January 15;.2013 © Volume 19 « Number2 ¢ Pages 309-508
`
`» Cancer
`Research
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`Editor-in-Chief
`Kenneth (¢. Anderson
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`Deputy Editors
`
`Editorial Board
`
`Research
`
`Clinical
`Cancer
`
`The Journalof Clinical and Translational Research
`
`Robert 1. Perris
`Soldano Perrone
`William D, Figg
`Richard S, Finn
`Michelangelo Fiorentino
`Antonio PT. Fojo
`David A. Frank
`Arthur E, Frankel
`vaul Frankel
`Ralph S. Freedman
`GaryE. Gallick
`Varsha V. Gandhi
`Stanton L, Gerson
`Giuseppe Giaccone
`luca Gianni
`Bonnie $. Glisson
`Ajay Goel
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`[less
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`Gary Kao
`Judith FE. Karp
`scott 1. Kaufmann
`StanleyB. Kaye
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`John M. Kirkwood
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`f. Anders Kolb
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`Jason A. Kouteher
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`

`
`
`Clinical
`Cancer
`Research
`The Journalof Clinical and Translational Research
`January 15, 2013 * Volume 19 ¢ Number 2
`
`Highlights of This Issue 309
`
`CANCER THERAPY: PRECLINICAL
`
`SPECIAL FEATURES
`
`CCR Translations
`
`311
`
`Targeted Isotretinoin in
`Neuroblastoma: Kinetics, Genetics, or
`Absorption
`Katherine K. Matthay
`See article, p. 469
`
`Statistics in Clinical Cancer Research
`
`314
`
`Tumor Burden Modeling Versus
`Progression-Free Survival for Phase I
`Decision Making
`Lee D. Kaiser
`
`Molecular Pathways
`
`320
`
`Molecular Pathways: Comparing the
`Effects of Drugs and TCells to
`Effectively Target Oncogenes
`Kathleen Anders and Thomas Blankenstein
`
`Review
`
`327
`
`The Role of JAK Pathway
`Dysregulation in the Pathogenesis and
`Treatment of Acute Myeloid Leukemia
`Hun Ju Lee, Naval Daver, Hagop M. Kantarjian,
`Srdan Verstovsek, and Farhad Ravandi
`
`HUMAN CANCER BIOLOGY
`
`336
`
`Tumoral Lymphocytic Infiltration and
`Expression of the Chemokine CXCL1O
`in Breast Cancers from the Ontario
`Familial Breast Cancer Registry
`Anna Marie Mulligan, Irene Raitman,
`Linda Feeley, Dushanthi Pinnaduwage,
`Linh T. Nguyen, Frances P. O'Malley,
`Pamela $8. Ohashi, and Irene 1. Andrulis
`
`347
`
`357
`
`367
`
`380
`
`393
`
`Milatuzumab-Conjugated Liposomes
`as Targeted Dexamethasone Carriers
`for Therapeutic Delivery in CD74!
`B-cell Malignancies
`Yicheng Mao, Georgia ‘Triantalillou,
`Erin Hertlein, William ‘Towns,
`MatthewStefanovski, Xiaokui Mo,
`David Jarjoura, Mitch Phelps, Guido Marcucet,
`Ly James Lee, David M. Goldenberg,
`Robert J. Lee, John C. Byrd, and
`Natarajan Muthusamy
`
`BMS-936564/MDX-1338: A Fully
`Human Anti-CXCR4 Antibody Induces
`Apoptosis In Vitro and Shows
`Antitumor Activity [1 Vivo in
`Hematologic Malignancies
`Michelle R. Kuhne, Tanya Mulvey.
`Blake Belanger, Sharline Chen, Chin Pan,
`Colin Chong, Fei Cao, Wala Niekro, Tom Kempe,
`Karla A. Henning, Lewis J. Cohen,
`Alan J. Korman, and Pina M. Cardarelli
`
`In Vitro Sensitivity of CLL Cells to
`Fludarabine May Be Modulated by the
`Stimulationof Toll-like Receptors
`onte, Benedetta Apollonio,
`/
`Eleonora I
`/
`a Ranghetli, Claudia Pazt,
`Lydia Searto, Pamel
`Paolo Ghia, Federico Caligaris-Cappio, and
`Marta Muzio
`
`¢-Sre Activation Mediates Erlotinib
`Resistance in Head and Neck Cancer by
`Stimulating ¢-Met
`Laura P. Stabile, Guoging He,
`Vivian Wai Yan Lut Cassandra Henry,
`Christopher 'T. Gubish. Sonali Joyee,
`Kelly M. Quesnelle. Jill M. Siegfried, and
`Jennifer R. Grandis
`BRAF Inhibition Increases Tumor
`Infiltration by T cells and Enhances
`the Antitumor Activity of Adoptive
`Immunotherapy in Mice
`ChengwenLiu, Weiyi Peng, Chunyu Xu,
`Yanyan Lou, Minying Zhang, Jennifer A. Wargo,
`Jie Qing Chen, Haiyan §. a;
`Stephanie 5. Watowich, Yan Yang,
`Dennie ‘Tompers Frederick, “Zachary A. Cooper,
`Rina M. Mbofung, Mayra Whittington,
`Keith ‘T. Flaherty, Seott E, Woodman,
`Michael A. Davies, Laszlo G. Badvanyi,
`Willem W. Overwijk, Gregory Lizee, and
`Patrick [wu
`
`6eeeeeeeeee
`The Journal of Clinical and Translational Research
`ili
`www.aacrjournals.org
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`

`

`
`
`404
`
`415
`
`428
`
`PLKI Inhibitors Synergistically
`Potentiate HDAC Inhibitor Lethality
`
`in Imatinib Mesylate—Sensitive or
`-Resistant BCR/ABL|) Leukemia
`Cells In Vitro and In Vivo
`Girija Dasmahapatra, Hiral Patel, Tri Neuyen,
`Elisa Attkisson, and Steven Grant
`
`Complete Regression of Metastatic
`
`Renal Cell Carcinoma by Multiple
`Injections of Engineered
`Mesenchymal Stem Cells Expressing
`Dodecameric TRAIL and HSV-TK
`Sae Won Kim, Su Jin Kim, Sang Hoon Park,
`Hyun Gul Yang, Moon Cheol Kang,
`Young Woo Choi, Seong Muk Kim,
`Sin-Soo Jeun, and Young Chul Sung
`
`Dysregulation of the Repressive
`H3K27 Trimethylation Mark in Head
`and Neck Squamous Cell Carcinoma
`Contributes to Dysregulated
`Squamous Differentiation
`Orla M. Gannon, Lilia Merida de Long,
`Liliana Endo-Munoz,
`Mehlika Hazar-Rethinam, and
`Nicholas A. Saunders
`
`CANCER THERAPY: CLINICAL
`
`462
`
`469
`
`Durable Cancer Regression Off-
`Treatment and Effective Reinduction
`Therapy with an Anti-PD-1 Antibody
`Evan ). Lipson, William 1. Sharfman,
`Charles G, Drake, Ira Wollner, Janis M. ‘aube,
`Robert A. Anders, Haiying Xu, Sheng Yao,
`Alice Pons, Lieping Chen, Drew M. Pardoll,
`Julie KR. Beahimer, and Suaanne 1. Topatian
`
`Adaptive Dosing Approaches to the
`Individualization of 13-Cis-Retinoic
`
`Acid (Isotre
`n) Treatment for
`Children with High-Risk
`Neuroblastoma
`Gareth J. Veal, Julie Errington,
`Sophie BE. Rowbotham, Nicola A. Wlingworth,
`Ghada Malik, Michacl Cole, Ann K. Daly,
`Andrew DJ. Pearson, and Alan V, Boddy
`see commentary, p. 311
`
`PREDICTIVE BIOMARKERS AND
`PERSONALIZED MEDICINE
`
`IMAGING, DIAGNOSIS, PROGNOSIS
`
`442
`
`450
`
`Variation in Precursor Lesions of
`Pancreatic Cancer among High-Risk
`Groups
`Thomas P. Potjer, Ingrid Schot. Peter Lanwer.
`Johannes 1. Heverhagen, Martin NLM Wasser,
`Emily P. Shaler, Gunter Kloppel,
`Hans M. Morreau, Bert
`A, bonsing,
`Wouter Th de Vos tot Nederveen Cappel,
`Mathias Margello, Uhonias Mo Gress,
`Hans FAL Vasen, and Detlel Ko Bartsely on
`behalhatthe Leiden Pamilial Panereatio (sneer
`Group ane the PaliCu registry
`
`Prognostic Significance of AKT/
`mTOR and MAPK Pathways and
`Antitumor Effect of mTOR Inhibitor
`in NFI-Related and Sporadic
`Malignant Peripheral Nerve Sheath
`Tumors
`Makoto Kodo, Hidetaka Yamamoto,
`Nokituka Setsu, Kemehi Kobashi,
`Yusuke Takahashi, Vakeaki Ishii,
`Ke-ichiro lida, Yoshihiro Matsumato,
`Michiyuki Hakovaki, Mikiko Aoki,
`Hiroshi Iwasaki. Yoh Dobushi,
`Kenichi Nishiyama, Yukihide Iwamoto, and
`Yoshinao Oda
`
`480
`
`491
`
`Detection of Novel Actionable Genetic
`Changesin Salivary Duct Carcinoma
`Helps Direct Patient Treatment
`Valentina Nardi, Peter M. Sadow, Dejan Juric,
`Dave Zhao, Arjola k. Cosper, Kristin Bergethon,
`Vanessa [.. Scialabba, Julie M, Batten,
`Darrell R. Borger, Anthony John lafrate,
`Rebecea S$. Heist, Donald PL Lawrence,
`keith T. Flaherty, Johanna C. Bendel,
`Daniel Deschler, Yi Li, Lori J. Wirth, and
`Dora Dias-Santagata
`
`Integration of Cell Line and Clinical
`Trial Genome-Wide Analyses
`Supports a Polygenic Architecture of
`Paclitaxel-Induced Sensory
`Peripheral Neuropathy
`Heather E. Wheeler, Eric BR. Gamazon,
`Claudia Wing, Uchenna O. Njiaju,
`Chidiamara Njoku; Robert Michael Baldwin,
`Kouros Owsar, Chen Jiang, Dorothy Watson,
`Ivo Shterey, Michiaki Kubo, Hitoshi Zembutsu,
`brie 1 Winer, Clifford A, Thadis,
`Lawrence No Shulman, Yusuke Nakamera,
`Mark —. Rattain, anid Deanna bo Kroety for the
`Cancer and Leukemia Croup ty Naney p. Cox,
`wo Mary Pileen Dahin
`
`
`AR. Lnerivean Association for CancerResearch
`iv
`Clinical Cancer Research
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`

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`Matthew P. Goetz, Vera |. Suman,
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`image showing the effects of the polycomb
`Confocal immunofluorescent
`repressor complex 2 inhibitor 3-deazaneplanocin A on tumor cellularity
`and apoptosis in a xenotransplant model of human head and neck cancer.
`immunodeficient mice were injected with a head and neck cancercell line
`which was allowed to establish prior to daily treatment with 5 mg/kg DZNep.
`Tumortissue has been stained with DAPI to highlight cell nuclei, Green
`immunofluorescence highlights the human epithelial tumor cells (AEI/II
`positive) and red fluorescence highlights caspase HI positive dying cells. For
`
`details, see the article by Gannon and colleagues on page 428 ofthis
`
`nn———
`The Journal of Clinical and Translational Research
`:
`__,v
`:
`www.aacrjournals.org
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Cancer Therapy:Clinical
`ES ED
`
`eters)
`
`Clinical
`Cancer
`
`Durable Cancer Regression Off-Treatment and Effective
`Reinduction Therapy with an Anti-PD-1 Antibody
`
`Evan J. Lipson’, William H. Sharfman'”, Charles G. Drake", Ira Wollner®, Janis M. Taube*",
`Robert A. Anders", Haiying Xu*, Sheng Yao'™, Alice Pons', Lieping Chen'*, Drew M. Pardoll',
`Julie R. Brahmer', and Suzanne L. Topalian®
`
`Abstract
`
`Purpose: Results from thefirst-in-human phase| trial of the anti-programmed death-1 (PD-1) antibody
`BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmaco-
`dynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow
`up on three patients from that trial who sustained objective tumor regressions off therapy, and test the
`hypothesis that reinduction therapyfor late tumor recurrence can beeffective.
`Experimental Design: Three patients with colorectal cancer, renal cell cancer, and melanomaachieved
`objective responses on an intermittent dosing regimen of BMS-936558. Following cessationoftherapy,
`patients werefollowedfor morethan3 years. A patient with melanomawho experienceda prolongedpartial
`regression followed by tumorrecurrence received reinduction therapy.
`Results: A patient with colorectal cancer experienced a complete response, whichis ongoingafter3 years.
`A patient with renal cell cancer experienced a partial responselasting 3 years off therapy, which convertedto
`a complete response, which is ongoing at 12 months. A patient with melanomaachievedapartial response
`that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-
`PD-1 therapy
`Conclusion: [hese data represent the most prolonged observation to dateofpatients with solid tumors
`responding to anu-PD-! immunotherapy andthefirst report of successful reinduction therapy following
`delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD- |
`to reset the equilibrium between tumor and the host immunesystem. Clin Cancer Res; 19(2); 462-8. ©2012
`AACR,
`
`Introduction
`
`Phe specific or selective expression of antigens by cancer
`cells creates an opportunity for cndopenous collimediated
`and serologic immune attack and for tmmunotherapectic
`interventions. Lhe development of effective cancer immu
`notherapies depends on reversing inhibitory and tolero
`genic signals ins
`the tumor microenvironment,
`thereby
`enhancing the visibility of
`tumor cells to the immune
`:
`system,
`In the last decade,
`it has become clear
`that
`the
`
`'Dermatolo
`Authors’ Affiliations: Departments of ‘Oncology, “Urology,
`gy. “Pathology, and “Surgery, Johns Hopkins University School of Med
`cn
`2
`icine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Mary-
`land; and “Departmentof Internal Medicine, Wayne State University School
`of Medicine and Henry Ford Hospital, Detroit, Michigan
`
`Current address for S. Yao and L. Chen: Department of Immunobiology,
`Yale University, New Haven, CT 06519.
`
`Corresponding Author: Evan J. Lipson, Department of Oncology, Johns
`Hopkins University School of Medicine and Sidney Kimmel Comprehensive
`Cancer Center, 1550 Orleans Street, David H. Koch Cancer Research
`Building, Baltimore, MD 21287. Phone: 410-502-8200; Fax: 410-502-
`1958; E-mail: evanlipson@jhmi.edu; and Suzanne L. Topalian. E-mail:
`stopalil @jhmi.edu
`doi: 10.1158/1078-0432.CCR-12-2625
`12012 American Association for Cancer Research,
`
`immune regulatory pathway composed of programmed
`death-1 (PD-1, CD279), a receptor expressed on activated
`Vand Bcells andits ligands PD-L1 (B7-111, CD274) and PD-
`1.2 (B7-DC, CD273), plays an integral role in the down
`modulation of antitumor immunity.
`Inhibition of this
`pathway using blocking monoclonal antibodies (mAb)
`against PD} or PD-LL is emerging as an effective method
`for reversing cancer immunosuppression and thereby caus
`iy
`UTUSSI
`i ye
`a
`»
`sc
`5
`ing Lumor repression in patients with advanced disease (1).
`Although such therapies are stillin development, they have
`shown promising Clinical results notonly for timors elas
`sically considered to be immunogenic such as melanoma
`and
`renal cell carcinoma
`(ROC),
`but.
`:
`ind
`(I
`), but
`also for common
`epithelial malignancies such as non-small cell lung cancer
`(NSCLC), historically resistant to immunotherapy,
`BMS-9360558 (MDX-1LL06/ONO-4538)
`is
`a) blo king
`mAbspecific for human PD 1. The firs-in-human single
`dose, dose-escalation trial of this agent reported by Brahmes
`and colleagues (2) enrolled 39 patients with treatment
`refractory metastatic solid tumors including melanoma,
`RCC, colorectal cancer (GRO), NSCLC, and castration-resis
`tant prostate cancer (CRPC). A favorable safety profile and
`preliminary evidence of clinical activity in all histologies
`except CRPC led to the design of a multidose trial of
`
`462
`
`Clin Cancer Res; 19(2) January 15, 2013
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`AR. TerieAsset for CancerResearch
`
`

`

`Durable Response and Effective Reinduction with Anti-PD-1 mAb
`
`
`
`Translational Relevance
`
`‘This report provides long-term follow-up on patients
`from the first-in-humantrial ofthe anti-PD-1 antibody
`BMS-936558 (MDX-1106) who achieved objective |
`tumorregressions. Theyincludepatients with metastatic
`melanoma, colorectal, and renal cancer. Remarkably,
`durable responses including continued tumor regression
`off therapy were observed. Furthermore, a patient with
`melanoma, who experienced tumor recurrence follow-
`ing a prolongedpartial response, respondedto reinduc-
`tion with anti-PD-1 therapy. These findings of durable
`treatment effect underscore the potential for immune-
`based therapies such as antibodies blocking the immu-
`nosuppressive PD-1/PD-L1 pathway to reset the equi-
`librium between tumor and the host immunesystem,
`distinguishing them from conventional chemotherapies
`as well as small-molecule inhibitors of oncogenic driver
`pathways. They represent the most prolonged observa-
`tion ofpatients with solid tumors responding to anti-
`| PD-1 immunotherapy to date, andthe first evidence that
`reinduction therapy with this agent after late tumor
`recurrence may be effective.
`
`
`
`institutional, first-in-human, phase | dose-escalation study
`(2). The protocol was approved by local
`Institutional
`Review Boards (IRB), andall participating subjects signed
`informed consent. The antibody was given as a single
`intravenous infusion at 0.3 to 10 mg/kg per dose, followed
`by radiologic restaging at 8 and 12 weeks. Responses were
`evaluated using Response [valuation Criteria in’ Solid
`‘Tumors (RECIST) 1.0, Patients whotoleratedthe drug well
`(no adverse events > grade 3. and no development of human
`antihuman antibodies) and showedstable disease or any
`evidence of tumorregression wereeligible for retreatment
`at weeks 12 and 16. Patients who achieved an objective
`response (PR or CR) discontinued dosing and were
`observed with periodic radiologic restaging.
`A patient with melanomawhoexperienceda prolonged
`PR followed by tumor progression received reinduction
`therapy with BMS-936558 10 mg/kg on days 1, 29, and
`86, repeated every 120days, on asingle patient useclinical
`trial following IRB approval and informed consent.
`In
`contrast to the original dosing schema, treatment onthis
`trial may continueuntil the patient develops a confirmed
`CR, confirmedprogressivedisease, or unacceptabletoxicity,
`
`Tumor biopsies and immunohistochemistry
`llistologic slides were reviewed to confirm the cancer
`diagnosis, and one representative formalin fixed, paraffin
`embedded(EEPE) block of tumor was chosen for immu-
`nohistochemical (IHC) analysis to characterize the tumor
`and its microenvironment, PD-L1 immunostaining was
`conducted with the mAb SIH as previously described
`(4). The method for PD-1 immunostaining parallels that
`reported for PD-L.1 with minor modifications. The murine
`antihuman PD-1 mAb, clone M3, was used ata concentra
`tion of 1.0 pg/mL. Citrate buffer (pl! 6.0) was used for
`antigen retrieval, and a CSA System (DAKO) was used for
`signal amplification, followedby development with diami-
`nobenzidine chromagen that results in brownstaining. In
`the heavily pigmented melanoma, a Giemsa counterstain
`was used for
`the PD-1 antibody.
`‘This
`results in green
`coloration ofthe melanin pigment andfacilitates interpre-
`tation ofthe brown signal (5). CD3, CD4, CD8, CD68, and
`‘T-cell
`intracytoplasmic anugen-!
`(TIA-1)
`immunostains
`were conducted according to routine automated methods.
`
`Results
`Among 39 patients with treatment-refractory solid
`tumors receiving BMS-936558 on an intermittent dosing
`regimen(2), 3 objective tumor regressions were observed.
`Followingaretheclinical and immunologic assessments of
`these patients during, prolonged observation.
`
`Durable complete response in colorectal cancer
`A 71-year-old male with CRC underwent a right hemi-
`colectomy in October 2003, revealing a moderately differ-
`entiated adenocarcinoma with metastases to 4 of
`16
`pericolonic lymph nodes andvascular and perineural inva-
`sion |G), pl3N2; microsatellite instability (MSI)-high gen-
`otype]. He received adjuvant 5-fluorouracil
`(5-PU) and
`
`BMS-936558 in 296patients that was recently reported(3),
`confirming antitumor efficacy in melanoma, RCC, and
`NSCLC.
`‘Theadaptive immunesystemhas avast capacityfor specific
`antigen recognition and holds the potential
`to adjust
`to
`ongoing tumor evolution, including genetic and epigenetic
`changes that
`typically cause resistance to. small-molecule
`inhibitors. Uhis adaptability, coupled with an immune mem-
`ory component, implies that immunotherapycan "reorient"
`endogenous antitumor immunity with durableeffects even
`after the cessation of therapy. Ilere, we provide long-term
`follow-up on patients from the first-in-humantrial of BMS-
`936558 who achieved objective tumorregressions, including
`a patient with CRC who maintained a complete response
`(CR) offtherapy; a patient with RCC who sustainedapartial
`response (PR)
`that converted to a CR off therapy; and a
`patient with melanomawho experienced a prolongedPRoff
`therapy followed by tumorprogression andthen responseto
`reinduction therapy with the sameanti-PD- 1 antibody. These
`data represent the most prolonged observation ofpatients
`with solid tumors responding to anti-PD-1 therapy and the
`first evidence that reinduction therapy with this agent after
`late tumor progression maybeeffective. The observed dura-
`bility of responses underscores the potential for immune
`checkpoint blockade with anti-PD-1 to reset the equilibrium
`between tumor and host and provide durable tumor control
`atter cessation of therapy.
`
`Materials and Methods
`
`Treatments administered and response evaluation
`BMS-936558, a fully human immunoglobulin G4 (lgG4)
`blocking mAb against PD-1, was administered in a multi-
`
`www.aacrjournals.org
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Clin Cancer Res; 19(2) January 15, 2013
`
`463
`
`

`

`Lipsonet al.—[———eeeeeEee
`
`preliminary evidence for a correlation between tumor cell
`membranous PD-L1 expression and the likelihood of
`response to anui-PD-1 therapy (2). Potential relationships
`between PD-L1 expression on nontumor cells and clinical
`outcomes require further study (4).
`
`Evolution of complete tumor regression off therapy in
`renal cell carcinoma
`A 76-year-old male underwent a right nephrectomy and
`vena caval thrombectomy in 2001, showingclear cell renal
`carcinoma. Le developed bilateral pulmonary metastases in
`2003 andreceived systemic therapies including the histone
`deacetylase inhibitor mocetinostat, sorafenib, and suniti
`nib, experiencing disease progression with new metastatic
`sites in mediastinal
`lymph nodes, bone, and paraspinal
`musculature.
`In January 2008, he began treatment with
`anu-PD-1 at 10 mg/kg per dose. Cl scans conducted in
`March 2008, 8 weeks after a single dose of anti-PD-1,
`showed a mixed response: pulmonary,
`lymph node, and
`intramuscular metastases were regressing, but lesions were
`enlarging in the pancreas and bone. The patient also devel
`oped hypothyroidism, which was assessed as possiblytreat
`ment related, He received 2 more doses of anti-PD-1 in April
`
`
`
`
`
`1, Response of metastatic
`Figure
`colorectal cancer to anti-PD-1
`therapy. A, computed tomographic
`scan showing partial regression of
`a representative lymph node
`metastasis in a patient with CRC,
`alter receiving a single dose of
`anti-PD-1. B, hematoxylin and
`eosin (H&E) staining and IHC
`analysis of primary colon tumor
`from this patient, showing PD-L1
`lymphohistiocytic intiltrates
`surrounding tumor cells, and rare
`PD-L1)
`tumor cells, interposed
`
`with CD3; and PD-1+infiltrating
`T cells. Arrow denotes tumor cells
`Original magnification,-200
`
`leucovorin; however, a Cl scan the following year revealed
`metastatic disease. Over the subsequent
`3 years, the patient
`received multiple chemotherapeutic regimens with tempo-
`rary response but then progression at multiple lymph node
`sites (gastrohepatic, portacaval, and peripancreatic); thera
`pies
`included