Isolated limb perfusion (ILP) is a treatment option for patients with in-transit metastases of malignant melanoma in the extremities, as well as locally advanced sarcoma. ILP allows for a delivery of high-dose chemotherapy to an isolated extremity with minimal systemic toxicity. However, local toxicity like oedema, blistering, nerve damage and compartment syndrome can occur. Myoglobin measurements have been used as a screening method to predict the most severe cases of local toxicity. The aim was to investigate if myoglobin is a predictive factor for local toxicity after ILP in patients with melanoma in-transit metastases.

One hundred and ninety-three patients were treated for the first time with ILP for in-transit metastases between 2001 and 2015. Myoglobin was measured once the first hours after the perfusion (POD0), and for the first five post-operative days (POD1-5). Local toxicity was graded according to Wieberdink, and grouped in mild (I and II), moderate (III), and severe (IV and V). Wieberdink-groups were compared with myoglobin measurements, and myoglobin measurements were compared between gender, perfusion time, perfusion temperature and cannulated vessels.

There is no statistically significant difference in myoglobin serum levels during the first five days post perfusion between patients suffering from mild, moderate or severe local toxicity. There is no difference between toxicity groups when it comes to distribution of sex, tumour size, or tumour numbers.

Levels of myoglobin do not predict local toxicity for patients with melanoma in-transit metastases treated with ILP when measured during the first five post-operative days.

We previously prepared a tumor necrosis factor (TNF)-α mutant (rmhTNF-α) that showed higher antitumor activity and lower systemic toxicity compared with native TNF-α. The safety profile and the pharmacokinetic characteristics of rmhTNF-α were suited for clinical use according to biological Investigational New Drug application, a standard guideline for new drug investigation in China. Here, we evaluate the activity and safety of rmhTNF-α combined with chemotherapies in head/neck, lung, colorectal, stomach, and renal cancer patients. Ninety-five eligible patients received i.m. rmhTNF-α treatment combined with standard chemotherapies. Another 95 patients were treated with standard chemotherapies. After two treatment cycles, one patient achieved a complete response and 24 patients had partial response, yielding an overall response rate (complete response + partial response) of 27.47% in the rmhTNF-α plus chemotherapy cohort. The chemotherapy alone group acquired only a 11.39% response rate (P < 0.05). When compared between different cancers, a 48.89% response rate was detected in the 45 lung cancer patients of the combination cohort. The most common grade 1-2 adverse events of rmhTNF-α were drug-related fever, allergy, flu-like symptoms, and myalgia. No significant difference was found in grade 3-4 toxicities between the two cohorts. Based on the results of this research, rmhTNF-α can significantly enhance the effectiveness of chemotherapy. An extended phase III trial of rmhTNF-α combined with standard chemotherapy is warranted for evaluating its antitumor activity and toxicity in a larger cohort of tumor patients. The studies in this paper were registered with the State Food and Drug Administration of China (No. 2003S00692).

Urine myoglobin continues to be used as a marker of rhabdomyolysis, particularly to assess risk of developing acute renal failure and evaluate treatment success. We sought to determine the predictive validity of urine myoglobin (uMb) for acute renal failure (ARF) in patients with suspected rhabdomyolysis.

We performed a broad systemic review of the literature from January 1980 to December 2006 using the search terms myoglobin$ AND (renal OR ARF OR kidney). Only primary studies published in English where uMb measurement was related to ARF were included.

Of 1602 studies screened, 52 met all selection criteria. The studies covered a wide spectrum of etiologies for rhabdomyolysis, dissimilar diagnostic criteria for ARF and rhabdomyolysis, and various methods of uMb measurement and were mostly case series (n = 32). There was poor reporting on the uMb method, and 17 studies failed to provide any information about the method. The reporting of clinical criteria for ARF with respect to timing, description, performance, and interpretation also lacked adequate detail for replication. Eight studies (total 295 patients) had data for 2-by-2 tables. Sensitivity of the uMb test was 100% in 5 of the 8 studies, specificity varied widely (15% to 88%), and CIs around these measures were high. Pooling of data was not possible because of study heterogeneity.

There is inadequate evidence evaluating the use of uMb as a predictor of ARF in patients with suspected rhabdomyolysis.

Isolated limb infusion (ILI) is a minimally invasive technique delivering regional chemotherapy to treat in-transit extremity melanoma. Determining perioperative factors that could predict toxicity is important to optimize strategies to improve clinical outcomes after regional chemotherapy in melanoma.

Perioperative factors from 171 ILI patients performed at eight centers from 2001 to 2008 were reviewed. The Wieberdink limb toxicity scale and creatine phosphokinase (CK) levels were used to measure toxicity. Logistic regression analysis was used to estimate the association between toxicity and perioperative parameters.

Mild (grades I-II) and severe (grades >or=III) limb toxicity developed in 68% and 32% of patients, respectively. Melphalan adjusted for ideal body weight (aIBW) and papaverine were used in 47% and 63% of patients, respectively. Median peak CK for all patients was 563 U/l, and median peak occurred at postoperative day 4. On univariate analysis, papaverine and high CK levels (>563 U/l) were significantly associated with higher toxicity. On the contrary, aIBW was significantly associated with a lower risk of severe toxicity. Perfusate blood gas at 30 min [pH, PaO(2), and base excess (BE) ], limb temperature, and ischemia time were not predictive of limb toxicity. On multivariate analysis, severe toxicity was associated with female sex (P = 0.01), papaverine (P = 0.01), and high peak CK levels (P < 0.01). Independent predictors of high CK levels included younger age, unadjusted melphalan dose, and low PaO(2) at 30 min.

ILI can be performed with an acceptable morbidity. Papaverine use, female gender, and high peak CK were associated with higher limb toxicity. CK levels can be diminished significantly with aIBW.

The management of limb-threatening soft tissue sarcomas has not yet been standardized. Although local disease control does not affect overall survival, amputation or highly mutilating surgery may be required, which impairs the patient's quality of life. Various neoadjuvant approaches have been proposed to allow limb-sparing surgery for these locally advanced tumors. With TNFalpha-based hyperthermic isolated limb perfusion, the majority of patients can be spared amputation, with acceptable rates of locoregional and systemic complications. As yet, no other available treatment seems to give comparable results when applied to limb-threatening soft tissue sarcomas. Nevertheless, several issues remain to be addressed, such as the type and dose of drugs, repeatability of the procedure, association with radiotherapy, further indications, and evaluation of response. The authors describe the principles underlying TNFalpha-based hyperthermic isolated limb perfusion, review the worldwide experience so far published, and discuss the above issues. The potential future developments of this locoregional therapeutic approach will also be reported.

Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan harbors the risk of septic shock-like syndrome. Pentoxifyllin (PTX) produced a beneficial effect on cytokine response and survival in animal experiments of septic shock, and we were interested to explore its effect during TNF-ILP in humans.

Eighteen consecutive patients underwent TNF-ILP and received PTX (30 mg/kg/day), whereas another 13 consecutive patients did not. PTX was given systemically after the limb extracorporeal circulation was started. Cardiac index, systemic vascular resistance (SVR), and pulmonary vascular resistance were recorded via a Swan-Ganz catheter. Blood levels of TNF-alpha, interleukin-6, procalcitonin, and lipopolysaccharide-binding protein were determined before, during, and after ILP.

After reperfusion, systemic levels of TNF-alpha were significantly less increased in the PTX group (peak, 2.8 vs. 1.3 ng/mL; P <.05), as were interleukin-6 values (peak, 68 vs. 22 pg/mL; P <.02) and lipopolysaccharide-binding protein plasma levels (peak, 215 vs. 105 micro g/mL; P <.03). Differences in cardiac index, SVR, and mean arterial blood pressure were not significantly different. Norepinephrine or dobutamine to maintain SVR was less required in the PTX group.

PTX attenuates systemic cytokine production and influences components of the systemic inflammatory response after TNF-ILP. PTX may play a beneficial role in the management of septic shock-like syndrome, particularly in patients with leakage from the ILP circuit.

Isolated limb perfusion (ILP) is a well-established locoregional procedure to deliver high doses of cytostatics to an extremity with multiple in-transit lesions from cutaneous melanoma, with minimal systemic and mild local toxicity. This approach is quite sophisticated and requires accurate monitoring of systemic leakage and of the temperature of the affected limb in order to avoid major systemic and local side effects. Mephalan (L-PAM) is considered the reference drug, although complete responses are reported in only about 50% of patients. Since the early 1990s, tumor necrosis factor-alpha (TNF-alpha) was administered with melphalan in ILP aiming to improve the therapeutic index of this procedure. However, despite the impressive results reported, its role still remains controversial, seemingly confined to large tumor bulk. Fotemustine ILP was proposed as a less toxic alternative to L-PAM, after the results of a pilot experience claiming similar response rates with less local toxicity. A formal phase 1-2 study is now underway to confirm these findings. More straightforward procedures, such as isolated limb infusion, are appealing, as they seem capable of achieving good response rates, are easily repeatable, and are less costly. Larger series are required to validate such results. As potential agents to be delivered through ILP, new vasoactive drugs and agents with new mechanisms of action that interplay with chemotherapy, as well as virus-mediated gene therapy, are being developed.

Rhabdomyolysis, a syndrome of skeletal muscle breakdown with leakage of muscle contents, is frequently accompanied by myoglobinuria, and if sufficiently severe, acute renal failure with potentially life-threatening metabolic derangements may ensue. A diverse spectrum of inherited and acquired disorders affecting muscle membranes, membrane ion channels, and muscle energy supply causes rhabdomyolysis. Common final pathophysiological mechanisms among these causes of rhabdomyolysis include an uncontrolled rise in free intracellular calcium and activation of calcium-dependent proteases, which lead to destruction of myofibrils and lysosomal digestion of muscle fiber contents. Recent advances in molecular genetics and muscle enzyme histochemistry may enable a specific metabolic diagnosis in many patients with idiopathic recurrent rhabdomyolysis.

Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP.

University surgical oncology division with an integrated eight-bed intensive care unit.

Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma.

The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel.

PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes.

Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.