2004 Pancreas Club Annual Meeting

Summary of Proceedings of the 38th Annual Meetingof the Pancreas ClubPanelists: Juan Sarmiento, M.D., Gregory Tsiotos, M.D., Kevin Behrns, M.D.,Michel Murr, M.D., Jose Eduardo Cunha, M.D., William H. Nealon, M.D.

The 38th Annual Meeting of the Pancreas Clubtook place during Digestive Disease Week in NewOrleans on Sunday, May 16, 2004. The papers pre-sented during the oral presentations are summarized.The Pancreas Club has four sessions. One of theseis known as “How I Do It,” and the summary ofthis session is published separately. The other threesessions were entitled, “Pancreatitis (basic and clinicalstudies),” “Basic Science Studies in PancreaticCancer,” and “Clinical Studies in Pancreatic Cancer.”Thesummarieswerepreparedby themoderators.Themoderators for the first session were Juan Sarmiento,M.D., from Atlanta, Georgia and Gregory Tsiotos,M.D., from Athens, Greece. The moderators for thesecond session were Kevin Behrns, M.D., fromChapelHill, North Carolina andMichelMurr,M.D.,from Tampa, Florida. The moderators for the thirdsession were Jose Eduardo Cunha, M.D., from SaoPaulo, Brazil and William H. Nealon, M.D., fromGalveston, Texas.

SESSION I—PANCREATITISFAS/FASL Interactions Play a Central Rolein Pancreatitis-Induced Liver Injury

Gallagher and colleagues from the University ofSouth Florida Health Science Center in Tampa,Florida, previously reported that Fas ligand derivedfrom Kupffer cells mediated liver injury during acutepancreatitis. With this new experiment, they aimedto characterize the role of such ligands in hepaticcellular apoptosis in the same setting. For that theyinduced pancreatitis with CDE diet in FAS knock-out mice andmeasured liver FAS, FASL, p38-MAPK,PARP, and cytochrome c. Also, apoptosis was deter-mined by DNA fragmentation and TUNEL staining.All measured values (including apoptosis determina-tion) were significantly higher in the pancreatitisgroup. In knock-out mice (FAS�/�, FASL�/�), the

� 2005 The Society for Surgery of the Alimentary TractPublished by Elsevier Inc.

response of those markers was significantly attenu-ated; even pancreatitis-induced DNA fragmentationwas reduced by 60% in the latter group. This studyconfirmed that pancreatitis-induced liver apoptosisby up-regulation of FAS/FASL ligands. The au-thors speculate that manipulation of those ligandscould play an important role in decreasing the hepato-cellular injury seen in pancreatitis.

Randomized Controlled Trial ofPylorus-Preserving Whipple VersusDuodenum-Preserving Pancreatic HeadResection in Chronic Pancreatitis

The second paper of the session was presentedby Makoweic and colleagues from the University ofFreiburg,Germany.Regarding thebackgroundof twounderpowered trials on the subject, this group ran-domized 87 patients with head-dominant changes ofchronic pancreatitis to Whipple (n � 44) vs. Beger(n � 43) procedures. Pain was the dominant symp-tom in this population (62%). Operative results werecomparable between the groups, although theWhip-ple procedures took longer than their counterparts(435 versus 368 minutes, mean values). Although theresults in terms of pain control, quality of life, andweight gain were improved significantly by each oper-ation, there was no difference between the groups.Even the incidence of postoperative diabetes was sim-ilar. The authors concluded that for patients withhead-dominant chronic pancreatitis, both operations(pylorus-preserving Whipple and the Beger proce-dure) were equally effective and had similar postoper-ative outcomes.

Surgical Management of the ComplicationsAssociated With Percutaneous and/orEndoscopic Management of Pseudocystsof the Pancreas

Nealon and colleagues from the University ofTexas Medical Branch, Galveston, describe the surgi-cal management of complications resulting from the

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use of nonoperative measures for decompression ofpancreatic pseudocysts spanning 11 years (up to2003). Seventy-nine patients underwent either percu-taneous or endoscopic decompression. In general,complications of nonoperative therapy (sepsis, 91%;bleeding, 20%; hypotension, 65%; renal failure,20%; need for ventilatory support, 24%; persistentfistula, 84%; ICU stay, 46%) document the magni-tude of such complications. The magnitude of com-plications in a separate groupmanaged with operativetreatments alone was significantly reduced. Thispaper emphasizes the importance of preoperative im-aging (MRCP, ERCP) to select the patients who willbenefit from primary surgical therapy. The authorsalso againmake a correlation between ductal anatomyand the complications in pseudocysts.

Bile-Pancreatic Juice Exclusion ExacerbatesStress Kinase Activation and CytokineProduction in Ligation-inducedPancreatitis in Rats

Samuel and colleagues from the University of IowaCollege of Medicine, Iowa City, Iowa, have shownthat biliopancreatic (BP) exclusion from gut exacer-bates acute pancreatitis, possibly mediated via cytok-ine production. Three groups of rats were studied:one sham, one with BP exclusion, and a third withBP exclusion and re-infusion of juice after ligationof the pancreatic duct. All cytokines studied (P38,JNK, TNF, IL-1) increased significantly after liga-tion of the pancreatic duct; this effect was clearlyameliorated by replacement of BP secretions. Theauthors concluded that BP exclusion from gut exacer-bates acute pancreatitis induced by ligation in rats,and opens the door for new therapies involving therole of enteral nutrition in this model.

Nonciception in Acute Pancreatitis is PartiallyMediated by TRPV-1 Receptor

Wick and colleagues from the University ofCalifornia San Francisco, San Francisco, California,demonstrate that the transient receptor potentialvanilloid-1 (TRPV-1) is a nonselective cation chan-nel present on nociceptive neurons. After inducingpancreatitis in male Sprague-Dawley rats with L-argi-nine, the activation of nociceptive pathways was mea-sured in the dorsal horn and also by abdominal wallcontractions. There was a two-fold increase in stain-ing of the spinal cord c-Fos expression (as an objectivemeasure of nociceptive activity) 24 hours after induc-tion of pancreatitis, seen especially in T9, T11, andL1, having a direct correlation with the number ofabdominal wall contractions. After antagonistic effect

of capsazepine in the treated group, there was a sig-nificant decrease in the amount of Fos-like reactivityin T9-L1, although it did not exert any effect on theserum amylase. The authors conclude that nociceptorin this model of pancreatitis depends partially uponactivation of TRPV-1 and that antagonistic agentscould be useful to treat pain in patients withpancreatitis.

Quality of Life After Total Pancreatectomy.Ten-Year Experience

Salvia and colleagues from Verona, Italy, sentquestionnaires (EORTCQLC-C30) to patients aftertotal pancreatectomy procedures performed between1994 and 2003. Reviewing a 66% response rate, themedian use of insulin was 30 U/day, with most pa-tients claiming daily (30%) and weekly (70%) hypo-glycemic episodes. These episodes and steatorrheawere prominent in this population.

Endothelial Injury Induced by Neutrophils inAcute Pancreatitis. Role of Endothelins

DeSouza and colleagues have collected blood fromcontrols and patients with acute pancreatitis (19 ineach group) and cocultured their neutrophils withendothelial cell monolayers to assess its integritythrough detachment. This was also measured aftertreatment with antagonists for endothelin types Aand B separately. There was a significant incrementin the level of detachment in the neutrophils of pa-tients with acute pancreatitis; also, antagonists to theendothelin receptors failed to inhibit detachment onthe same group (as opposed to neutrophils comingfrom controls). The authors conclude that endothel-ins play an important role in the endothelial injurythat is seen in acute pancreatitis and speculate thatdistant organ damage could be attenuated by antago-nists of endothelins receptors.

SESSION II—BASIC SCIENCE STUDIES INPANCREATIC CARCINOMAPGE2 Enhances Pancreatic CancerInvasiveness Through an ETS-1–DependentInduction of MMP-2

Ito and colleagues from Brigham and Women’sHospital, Harvard University, Boston, Massachusetts,tested the hypothesis that PGE2 enhances cancerinvasiveness by inducing MMP-2 expression in twopancreatic cell lines in the presence or absence ofrofecoxib, a selective COX-2 inhibitor. Rofecoxib sig-nificantly attenuated the PGE2-induced increase inthe binding of the transcription factor ETS-1 as well

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as MMP-2 promoter activity, and reduced cellularinvasiveness as determined by Matrigel assay.Furthermore, silencing of ETS gene by siRNA re-duced baseline expression of MMP-2, as did adminis-tration of an MMP antibody. The authors concludethat COX-2–derived PGE2-mediated pancreaticcancer cell line attains invasiveness through an ETS-1–dependent induction of MMP-2 expression. Thisstudy demonstrates the complex interplay of MMPand COX-2 in cell invasiveness and cancer cell metas-tasis. These data are important and should be vali-dated by further examination of upstream regulatorsand in full animal models.

SKI Overexpression Attenuates the Inductionof p21 by TGF-b in Human Pancreatic Cancer

TGF-β plays an important role in cellular growthand proliferation. Heider and Behrns from the Uni-versity of North Carolina Chapel Hill, North Caro-lina, sought to determine whether overexpression ofSKI, which is an upstream cell signaling system, at-tenuates TGF-β signaling in human pancreaticcancer specimens and human pancreatic cell lines.SKI overexpression was very common in human pan-creatic cancer specimens, as demonstrated by immu-nohistochemistry or Western blotting, and in Panc-1cells, as demonstrated by immunohistochemistry orWestern blotting. Manipulating SKI expression withsiRNA significantly increased the TGF-β–inducedactivity of the p3TP/luciferase reported and induc-tion of p21 in Panc-1 cells. The investigators con-cluded that the transient inhibition of SKI throughRNA interference results in increased activity at theTGF-β promoter and enhanced transcription of p21in response to TGF-β treatment, supporting the roleof SKI as a suppressor of TGF-β signaling in pan-creatic cancer. These findings are very interestingas we learn more about the role of SKI in TGF-β signaling. The small discrepancy in detecting SKIoverexpression using immunochemistry andWesternblots may be overcome with a larger number ofspecimens.

Potential Involvement of the ERK Pathway inthe Resistance of Pancreatic Cells to Anoikis.A Central Step in the Development ofMetastatic Disease

Cancer cells are resistant to anoikis, a special pro-grammed mode of cell death dependent upon loss ofcell–cell and cell–matrix interaction. This resistanceis thought to play a role in metastatic potential. Ga-lante and Bold from the University of CaliforniaDavis, Sacramento, California, hypothesized that

pancreatic cell lines are resistant to anoikis via upreg-ulation of ERK and overexpression of the antiapop-totic protein BCL-2. In two cell lines, MIA-PACa-2and BxPC-3, the percentage of anoikis as detectedby flow cytometry inversely correlated with levelsof phosphorylated ERK and BCL-2, suggesting thatthese may confer resistance to anoikis in pancreaticcell lines. These are interesting findings. The emerg-ing field of anoikis warrants further investigation—specifically, the mechanistic link between anoikis andupstreamcell signaling systems innontransformedcelllines. Furthermore, the specificity of flow cytometryin detecting anoikis versus apoptosis needs to bevalidated.

Suramin Inhibits Not Only Tumor Growth andMetatasis But Also Angiogensis in ExperimentalHuman Pancreatic Cancer

Porebski and colleagues from UCLA MedicalCenter, Los Angeles, California, examined the effectof an increasing doses of suramin on metastaticgrowth potential in an orthotopic model of pancre-atic cancer in nude mice. They evaluated tumorvolume, dissemination score, and microvascular den-sity of subcutaneously grown tumors of three celllines—MIA-PaCa-2, AsPC-1, and Capan-1—each ofwhich has a spectrum of differentiation. Suramin athigh doses (60 mg/kg), but not at low doses, signifi-cantly reduced tumor volumes and microvasculardensity in all three cell lines and reduced the dissemi-nation score in MIAPcCa-2 cell line tumors only.These preliminary and descriptive data are importantin furthering our understanding of the role that angi-ogenesis plays in the metastatic potential of cancercells and should be used to explore the mechanism ofsuramin’s effect on tumor growth and dissemination.

CEACAM6 Is a Novel Tumor Marker inPancreatic Adenocarcinoma and PanIN Lesions

Matros and colleagues from Brigham andWomen’s Hospital, Harvard University, Boston,Massachusetts, presented work on the association ofthe novel pancreatic cancer tumor marker, carci-noembryonic antigen–related cell adhesion molecule(CEACAM6), and outcome from treatment. The in-vestigators used the robust tissue microarray methodto examine pancreatic cancer specimens from 89 pa-tients who underwent a pancreatectomy with curativeintent. In addition, 54 PanIN lesions from 44 patientswere analyzed for expression of CEACAM6. Lackof expression was correlated with decreased lymphnode involvement and lower disease stage. Multivari-ate analysis demonstrated that carcinomas with

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CEACAM6 expression tended to have lower sur-vival (P � 0.09). Furthermore, in PanIN lesions,CEACAM6 was expressed more frequently in high-grade lesions (PanIN III) compared with low-gradePanIN tumors. These findings suggest that the ab-sence of CEACAM6 expression is associated withfavorable histologic and clinical outcome, but thatthe expression of CEACAM6 was not definitely asso-ciated with poor prognosis. This study used the latesttissue array technology to perform an importanttranslational study. With the use of this technol-ogy, the authors can examine other tumor markersand, more important, they can validate theirCEACAM findings by providing altered regulationof downstream effectors of CEACAM6.

EGF Receptor Antagonism Produces CellDeath and an In Vivo Survival Benefit ina Murine Model of Pancreatic DuctalAdenocarcinoma

Because epidermal growth factor receptor (EGFR)is differently up-regulated in pancreatic carcinomacompared with normal pancreas, the role of this onco-gene has been examined as a potential therapeutictarget. Durkin and colleagues from the University ofSouth Florida, Tampa, Florida, presented their dataon inhibition of EGFR with erlotinib, a specific an-tagonist, on in vitro and in vivo growth of the pancre-atic carcinoma cell line HPAC. The HPAC cellline expressed the EGFR transcript and protein andin the presence of erlotinib displayed decreased invitro growth. Growth in vivo after treatment withEGFR inhibitor was also inhibited and survival wasimproved compared with control and compared withreference, matrix metalloproteinase inhibitor–treatedanimals. The animals treated with erlotinib also dem-onstrated decreased orthotopic implantation, tumorsize, weight, and metastases compared with controland reference-treated animals. This study demon-strates proof of principle that EGFR antagonism de-creases tumor growth and virulence in a mouse modelof pancreatic carcinogenesis. The molecular mecha-nism of this growth inhibition was not clear, however,because decreasedEGFRphosphorylationwith erlot-inib has not been demonstrated by the authors. Fur-thermore, because EGFR functions as a tyrosinekinase and multiple other growth-regulating tyro-sine kinase pathways exist, the specificity and poten-tial side effects of any eventual therapy against EGFRmust be investigated rigorously. Nonetheless, thisstudy displays the utility of tyrosine kinase inhibitionin pancreatic cancer growth regulation and adds fur-ther insights into the important cell signaling path-ways in this chemoresistant cancer.

A Novel Method of Metronomic GemcitibineDosing in a Murine Model of PancreaticAdenocarcinoma Increases Efficacy OverConventional Therapy

The current methods of delivery of chemother-apy are likened to a blast effect, in that the tumor cellssee a high concentration of drug for a short periodof time and the cells that survive this insult mutateto avoid further such insult. This pattern of drugdelivery may result in chemoresistance. To avoid thispotential phenomenon, metronomic dosing, orchronic low-dose therapy, has been proposed, and itpresumably acts through destruction of endothelialcells and inhibition of angiogenesis. Barnett and Beckfrom University of Texas Southwestern MedicalCenter, Dallas, Texas, studied metronymic dosing ofgemcitabine in an animal model, in which pancreaticcancer cells were implanted in one flank and, afterthe tumors were established, the mice were treatedwith intraperitoneal gemcitabine or contralateralflank implantation of gemcitabine in a polymer gel(GemGel) that permits slow release. With the useof this delivery system, the authors found decreasedtumor size compared with conventional therapy. Fur-thermore, histology of the GemGel-treated groupshowed extensive necrosis and decreased expressionof CD31, an endothelial cell marker. This workdemonstrates the importance of investigating thebenefit of existing drug administration regimensand re-thinking the mechanisms of carcinomachemoresistance.

SESSION III—CLINICAL STUDIES INPANCREATIC CARCINOMAIntraductal Papillary Mucinous Neoplasms of thePancreas (IPMN): An Updated Experience

Sohn and colleagues reported on 136 pancreaticresections performed at John Hopkins Hospital, Bal-timore, Maryland, between 1987 and 2003 for pa-tients with IPMNs. Pancreatoduodenectomy wasperformed in 71% of patients, total pancreatectomyin 15%, distal pancreatectomy in 12%, and centralpancreatic resection in 2%. Pathology was reviewedto identify main duct or branch duct orgin of thetumors. No evidence of invasive cancer was found in84 patients (62%) with IPMN. The remaining 52patients (38%) had invasive cancer: tubular (60% ofthese), colloid (27%), mixed (7%), and anaplastic(6%). The patient ages of this study were 63 yearsfor these with adenomas and 68 years for these withinvasive cancer and suggest that there may be a 5-year time lag for an adenoma to develop into aninvasive cancer. Final positive margins were found

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in 15% of patients with invasive cancer, and 54%had positive nodes. In 24% of patients with noninva-sive IPMNs, residual tumor was identified at the pan-creatic neck or uncinate margin. The 5-year overallsurvival for patients without invasive cancer was 77%,with many deaths secondary to metachronous inva-sive cancer. The survival rate was significantly higherthan the 43% survival rate in patients with an invasivecomponent. No differences in survival were observedregarding adenomas, borderline tumors, and carcino-mas in situ. Surprisingly, survival was statistically sim-ilar when comparing branch duct or main duct originof the tumor. Fourteen patients with colloid carcino-mas had a better 5-year survival rate (83%) comparedwith the 31 patients with tubular carcinomas (24%).IPMN recurrences and deaths from cancer occurredregardless of the benign or malignant nature of thelesion at initial resection. The genetic progressionfrom IPMN adenoma to IPMNwith invasive cancersappears to be distinct from the progression ofPanINs to pancreatic adenocarcinomas.Dpc4 expres-sion is lost in more than 50% of pancreatic ductaladenocarcinomas but only 16% of invasive IPMNs.Additionally, loss of heterozygosity of the STK11/LKB1 gene was identified in 32% of IPMN patients,with subsequent germline and somatic mutationsidentified in remaining alleles. In addition, invasiveIPMNs demonstrate much higher rates of methyla-tion at multiple gene loci, including p16, E-cadherin,MGMT, and hMLH1, compared with pancreaticductal adenocarcinoma.

Pancreaticoduodenectomy for PancreaticAdenocarcinoma: Impact of Margin Status onPattern of Failure and Survival

The importance of retroperitoneal (RP) marginstatus on pattern of failure and survival after pancrea-toduodenectomy (PD) for pancreatic cancer was dis-cussed in a paper by Raut and colleagues from theSurgical Oncology Department of TheM. D. Ander-son Cancer Center, Houston, Texas. From 258 con-secutive patients who underwent PD for pancreaticadenocarcinoma from 1992 to 2002, 253 were studiedwith a minimum follow-up of 12 months (median,12 months) The RP margin, defined as the soft tissuemargin adjacent to the lateral wall of the superiormesenteric artery,wasmicroscopically positive (R1) in36 patients (14%) and negative (R0) in 222 (86%).There were no significant differences in the standardprognostic factors such as tumor size and lymph nodemetastases or in the preoperative and postoperativetherapy between the R1 and R0 groups. Patterns ofrecurrence (local, regional, and distant), overall sur-vival, and the disease-free interval were not statisti-cally different in the R1 and R0 groups. Considering

the unique findings of this study, the authors specu-late on the possible influence of the technical aspectsof the surgical resection and the frequent use ofmultimodal therapy in this study on the reversionof the biological disadvantage ofmicroscopically posi-tive RP margin.

18-FDG PET in Differentiating MalignantFrom Benign Pancreatic Cystic Lesions:A Prospective Study

A previous report from the University of Padua,Italy, demonstrated the usefulness of 18-FDG PETscan in discriminating malignant from benign cysticpancreatic lesions (Ann Surg 2001;134:675–680). Thegroup of Sergio Pedrazzoli from the University ofPadova, Padova, Italy, report on an additional 50patients with suspected cystic neoplasms (n � 33) orIPMN (n � 17) who were prospectively investigatedwith 18-FDP PET scan, abdominal computed to-mography (CT), serum CA 19-9, and, in some in-stances, magnetic resonance imaging (MRI). Thefinal diagnosis was based on the pathologic findingsin 33 operated patients and percutaneous biopsy in3 but only on clinical follow-up in 14. Sixteen of 17patients with malignant tumors (94%) showed 18-FDG uptake, including two patients with carcinomain situ. Eleven patients (65%) were correctly identi-fied as having malignancy by CT. Only 2 of 30 pa-tients with benign tumors had FDGuptake. Althoughthe authors concluded that 18-FDG PET is accurateand better than CT in identifying malignant pan-creatic cystic lesions, the study did not point out howPET scan influenced the management of thesepatients.

Five-year Actual Survival Following ExtendedLymphatic Clearance in Cancer of theHead of the Pancreas

A clinical study by Boggi and colleagues wascarried out at the University of Pisa in Italy to deter-mine the 5-year survival rates of extended versus stan-dard lymphadenectomy in pancreatic head cancer.The authors reported on 87 pancreatectomies with-out neoadjuvant or adjuvant treatments performedfor nonadvanced pancreatic cancer between 1987and 1988, with a minimum follow-up of 5 years.Forty-four patients underwent extended lymphaticclearance (ELC) with a mean number of 25.3 � 1.8dissected nodes. In 43 patients who underwent stan-dard lymphatic clearances (SLC), the mean numberof dissected nodes was 9.8� 1.3. Postoperative lengthof stay was 21 � 8.9 days for ELC patients and20� 6.2 days after SLC.Themorbidity andmortalityrates after ELC were 47.6% and 2.3% compared

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with 33.3% and 4.5% for SLC, respectively. Severediarrhea, requiring medical treatment, was signifi-cantly more frequent after ELC than after SLC (33%versus 2%). Actual survival rate at 1, 3, and 5 yearswas 71%, 25%, and 14% after ELC and 57%, 15%,and 8% after SLC, respectively. The correspondingfigures for patients with lymph node metastases were61%, 24%, and 14% and 52%, 10%, and 0% for ELCand SLC respectively. The incidence and pattern ofcancer recurrence were similar after the two typesof operations, confirming that extended lymphade-nectomy does not significantly enhance survival com-pared with the standard resection.

Distal Pancreatectomy for ResectableAdenocarcinoma of the Bodyand Tail of the Pancreas

The role of surgical resection of adenocarcinomaof the pancreatic body and tail has been questioneddue to the low resectability rates and the poorlong-term survival of these tumors. This issue wasaddressed in a retrospective review by Christein andcolleagues of 93 patients undergoing distal pancreate-ctomy for adenocarcinoma of the body and tail ofthe pancreas at the Mayo Clinic, Rochester, Minne-sota, from 1987 to 2003. Thirty-three (35%) of pa-tients underwent an en bloc pancreatic resection(EDP), including at least one adjacent organ, andthe other 60 (65%) underwent a standard distalpancreatectomy (SDP). Pathologic analysis demon-strated invasive ductal adenocarcinoma in 66 patients(71%), mucinous cystadenocarcinoma in 18 (19%),and invasive adenocarcinoma associated with intra-ductal papillary mucinous neoplasm (IPMN) in 9patients (10%). An R0 resection was possible in 78(84%) patients. The overall complication rate was46%, with pancreatic stump leak being the mostcommon morbidity (20%). There was no operativelyinduced mortality. Median survival was 19.6 months,and the 5-year survival rate was 11.8%. Survival ofpatients undergoing EDP did not differ from thatof those who underwent SDP (P � 0.26). Survivalalso was not significantly affected by blood transfu-sion requirements (P � 0.40), adjuvant therapy(P � 0.15), lymph node status (P � 0.11), or marginstatus (P � 0.08) but correlated positively with tumorstaging (P � 0.004). Patients with cystadenocarci-noma or with IPMN-associated adenocarcinoma hada median survival of 32.2 months, significantly betterthan the 15.4-month median survival for those withinvasive ductal adenocarcinoma (P � 0.003).

Differences in Survival for Patients withResectable Versus Unresectable MetastasesFrom Pancreatic Islet Cell Cancer

From theDepartments of Surgery of JohnHopkinsUniversity, Baltimore, Maryland, and University of

Indiana, Indianapolis, Indiana, House and colleaguesreported on 31 patients with islet cell tumors withsynchronous liver metastases at the time of initialpresentation: 23 with nonfunctional tumors, 2 withgastrinomas, 2 with glucagonomas, 3 with VIP-omas,and 1 with an insulinoma. The patients were dividedinto two groups according to liver metastasis resec-tion (group PL, n� 26) or no metastasis resection(group P, n � 5). In two patients of group PL, acombination of resection and ablation was applied.Multiple (�10) small bilobarmetastaseswere found inall of the P group patients. There were no statisticaldifferences between the PL and P groups in primarytumor size, lymph node metastases, and concomitantliver disease or adjuvant treatments. All patients un-derwent resection of the pancreatic primary by meansof 12 pancreaticoduodenectomies—11 (42%) in thePL group and only 1 (20%) in the P group—or 19distal pancreatectomies—15 (58%) in group PL and4 (80%) in group L. The median overall survival forthe respectable liver metastases group was 78 monthsversus 17 months for those with unresectable livermetastases (P � 0.06). This result indicates that pat-terns of liver metastases from islet cell tumors, spe-cifically bilobar miliary metastases that are notamenable to resection or ablation, predict a pooroutcome despite resection of the primary pancre-atic tumor.

Phase III Trial of Radiosensitizer PR-350Combined With Intraoperative Radiotherapyfor the Treatment of Locally AdvancedPancreatic Cancer

Well-oxygenated cells are believed to bemore sen-sitive to intraoperative radiotherapy (IOR) than hyp-oxic cells. Based on this theory, a prospective studyto clarify the role of a novel radiosensitizer for hyp-oxic cells, PR-350 (doranidazole), combined withIOR was conducted in Sendai and Tokyo, Japan, andpresented by Makoto Sunamura. PR-350 is a 2-nitro-imidazole nucleoside analogue, less neurotoxic thanetanidazole, that has the ability to sensitize radioresis-tant tumor cells to the lethal effects of ionizing radia-tion under extremely hypoxic conditions. Forty-eightpatients treated with IOR for locally advanced pan-creatic cancer were randomized, in a 3-year period,to PR-350 or placebo. Efficacy of the treatment, eval-uated by CT examination, was reported in 47.4% ofthe PR-350 group, which was significantly better thanthe 21.7% effective response in the control group.Tumor mass reduction rate was also significantly im-proved in the PR-350 group at 6 months followingtherapy. Although there were little differences inmedian survival (318 days versus 303 days) and in the1-year survival rate (36% versus 32%) between thetreated and the control group, respectively, it is worthmentioning that four of the PR-350–treated patientslived longer than 2 years after the end of the trialcompared with only one in the control group.