Pancreatology 14 (2014) 149e150
Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Snapshots 1. Evidence of central processing abnormalities in painful chronic pancreatitis (CP) Painful CP is one of the most challenging problems in clinical pancreatology. Clinicians will be familiar with the limitations of analgesic medication, local therapies such as nerve blocks and splanchnicectomy, and even major surgery in this group of patients. Three current publications examine whether changes in the central processing of noxious stimuli may contribute to the intractable pain suffered by these patients. deVries and colleagues [1] looked at changes to the alpha rhythm, which is known to be altered in acute and chronic pain. They analysed EEG traces from 16 CP patients (8 alcohol abuse) with typical chronic pancreatic pain and 16 healthy controls (HC) matched for age, sex and educational attainment. Readings were acquired with subjects relaxing, seated and with eyes closed to facilitate alpha rhythm. A standard mathematical transformation was applied to obtain the peak alpha frequency (PAF), from the frequency and power-density measurements for each 10-s segment (see paper for details). PAFs were further calculated for Frontal, Central, Parietal and Occipital regions of interest (ROI). They found a shift in PAF towards lower frequencies in CP vs. HC (F ¼ 4.20; p ¼ 0.049). There was also a difference in activity recorded between the ROIs, which was statistically significant (F ¼ 11.62; p ¼ 0.001) for the parietal and occipital ROIs. No differences were found between subgroups medicated with and without opioids. The authors state that their results are consistent with thalamocortical dysrythmia (TCD), which has been postulated as a mechanism underlying the generation of neuropathic pain. They speculate that their technique might provide a biomarker for chronic pain and help identify patients who may benefit from treatments targeting central pain mechanisms. Lelic and colleagues [2] studied the differences in central Contact Heat-Evoked Responses (CHEPs) to stimuli generated from abdominal (T10) and forearm (C5-6) dermatomes in 15 CP subjects (9 alcohol aetiology; 9 diabetes mellitus; 8 exocrine insufficiency) and 15 HC. Details of the capture and analysis of the CHEPs are provided in the paper. Following forearm stimulation no differences were seen in the amplitudes of CHEPS in HC and CP. Following abdominal stimulation, HC had significantly higher CHEPS amplitudes (p ¼ 0.04) than CP and there was a non-significant trend for CP to have prolonged latencies. Studies of the localisation of CHEPS again showed no differences for forearm stimulation, but following abdominal stimulation there were significant changes in signals localised to the operculo-insulate and cingulate regions in CP subjects (p < 0.001). The authors comment that the differences in amplitude would be compatible with damping of the afferent signal at a spinal or brainstem level. They discuss the changes in localisation of CHEPS after abdominal stimulation (but
not forearm stimulation) and postulate that this may represent a maladaptive response to chronic pain. Bouwense and colleagues [3]used quantitative sensory testing (QST) to examine 48 CP patients and 15 HC. In contrast to the Lelic study, they were interested in whether altered central pain processing had led to generalised hyperalgesia in CP. Dermatomes C5 and L4 were used to determine electrical pain detection (ePDT) and electrical pain tolerance (ePTT) thresholds to constant-current electrical skin stimulation. CP patients had undergone surgery for pain relief at a median time of 66 (44e115) months previously. Visual analogue score (VAS) and Izbicki pain scores were used to stratify patients into good- and poor-outcome groups. For each parameter, comparisons were made between 1) summed thresholds for all dermatomes and 2) thresholds for individual dermatomes. In addition the conditioned pain response (CPM), a measure of descending inhibitory modulation was made utilising a cold pressor test. They report that with the exception of individual ePPT values for C5, all pain thresholds were significantly lower in the CP group. CP patients also had a significantly lower tolerance of the cold pressor test and a lesser CPM. 18 CP with a VAS 30. CPM response was also significantly impaired in poor- vs. good-outcome patients. The authors discuss their results in detail and conclude that patients with evidence of autonomous pain processing might be less likely to respond to surgery and benefit more from treatments targeting central pain processing. Editor comment: Taken together these papers provide convincing evidence for the role of central processes in the pain suffered by CP patients. Adoption of one or more of these techniques might be valuable in stratifying patients according to their suitability for surgical and other treatments, but this would require resources which are unlikely to be available to the majority of pancreas clinics. 2. Portal vein resection for T3 adenocarcinoma of head of pancreas A UK multicentre study [4] assessed the risks and benefits of portal vein resection for borderline resectable carcinoma of the head of pancreas (CaHOP). 1588 patients were retrospectively recruited from 9 UK centres. All underwent surgery for T3 CaHOP (American Joint Commission on Cancer Staging System for Pancreatic Adenocarcinoma, 6th edition 2003). 840 patients had standard pancreaticoduodenectomy (PD); 230 PDþ vein resection (PDVR); 518 surgical bypass (SB). 129 PDVR patients had primary closure (56%), 65 end to end anastomosis (28%), and 36 interposition grafts (16%). Median operation time was significantly longer for PDVR than PD (median 300 min vs. 250 min, p ¼ 0.0001). Median ICU
http://dx.doi.org/10.1016/j.pan.2014.03.001 1424-3903/Copyright Ó 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
150
D.R. Fine / Pancreatology 14 (2014) 149e150
stay was 0 days for all 3 groups. Hospital stay was similar for PD (median 13 (0e130) days) and PDVR (median 14 (0e90) days) but significantly shorter for SB (median 9 (0e96) days, p ¼ 0.0001). Delayed gastric emptying (4.6% PD vs. 10.9% PDVR; p ¼ 0.0006) and blood transfusion (21.8% PD vs. 31.9% PDVR; p ¼ 0.02) were more common in PDVR. There were 12 (5.2%) vein resectionrelated complications. Seven patients had PV thrombosis, 2 of which required a relaparotomy and five had postoperative bleeding In-hospital survival was similar for all three groups. Overall median survival was significantly shorter (0.67 years) among patients undergoing SB than in those undergoing either PD (1.50 years) or PDVR (1.52 years; p ¼ 0.0001, log-rank test). The authors contend that the strengths of their study are the inclusion only of borderline resectable patients and what they believe to be the largest cohort of PDVR yet published. They think it unlikely that a prospective randomised study would be accomplishable. They conclude that “isolated involvement of the portomesenteric axis is not a contraindication to resection with a curative intent and should be routinely offered to patients with borderline resectable pancreatic cancer treated in high-volume specialised centers”. 3. The importance of SMAD4 signalling in the development of KRAS-driven pancreatic ductal adenocarcinoma (PDAC) Leung and colleagues [5] report that loss of SMAD4 signalling enhances the invasive potential of a KRAS-mutated human cell line [5]. KRAS mutations occur in >90% of invasive PDAC and are pivotal in multi-stage PDAC carcinogenesis. Genetically modified mouse models (GEMMs) expressing KRASG12D oncogene model human PanIN lesions, but only a subset of mice develop PDAC. SMAD4 inactivation alone does not predispose to PDAC, but if KRASG12D is also present PANIN and cystic tumours rapidly develop. The authors previously developed H6c7, “an immortalised near normal human pancreatic duct epithelial cell line”. Expressing KRASG12D (HPDE) in H6c7 produced a line which then expressed partial tumour differentiation. They now report a series of experiments in which SMAD4 was knocked down or no longer expressed in H6c7. 80% SMAD4 knockdown in H6c7 reduced TGF-b sensitivity but did not affect baseline proliferation; it enhanced invasion in a matrigel assay but cells injected into NODSCID mice failed to form tumours. Complete loss of SMAD4 expression in a line named TbR, however, resulted in 5-fold enhancement of invasion in vitro, but again failed to generate tumours in NODSCID mice. Addition of the KRASG12D mutation to generate a TbR-KRAS line did not enhance invasion
in vitro, but TbR-KRAS cells formed aggressive tumours when injected both subcutaneously and orthotopically in NODScID mice. Re-expression of SMAD4 attenuated in vitro invasion of TbR, but not of TbR-KRAS. In vivo, SMAD4 expression attenuated subcutaneous xenograft growth. Nodules were palpable at 41 days after injection compared to 8 days for SMAD4-deficient cells (p < 0.0001); median survival increased from 27.7 to 73 days (p < 0.0001). Similar results were found for orthotopic injection. The authors discuss the role of SMAD4 in tumorigenesis, including its effect on the expression of other factors such as Wnt, JAK-STAT and VEGF in KRAS mutated cells and conclude that “introducing the early genetic aberrations into normal pancreatic duct epithelial cells can recapitulate what has been observed PDAC, and is a key system for modelling molecular mechanism of human PDAC pathogenesis”.
References [1] de Vries M, Wilder-Smith OH, Jongsma ML, van den Broeke EN, Arns M, van Goor H, et al. Altered resting state EEG in chronic pancreatitis patients: toward a marker for chronic pain. J Pain Res 2013;2013(6):815e24. PMID: 24379694, http://www.dovepress.com/altered-resting-state-eeg-in-chronic-pancreatitispatients-toward-a-ma-peer-reviewed-article-JPR. [2] Lelic D, Olesen S, Hansen T, Valeriani M, Drewes A. Functional reorganization of brain networks in patients with painful chronic pancreatitis. Eur J Pain. http:// dx.doi.org/10.1002/j.1532-2149.2013.00442.x [Epub ahead of print]. PMID: 24402765, http://onlinelibrary.wiley.com/doi/10.1002/j.1532-2149.2013.00442. x/abstract; 2014 Jan 9. [3] Bouwense SA, Ahmed Ali U, ten Broek RP, Issa Y, van Eijck CH, Wilder-Smith OH, et al. Altered central pain processing after pancreatic surgery for chronic pancreatitis. Br J Surg 2013 Dec;100(13):1797e804. http://dx.doi.org/10.1002/bjs. 9322. PMID: 24227367, http://onlinelibrary.wiley.com/store/10.1002/bjs.9322/asset/ bjs9322.pdf?v¼1&t¼hrg5rayr&s¼90d2e9c8ba2cff9a628c5a07d17326f331b22058. [4] Ravikumar R, Sabin C, Hilal MA, Bramhall S, White S, Wigmore S, et al., UK Vascular Resection in Pancreatic Cancer Study Group. Portal vein resection in borderline resectable pancreatic cancer: a United Kingdom Multicenter Study. J Am Coll Surg. http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.017. pii:S10727515(13)01252-0. [Epub ahead of print]. PMID: 24484730, http://www. sciencedirect.com/science/article/pii/S1072751513012520; 2013 Nov 27. [5] Leung L, Radulovich N, Zhu CQ, Wang D, To C, Ibrahimov E, et al. Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis. PLoS One 2013 Dec 27;8(12):e84366. http://dx.doi.org/10.1371/journal.pone.0084366. eCollection 2013. PMID: 24386371, http://www.plosone.org/article/info%3Adoi%2F10. 1371%2Fjournal.pone.0084366.
David R. Fine E-mail address: [email protected]
Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Snapshots 1. Evidence of central processing abnormalities in painful chronic pancreatitis (CP) Painful CP is one of the most challenging problems in clinical pancreatology. Clinicians will be familiar with the limitations of analgesic medication, local therapies such as nerve blocks and splanchnicectomy, and even major surgery in this group of patients. Three current publications examine whether changes in the central processing of noxious stimuli may contribute to the intractable pain suffered by these patients. deVries and colleagues [1] looked at changes to the alpha rhythm, which is known to be altered in acute and chronic pain. They analysed EEG traces from 16 CP patients (8 alcohol abuse) with typical chronic pancreatic pain and 16 healthy controls (HC) matched for age, sex and educational attainment. Readings were acquired with subjects relaxing, seated and with eyes closed to facilitate alpha rhythm. A standard mathematical transformation was applied to obtain the peak alpha frequency (PAF), from the frequency and power-density measurements for each 10-s segment (see paper for details). PAFs were further calculated for Frontal, Central, Parietal and Occipital regions of interest (ROI). They found a shift in PAF towards lower frequencies in CP vs. HC (F ¼ 4.20; p ¼ 0.049). There was also a difference in activity recorded between the ROIs, which was statistically significant (F ¼ 11.62; p ¼ 0.001) for the parietal and occipital ROIs. No differences were found between subgroups medicated with and without opioids. The authors state that their results are consistent with thalamocortical dysrythmia (TCD), which has been postulated as a mechanism underlying the generation of neuropathic pain. They speculate that their technique might provide a biomarker for chronic pain and help identify patients who may benefit from treatments targeting central pain mechanisms. Lelic and colleagues [2] studied the differences in central Contact Heat-Evoked Responses (CHEPs) to stimuli generated from abdominal (T10) and forearm (C5-6) dermatomes in 15 CP subjects (9 alcohol aetiology; 9 diabetes mellitus; 8 exocrine insufficiency) and 15 HC. Details of the capture and analysis of the CHEPs are provided in the paper. Following forearm stimulation no differences were seen in the amplitudes of CHEPS in HC and CP. Following abdominal stimulation, HC had significantly higher CHEPS amplitudes (p ¼ 0.04) than CP and there was a non-significant trend for CP to have prolonged latencies. Studies of the localisation of CHEPS again showed no differences for forearm stimulation, but following abdominal stimulation there were significant changes in signals localised to the operculo-insulate and cingulate regions in CP subjects (p < 0.001). The authors comment that the differences in amplitude would be compatible with damping of the afferent signal at a spinal or brainstem level. They discuss the changes in localisation of CHEPS after abdominal stimulation (but
not forearm stimulation) and postulate that this may represent a maladaptive response to chronic pain. Bouwense and colleagues [3]used quantitative sensory testing (QST) to examine 48 CP patients and 15 HC. In contrast to the Lelic study, they were interested in whether altered central pain processing had led to generalised hyperalgesia in CP. Dermatomes C5 and L4 were used to determine electrical pain detection (ePDT) and electrical pain tolerance (ePTT) thresholds to constant-current electrical skin stimulation. CP patients had undergone surgery for pain relief at a median time of 66 (44e115) months previously. Visual analogue score (VAS) and Izbicki pain scores were used to stratify patients into good- and poor-outcome groups. For each parameter, comparisons were made between 1) summed thresholds for all dermatomes and 2) thresholds for individual dermatomes. In addition the conditioned pain response (CPM), a measure of descending inhibitory modulation was made utilising a cold pressor test. They report that with the exception of individual ePPT values for C5, all pain thresholds were significantly lower in the CP group. CP patients also had a significantly lower tolerance of the cold pressor test and a lesser CPM. 18 CP with a VAS 30. CPM response was also significantly impaired in poor- vs. good-outcome patients. The authors discuss their results in detail and conclude that patients with evidence of autonomous pain processing might be less likely to respond to surgery and benefit more from treatments targeting central pain processing. Editor comment: Taken together these papers provide convincing evidence for the role of central processes in the pain suffered by CP patients. Adoption of one or more of these techniques might be valuable in stratifying patients according to their suitability for surgical and other treatments, but this would require resources which are unlikely to be available to the majority of pancreas clinics. 2. Portal vein resection for T3 adenocarcinoma of head of pancreas A UK multicentre study [4] assessed the risks and benefits of portal vein resection for borderline resectable carcinoma of the head of pancreas (CaHOP). 1588 patients were retrospectively recruited from 9 UK centres. All underwent surgery for T3 CaHOP (American Joint Commission on Cancer Staging System for Pancreatic Adenocarcinoma, 6th edition 2003). 840 patients had standard pancreaticoduodenectomy (PD); 230 PDþ vein resection (PDVR); 518 surgical bypass (SB). 129 PDVR patients had primary closure (56%), 65 end to end anastomosis (28%), and 36 interposition grafts (16%). Median operation time was significantly longer for PDVR than PD (median 300 min vs. 250 min, p ¼ 0.0001). Median ICU
http://dx.doi.org/10.1016/j.pan.2014.03.001 1424-3903/Copyright Ó 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
150
D.R. Fine / Pancreatology 14 (2014) 149e150
stay was 0 days for all 3 groups. Hospital stay was similar for PD (median 13 (0e130) days) and PDVR (median 14 (0e90) days) but significantly shorter for SB (median 9 (0e96) days, p ¼ 0.0001). Delayed gastric emptying (4.6% PD vs. 10.9% PDVR; p ¼ 0.0006) and blood transfusion (21.8% PD vs. 31.9% PDVR; p ¼ 0.02) were more common in PDVR. There were 12 (5.2%) vein resectionrelated complications. Seven patients had PV thrombosis, 2 of which required a relaparotomy and five had postoperative bleeding In-hospital survival was similar for all three groups. Overall median survival was significantly shorter (0.67 years) among patients undergoing SB than in those undergoing either PD (1.50 years) or PDVR (1.52 years; p ¼ 0.0001, log-rank test). The authors contend that the strengths of their study are the inclusion only of borderline resectable patients and what they believe to be the largest cohort of PDVR yet published. They think it unlikely that a prospective randomised study would be accomplishable. They conclude that “isolated involvement of the portomesenteric axis is not a contraindication to resection with a curative intent and should be routinely offered to patients with borderline resectable pancreatic cancer treated in high-volume specialised centers”. 3. The importance of SMAD4 signalling in the development of KRAS-driven pancreatic ductal adenocarcinoma (PDAC) Leung and colleagues [5] report that loss of SMAD4 signalling enhances the invasive potential of a KRAS-mutated human cell line [5]. KRAS mutations occur in >90% of invasive PDAC and are pivotal in multi-stage PDAC carcinogenesis. Genetically modified mouse models (GEMMs) expressing KRASG12D oncogene model human PanIN lesions, but only a subset of mice develop PDAC. SMAD4 inactivation alone does not predispose to PDAC, but if KRASG12D is also present PANIN and cystic tumours rapidly develop. The authors previously developed H6c7, “an immortalised near normal human pancreatic duct epithelial cell line”. Expressing KRASG12D (HPDE) in H6c7 produced a line which then expressed partial tumour differentiation. They now report a series of experiments in which SMAD4 was knocked down or no longer expressed in H6c7. 80% SMAD4 knockdown in H6c7 reduced TGF-b sensitivity but did not affect baseline proliferation; it enhanced invasion in a matrigel assay but cells injected into NODSCID mice failed to form tumours. Complete loss of SMAD4 expression in a line named TbR, however, resulted in 5-fold enhancement of invasion in vitro, but again failed to generate tumours in NODSCID mice. Addition of the KRASG12D mutation to generate a TbR-KRAS line did not enhance invasion
in vitro, but TbR-KRAS cells formed aggressive tumours when injected both subcutaneously and orthotopically in NODScID mice. Re-expression of SMAD4 attenuated in vitro invasion of TbR, but not of TbR-KRAS. In vivo, SMAD4 expression attenuated subcutaneous xenograft growth. Nodules were palpable at 41 days after injection compared to 8 days for SMAD4-deficient cells (p < 0.0001); median survival increased from 27.7 to 73 days (p < 0.0001). Similar results were found for orthotopic injection. The authors discuss the role of SMAD4 in tumorigenesis, including its effect on the expression of other factors such as Wnt, JAK-STAT and VEGF in KRAS mutated cells and conclude that “introducing the early genetic aberrations into normal pancreatic duct epithelial cells can recapitulate what has been observed PDAC, and is a key system for modelling molecular mechanism of human PDAC pathogenesis”.
References [1] de Vries M, Wilder-Smith OH, Jongsma ML, van den Broeke EN, Arns M, van Goor H, et al. Altered resting state EEG in chronic pancreatitis patients: toward a marker for chronic pain. J Pain Res 2013;2013(6):815e24. PMID: 24379694, http://www.dovepress.com/altered-resting-state-eeg-in-chronic-pancreatitispatients-toward-a-ma-peer-reviewed-article-JPR. [2] Lelic D, Olesen S, Hansen T, Valeriani M, Drewes A. Functional reorganization of brain networks in patients with painful chronic pancreatitis. Eur J Pain. http:// dx.doi.org/10.1002/j.1532-2149.2013.00442.x [Epub ahead of print]. PMID: 24402765, http://onlinelibrary.wiley.com/doi/10.1002/j.1532-2149.2013.00442. x/abstract; 2014 Jan 9. [3] Bouwense SA, Ahmed Ali U, ten Broek RP, Issa Y, van Eijck CH, Wilder-Smith OH, et al. Altered central pain processing after pancreatic surgery for chronic pancreatitis. Br J Surg 2013 Dec;100(13):1797e804. http://dx.doi.org/10.1002/bjs. 9322. PMID: 24227367, http://onlinelibrary.wiley.com/store/10.1002/bjs.9322/asset/ bjs9322.pdf?v¼1&t¼hrg5rayr&s¼90d2e9c8ba2cff9a628c5a07d17326f331b22058. [4] Ravikumar R, Sabin C, Hilal MA, Bramhall S, White S, Wigmore S, et al., UK Vascular Resection in Pancreatic Cancer Study Group. Portal vein resection in borderline resectable pancreatic cancer: a United Kingdom Multicenter Study. J Am Coll Surg. http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.017. pii:S10727515(13)01252-0. [Epub ahead of print]. PMID: 24484730, http://www. sciencedirect.com/science/article/pii/S1072751513012520; 2013 Nov 27. [5] Leung L, Radulovich N, Zhu CQ, Wang D, To C, Ibrahimov E, et al. Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis. PLoS One 2013 Dec 27;8(12):e84366. http://dx.doi.org/10.1371/journal.pone.0084366. eCollection 2013. PMID: 24386371, http://www.plosone.org/article/info%3Adoi%2F10. 1371%2Fjournal.pone.0084366.
David R. Fine E-mail address: [email protected]
