Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Previously we demonstrated that addition of Tumour Necrosis Factor-α to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan

Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents

Outcome After Therapeutic Lymph Node Dissection in Patients with Unknown Primary Melanoma Site

Purpose: The aim of this study was to evaluate the incidence and outcome of melanoma of unknown primary site (MUP) after therapeutic lymph node dissection (TLND) of palpable nodal melanoma metastases. Disease-free (DFS) and overall survival (OS) time of MUP patients were analyzed and compared to patients undergoing a TLND for known primary melanomas (MKP). Methods: This single institution retrospective study analyzed 342 consecutive patients who were treated with 415 TLNDs for palpable nodal disease from 1982 to 2009. Univariate and multivariate analyses included: MUP versus MKP, gender, Breslow thickness, ulceration of primary tumor, site of prima

20 Years Experience of TNF-Based Isolated Limb Perfusion for In-Transit Melanoma Metastases: TNF Dose Matters

Background: Approximately 5-8% of melanoma patients will develop in-transit metastases (IT-mets). Tumor necrosis factor-α (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is an attractive treatment modality in melanoma patients with multiple IT-mets. This study reports on a 20 years experience and outlines the evolution and major changes since the introduction of TNF in ILP. Methods: A total of 167 TM-ILPs were performed in 148 patients, between 1991 and 2009. TM-ILPs were performed at high doses of TNF (3-4 mg) from 1991 to 2004 (n = 99) and at low doses of TNF (1-2 mg) from 2004 to 2009 (n = 68) under mild hyperthermic conditions (38°C-39.5°C.). Melphalan doses were unchanged at 10-13 mg/l (leg and arm, respectively). Characteristics for the 167 ILPs were

Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-α) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-α in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-α contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastas

Radiotherapy for Soft Tissue Sarcomas after Isolated Limb Perfusion and Surgical Resection: Essential for Local Control in All Patients?

Background: Standard treatment for localized soft tissue sarcoma (STS) is resection plus adjuvant radiotherapy (RTx). In approximately 10% of cases, resection would cause severe loss of function or even require amputation because of the extent of disease. Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-α) and melphalan can achieve regression of the tumor, facilitating limb-saving resection. RTx improves local control but may lead to increased morbidity. Methods: In our database of over 500 ILPs, 122 patients with unifocal STS were treated by ILP followed by limb-sparing surgery. All included patients were candidates for amputation. Results: Surgery resulted in 69 R0 resections (57%), and in 53 specimens (43%) resection margins contained microscopic evidence of tumor (R1). Histopathological examination revealed >50% ILP-induced tumor necrosis in 59 cases (48%). RTx was administered in 73 patients (60%). Local recurrence rate was 21% after median follow-up of 31 months (2-182 months). Recurrence was significantly less in patients with >50% ILP-induced necrosis versus ≤50% necrosis (7% vs. 33%, P = 0.001). A similar significant correlation was observed for R0 versus R1 resections (15% vs. 28%, P = 0.04). In 36 patients with R0 resection and >50% necrosis, of whom 21 were spared RTx, no recurrences were observed during follow-up. Conclusions: In patients with locally advanced primary STS, treated with ILP followed by R0 resection, and with >50% ILP-induced necrosis in the resected specimen, RTx is of no further benefit

Transient reduction of tinnitus intensity is marked by concomitant reductions of delta band power

<p>Abstract</p> <p>Background</p> <p>Tinnitus is an auditory phantom phenomenon characterized by the sensation of sounds without objectively identifiable sound sources. To date, its causes are not well understood. Previous research found altered patterns of spontaneous brain activity in chronic tinnitus sufferers compared to healthy controls, yet it is unknown whether these abnormal oscillatory patterns are causally related to the tinnitus sensation. Partial support for this notion comes from a neurofeedback approach developed by our group, in which significant reductions in tinnitus loudness could be achieved in patients who successfully normalized their patterns of spontaneous brain activity. The current work attempts to complement these studies by scrutinizing how modulations of tinnitus intensity alter ongoing oscillatory activity.</p> <p>Results</p> <p>In the present study the relation between tinnitus sensation and spontaneous brain activity was investigated using residual inhibition (RI) to reduce tinnitus intensity and source-space projected magnetencephalographic (MEG) data to index brain activity. RI is the sustained reduction (criteria: 50% for at least 30 s) in tinnitus loudness after cessation of a tonal tinnitus masker. A pilot study (n = 38) identified 10 patients who showed RI. A significant reduction of power in the delta (1.3–4.0 Hz) frequency band was observed in temporal regions during RI (p ≤ 0.001).</p> <p>Conclusion</p> <p>The current results suggest that changes of tinnitus intensity induced by RI are mediated by alterations in the pathological patterns of spontaneous brain activity, specifically a reduction of delta activity. Delta activity is a characteristic oscillatory activity generated by deafferented/deprived neuronal networks. This implies that RI effects might reflect the transient reestablishment of balance between excitatory and inhibitory neuronal assemblies, via reafferentation, that have been perturbed (in most tinnitus individuals) by hearing damage. As enhancements have been reported in the delta frequency band for tinnitus at rest, this result conforms to our assumption that a normalization of oscillatory properties of cortical networks is a prerequisite for attenuating the tinnitus sensation. For RI to have therapeutic significance however, this normalization would have to be stabilized.</p

Short and Intense Tailor-Made Notched Music Training against Tinnitus: The Tinnitus Frequency Matters

Tinnitus is one of the most common diseases in industrialized countries. Here, we developed and evaluated a short-term (5 subsequent days) and intensive (6 hours/day) tailor-made notched music training (TMNMT) for patients suffering from chronic, tonal tinnitus. We evaluated (i) the TMNMT efficacy in terms of behavioral and magnetoencephalographic outcome measures for two matched patient groups with either low (≤8 kHz, N = 10) or high (>8 kHz, N = 10) tinnitus frequencies, and the (ii) persistency of the TMNMT effects over the course of a four weeks post-training phase. The results indicated that the short-term intensive TMNMT took effect in patients with tinnitus frequencies ≤8 kHz: subjective tinnitus loudness, tinnitus-related distress, and tinnitus-related auditory cortex evoked activity were significantly reduced after TMNMT completion. However, in the patients with tinnitus frequencies >8 kHz, significant changes were not observed. Interpreted in their entirety, the results also indicated that the induced changes in auditory cortex evoked neuronal activity and tinnitus loudness were not persistent, encouraging the application of the TMNMT as a longer-term training. The findings are essential in guiding the intended transfer of this neuro-scientific treatment approach into routine clinical practice