Histamine’s vasoactive properties improving response rates in solid tumor treatment

Soft tissue sarcomas account for approximately 5000 new cases per year in Europe. 60% of them occur in the extremities and are often large at first diagnosis with a high propensity for hematogenic spread so that half of the patients die of disseminated disease. The use of aggressive approaches, such as amputation has no positive impact in survival rates, as compared to conservative approaches. In this sense, Isolated limb perfusion (ILP) plays a major role, consisting of the regional administration of high doses of drugs to an isolated limb. TNF/melphalan (TM-ILP) leads to overall response rates of circa 100% for melanoma patients and circa 70% for sarcoma patients, with a limb salvage index of approximately 75%. The mechanism of action of TNF is first a higher tumor drug uptake and secondarily the destruction of the tumor associated vasculature (TAV). Based on this success, there was a renewed interest in organ perfusion, unfortunately, the use of TNF in t! hese settings remains controversial with lack of confirmatory positive or synergistic responses in lung perfusion and with unacceptable hepatotoxicity in liver perfusion. In the Experimental Surgical Oncology experimental rat models of ILP and Isolated Hepatic Perfusion (IHP) were developed for a better understanding of the mechanism of action of these techniques and for the evaluation of new drugs. The aim of our study was to evaluate the potential use of Histamine, IL-2 and their combination, in the regional setting as an alternative to TNF. Hi showed a synergistic effect, when combined to doxorubicin in the experimental ILP, and when combined to melphalan in the experimental ILP and IHP. IL-2 also had a synergistic effect when combined to melphalan in the experimental ILP. Yet, the combination of Hi and IL-2 to melphalan in the ILP led to decreased response rates as compared to each agent alone combined to melphalan. The mechanism of action of Hi in the regional setting was very similar to the mechanism of action of TNF with a better tumor drug uptake, TAV destruction, and best responses seen with its combination to chemotherapeutic drugs.! Additionally, Hi had a direct cytotoxic effect against both tumor cells and TAV

One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases

OBJECTIVE: The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival. METHODS: One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume. RESULTS: Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate. CONCLUSIONS: TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor

Corrections to Scaling for the Two-dimensional Dynamic XY Model

With large-scale Monte Carlo simulations, we confirm that for the two-dimensional XY model, there is a logarithmic correction to scaling in the dynamic relaxation starting from a completely disordered state, while only an inverse power law correction in the case of starting from an ordered state. The dynamic exponent $z$ is $z=2.04(1)$.Comment: to appear as a Rapid commu. in Phys. Rev.

Monte Carlo Simulations of Short-time Critical Dynamics with a Conserved Quantity

With Monte Carlo simulations, we investigate short-time critical dynamics of the three-dimensional anti-ferromagnetic Ising model with a globally conserved magnetization $m_s$ (not the order parameter). From the power law behavior of the staggered magnetization (the order parameter), its second moment and the auto-correlation, we determine all static and dynamic critical exponents as well as the critical temperature. The universality class of $m_s=0$ is the same as that without a conserved quantity, but the universality class of non-zero $m_s$ is different.Comment: to appear in Phys. Rev.

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

Low-Energy Constraints on New Physics Revisited

It is possible to place constraints on non-Standard-Model gauge-boson self-couplings and other new physics by studying their one-loop contributions to precisely measured observables. We extend previous analyses which constrain such nonstandard couplings, and we present the results in a compact and transparent form. Particular attention is given to comparing results for the light-Higgs scenario, where nonstandard effects are parameterized by an effective Lagrangian with a linear realization of the electroweak symmetry breaking sector, and the heavy-Higgs/strongly interacting scenario, described by the electroweak chiral Lagrangian. The constraints on nonstandard gauge-boson self-couplings which are obtained from a global analysis of low-energy data and LEP/SLC measurements on the Z pole are updated and improved from previous studies. Replaced version: tables and figures of Section VIb recalculated. There were roundoff problems, especially in Fig. 8. Text unchanged.Comment: \documentstyle[preprint,aps,floats,psfig]{revtex}, 10 figures, postscript version available from ftp://ftp.kek.jp/kek/preprints/TH/TH-51