Letters to the Editor

Letters to the Editor

The Editor welcomes submissions for possible publication in the Letters to the Editor section.

Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published. Authors of the article being commented on will be given an opportunity to offer a timely response to the letter. Authors of letters will be notifed that the letter has been received. Unpublished letters cannot be returned.

Comment on “p38 MAPK inhibition alleviates experimental acute pancreatitis in mice“

To the Editor:

I read with great interest the article by Cao et al[1]reporting a potential therapeutic utility of p38 inhibitors for acute pancreatitis. Using a preclinical mouse model where acute pancreatitis was induced by administration of cerulein (a cholecystokinin analog derived from the tree frogLitoria caerulea), the authors reported that the p38 MAPK inhibitor SB203580, administered intraperitoneally before and after the frst administration of cerulein, relieved signs associated with acute pancreatitis, including decreased HSP60 and HSP70 expression, and serum IL-6, amylase and lipase activities. Although the study remains descriptive and pharmacodynamic aspects were not examined in depth, it still has a merit as it undoubtedly provides a basis for further investigation into the potential utility of targeting p38 signaling for acute pancreatitis, a common serious condition that can be life-threatening.

In the context of this study, it is worth discussing two main caveats to help future perspectives of using inhibitors of p38 and MAPK in general for acute pancreatitis. The frst is regarding the selectivity of the p38 inhibitor used in this study, namely the SB203580. This molecule is a pyridinyl imidazole derivative with a broad selectivity not necessarily limited to p38 kinase.[2]Certainly, testing more selective inhibitors under development, some of which have shown specifcity towards specifc p38 isoforms (p38 MAPK has 4 isoforms： α, β, γ and δ) and revealed a good safety profle in clinical trials primarily focusing on improving the outcome of patients with acute coronary syndrome.[3-6]The second caveat is the preclinical model used, which is limited to acute cerulein-induced pancreatitis. This model has been widely investigated for pancreatitis-related pulmonary pathogenesis. At present there is no standard animal models for acute pancreatitis but rather a broad range of models ranging from non-invasive to invasive mouse models; each of which has advantages and limitations.[7]Thus, investigating p38 inhibitors in alternative models for acute pancreatitis is suitable to refne the potential utility of targeting the p38 pathway and for optimizing pharmacological properties for future translation into discovery of effective therapeutics for this condition.

Several therapeutic discoveries have been guided by incidental observations in defned animal models and further efforts to extend these interesting preliminary observations are timely to establish facts. As well, we cannot dismiss the alternative possibility that a p38 inhibitor can eventually be more effective in combination with existing therapeutics.

Moulay Alaoui-Jamali Professor at McGill University Depart. Medicine and Oncology Lady Davis Institute for Medical Research, Segal Cancer Centre, Room E525; 3755, Chemin Cote Ste-Catherine;

Montreal, Quebec H3T 1E2; Canada Email: Moulay.alaoui-jamali@mcgill.ca

1 Cao MH, Xu J, Cai HD, Lv ZW, Feng YJ, Li K, et al. p38 MAPK inhibition alleviates experimental acute pancreatitis in mice. Hepatobiliary Pancreat Dis Int 2015;14：101-106.

2 Lali FV, Hunt AE, Turner SJ, Foxwell BM. The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J Biol Chem 2000;275：7395-7402.

3 Norman P. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2015;24：383-392.

4 Watz H, Barnacle H, Hartley BF, Chan R. Effcacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease： a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014;2：63-72.

5 Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, et al. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction： a randomised phase 2 trial. Lancet 2014;384：1187-1195.

6 Martin ED, Bassi R, Marber MS. p38 MAPK in cardioprotection - are we there yet? Br J Pharmacol 2015;172：2101-2113.

7 Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis：can it be translated to human pain study? World J Gastroenterol 2013;19：7222-7230.

Published online May 6, 2015

Potential therapeutic benefts stemming from the thermal nature of irreversible electroporation of solid cancers

To the Editor:

Irreversible electroporation (IRE) is a CE- and FDA-approved treatment modality for pancreatic and liver tumors that is based on the site-confned destruction of tumor tissue by multiple short, high-intensity electrical pulses.[1]Currently there is a heated debate about whether the therapy is thermal or non-thermal. The 'non-thermal proponents' advocate that thermal evolution does occur to a limited extent but plays no important role[1]or is absent altogether, as advertised by some distributors of IRE instruments (Fig. 1). The 'thermal proponents' claim that the therapeutic effect of IRE stems in part from the consequences of heating.[2,3]In our opinion, IRE has an important thermal component[3,4]that contributes to treatment outcome. In addition to direct tumor destruction by heat, we believe that Joule heating during IRE is indirectly benefcial to treatment outcome due to the anti-tumor immune response induced by heating, as is elaborated in this letter.

Recently we published a study in which the thermal dynamics of IRE in non-vascularized and vascularized tissue was explained through several mathematical approximations.[2]The main conclusion was that, at the clinically employed settings, IRE-induced Joule heating mainly affects perivascular tissue, whereby the temperatures that can be generated range between 67-92 ℃. Moreover, the larger blood vessels that are located in the electrical feld are expected to remain patent due to heat convection, as has also been shown experimentally.[5]The residual patency of larger vascular structures is particularly important for the pancreas, which is more susceptible to the consequences of vascular occlusion than for example, the liver.

As IRE is overtly promoted as a non-thermal cancer therapy, our report[2]triggered some dismay among the 'non-thermal proponents'. However, in our opinion, Joule heating during IRE may be a potentially benefcial side-effect of IRE that promotes the immunological removal of residual viable tumor cells after treatment. Thermally-induced cell death may lead to sterile infammation[6]and an anti-tumor immune response, as has also been described for modalities such as photodynamic therapy[7]and radiotherapy.[8]As evidenced from the histological image taken of a porcine liver following IRE (Fig. 2), IRE-afficted tissue is characterized by coagulative necrosis, underscoring the manifestation of extensive cell death as a result of IRE, although it is not clear whether the histological damage in Fig. 2 was caused by an electrical feld or heat. In case of heat evolution during IRE,[3]heat-induced cell death is expected to encompass thermal denaturation of proteins and subsequent necrosis (severe heating), apoptosis/necroptosis, and autophagy (milder heating) (Fig. 2). All modes of cell death, whether thermally or electrically induced, are accompanied by the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs), both of which have important functions in triggering an innate and adaptive immune response. The DAMPs and denatured proteins chemotactically recruit cells of the innate immune system to remove the dead and dying tumor cells, facilitate tissue remodeling, and amplifythe overall immune response (Fig. 2).[6]With respect to the innate immune response, the TAAs are picked up by dendritic cells (antigen-presenting cells) that process the antigens and relay respective immune signals to CD8+T-cells, which subsequently host an anti-tumor immune response to eliminate the tumor cells that ft the antigen signature profle (Fig. 2). The adaptive immune response may also trigger so-called abscopal effects,[9]whereby distal, non-treated tumor cells are eliminated on the basis of IRE-mediated immunorecognition. Abscopal effects are benefcial for therapeutic outcome.[9]

Fig. 1.Screenshot of the NEOVITALIS website on which the NanoKnife system is advertised as being non-thermal (highlighted text). The company is a reseller of the NanoKnife system, which is used for IRE. Source： http：//www.neovitalis.dk/benefits.htm, accessed on 22 Nov 2014, 1：50 pm.

Vascular patency is not only critical for the sustenance of peri- and post-operative organ function and, in case of hepatic and pancreatic tumors, patient survival, but also for effectively orchestrating the immune response. Retention of blood fow after IRE provides a conduit for the DAMPs and TAAs to rapidly reach their target cells and orchestrate an anti-tumor immune response before afficted-but-still-viable tumor cells can recover from the treatment. Cancer cells can execute several survival pathways in response to treatment-induced stress that account for a tumor's recalcitrance to therapy and tumor recurrence.[10]Accordingly, the non-thermal as well as the thermal effects of IRE trigger the release of proinfammatory, anti-cancer mediators while the vasculature-saving nature of the treatment ensures organ viability and optimal immune signaling. Evidently, these combined effects distinguish IRE from other thermal therapies such as radiofrequency ablation and hyperthermia, which work solely on the basis of considerable Joule heating.

On a fnal note, pre-surgical planning that involves IRE should always focus on proper perioperative thermal management, whereby controlled thermal evolution should be embraced for its potentially therapyenhancing effects rather than shunned to distinguish IRE from alternative thermal therapies. In that respect, our previous message regarding the thermal nature of IRE[2]should not be taken lightly in juxtaposition to what has been published[1]and advertised (Fig. 1), as thermal effects may have undesired clinical consequences. Furthermore, the postulations in this letter regarding the IRE-induced immune response are yet to be demonstrated clinically, in anticipation of which we have started a clinical trial (NTR4230) in which DAMPs and TAAs will be quantifed before and after IRE. Finally, the thermal nature of IRE opens up novel treatment avenues. A possible combinatorial modality may entail for example IRE with the concomitant use of doxorubicin-containing thermosensitive liposomes or hydrogels, whereby the doxorubicin is released upon elevation of the temperature to a few degrees Celsius above body temperature in the target tissue. More recently, our department (Department of Pharmaceutics in Utrecht) has developed hydrogel-based embolization material that contains doxorubicin-encapsulating thermosensitive liposomes. This material can be used to embolize tumors which are subsequently subjected to IRE, thus inducing the release of liposome-laden chemotherapeutics as an adjuvant form of therapy. Taken altogether,the fact that IRE is a heat-producing modality comes with potential clinical drawbacks but also clinical benefts and paves the way for novel therapeutic approaches.

Fig. 2.Mechanistic explanation of the proposed IRE-mediated immune response. The histological section displays liver tissue in native state (“unaffected“) and a tissue segment affected by IRE (“affected“) (adapted from IEEE Trans Biomed Eng 2006;53(7)：1409-1415), separated by the dashed line. IRE-mediated Joule heating as well as electrical effects cause protein denaturation and the induction of various forms of cell death (necrotic, apoptotic/necroptotic, autophagic), which leads to the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs). The DAMPs facilitate chemotaxis of neutrophils and macrophages to the treated region, which leads to the effects specifed under “INNATE IMMUNITY“. The TAAs are processed by cells of the adaptive immune system that subsequently mount an anti-tumor immune response to eliminate the tumor cells, which may include abscopal effects.

Michal HegerMembrane Biochemistry and Biophysics, Institute of Biomembranes, University of Utrecht, Utrecht, the Netherlands Email: m.heger@amc.nl

Allard C van der Wal

Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the NetherlandsMichal Heger and Gert StormDepartment of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

Gert Storm

Department of Controlled Drug Delivery, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands

Martin J van Gemert

Biomedical Engineering and Physics,

Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

References

1 Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng 2005;33：223-231.

2 van Gemert MJ, Wagstaff PG, de Bruin DM, van Leeuwen TG, van der Wal AC, Heger M, et al. Irreversible electroporation： just another form of thermal therapy? Prostate 2015;75：332-335.

3 Wagstaff PG, de Bruin DM, van den Bos W, Ingels A, van Gemert MJ, Zondervan PJ, et al. Irreversible electroporation of the porcine kidney： Temperature development and distribution. Urol Oncol 2014.

4 Faroja M, Ahmed M, Appelbaum L, Ben-David E, Moussa M, Sosna J, et al. Irreversible electroporation ablation： is all the damage nonthermal? Radiology 2013;266：462-470.

5 Bower M, Sherwood L, Li Y, Martin R. Irreversible electroporation of the pancreas： defnitive local therapy without systemic effects. J Surg Oncol 2011;104：22-28.

6 Heger M, van Golen RF, Broekgaarden M, van den Bos RR, Neumann HA, van Gulik TM, et al. Endovascular laser–tissue interactions and biological responses in relation to endovenous laser therapy. Lasers Med Sci 2014;29：405-422.

7 Mroz P, Hashmi JT, Huang YY, Lange N, Hamblin MR. Stimulation of anti-tumor immunity by photodynamic therapy. Expert Rev Clin Immunol 2011;7：75-91.

8 Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers. Int J Mol Sci 2014;15：927-943.

9 Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, et al. Photodynamic-therapy-activated immune response against distant untreated tumours in recurrent angiosarcoma. Lancet Oncol 2007;8：950-952.

10 Broekgaarden M, Weijer R, van Gulik TM, Hamblin MR, Heger M. Tumor cell survival pathways activated by photodynamic therapy： a molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev 2015, in press.

(doi： 10.1016/S1499-3872(15)60370-8)

Published online May 15, 2015

10.1016/S1499-3872(15)60366-6)