tumor response, 1 mg is recommended as the dose able to provide a high tumor necrosis rate and low local and systemic toxicity. This association appears to play an important role in the neoadjuvant treatment of soft tissue limb sarcoma.