Abdominal cavity lymph node chains, 75 Accessory saphenous bundle, 66

(1)

A

Abdominal cavity lymph node chains, 75 Accessory saphenous bundle, 66

AJCC classification, melanoma stage IV chemosensitivity testing

ATP-TCA in, 282, 283 DTIC and, 282, 284, 285 perspectives of, 284, 285 A375 melanoma cells

lymphangiogenesis in, 17

transfected with cDNA encoding soluble VEGFR-1, 21, 22

American College of Surgeons Surgical Oncology Group, trial

of Z0011, 215

Angioblasts and hemangioblasts, 19 Angiogenic drugs target, 239 Angiopoietins 1 and 2, 9, 11

Anti-CD3/IL-2 activated tumor-draining LN cells immunotherapy, 229 Anti-CD3/IL-2 method stimulated Tcell

growth, 229

Anti-EGFR agents for cancer therapy, current status, 259

Anti-EGFR therapy

molecular aspects, 260, 261 predictive markers, 266, 267 strategies for, 258

Antigen-presenting cells (APCs), 224 Anti-LYVE-1 production, 34

Antitumor immunity and draining LN, 225 Anti-VEGF agents, bevacizumab

antibody, 241

Anti-VEGF receptor agents, 241, 242 Aortolumbar lymph nodes, 76 Apoptosis, 260

Arms, deep bundles and lymph nodes of, 60, 61, 63

Array-CGH (comparative genomic hybridization), 173

ATP bioluminescence assay (ATP-TCA), in chemosensitivity testing, 282 Axilla lymph nodes, 64

anterior group, 60

intermediate and medial group, 65 lateral and posterior group, 61

Axillary lymph node metastasis, prognostic

value of, 159

(2)

B

Bacillus Calmette-Guerin (BCG), 225 B-and T-lymphocytes, 86

Barrett’s cancer, 211 Basilic bundles, 60, 64 B-cell-enriched follicles, 224 Bevacizumab, 264

anti-VEGF agents, 241 phase III clinical trial of, 241

in treatment of colorectal carcinoma, 264 Bleomycin oil suspension, 104. See also

Oil Bleo in dog’s blood, 105

serum concentration of, 105 Blood capillaries, 56

Blood-lymph circulatory loop, 4, 6 Blood vascular endothelial cells (BECs),

17–19, 139 Blue dye technique, 214

“B” lymphocytes, 187

B16 melanoma cells, 119, 121, 140 Bortezomib, metastatic melanoma and,

287, 288 Breast cancer, 210

axillary nodal metastases, risk of, 196 biological models of lymphatic metastasis

in, 160 detection of, 195

ErbB receptor inhibitor, treatment in metastatic breast cancer, 247 IHC staining, use of, 197

immunohistotochemical and RT-PCR positive SLNs in, 215

injection techniques for, 93 internal mammary drainage, 94, 95 in ipsilateral axilla, SLNs identification,

214 lymphatic localization techniques in, 93 lymphatic metastasis in, 157

parenchymal peritumoral injection, 94 sentinel node, 93, 188

T1a breast cancer, 188 Breast lymphoscintigraphy

delayed imaging, 96

patient positioning during, 95 radiosensitive probes in, 96

Bronchioalveola cancer (BAC), 267 Bronchomediastinal trunks, 57

Brown University Oncology Group, 249 B16 tumor-bearing mouse leg model, 143

C

CAM. See Chorioallantoic membrane Cancer

EGFR-TK activity in, 246 and lymphatic system, 10–12 progressive behavior of, 194, 195 therapy, 182

treatment tumor-sensitized Tcells, 229 Virchow’s cell theory of, 10

Cancer metastasis

future perspectives, 293–295 Paget and homing theory, 177 Capecitabine, 266

Carcinoembryonic antigen (CEA), 170 Carcinoma cells

process of evolution of, 194

twist expression in mammary, 189, 190 CA-repeat polymorphisms in intron 1 of

EGFR gene, 266

Cascade hypothesis and metastatic disease, 213

CC-5013, blocker of VEGF, 288 CCI-779 inhibitor, in melanoma

patients, 287

CD3. See Low MW proteins cluster CD80 and CD86 costimulatory

molecules, 230 CD34

⁺

progenitor cells, 230 Celecoxib, 147

Celiac aortic lymph nodes, 75 Cells, metastatic cascade of, 189 Cellular immune responses LN

draining, 224 Cetuximab, 257, 261

in treatment of HNSCC, 263, 264 Chemoattractant cytokines (CC), 146 Chemokine receptor-ligand axis, 177 Chemokines

for cancer therapy, 182

on carcinomas, 181

CCL21/SLC, 178

(3)

CCR7 and CXCR4, 179 epigenetic regulation of receptors,

179, 180

microenvironment for chemokine ligands, 181, 182

and receptors, 161, 177, 178 subfamilies of, 177–179 Cholesterol, in lymph, 110 Chondrosarcoma, 217 Chorioallantoic membrane

of avian embryos, 20, 21 of chick embryos, 22

Chronic lymphatic leukemia, pegylated interferon-α and, 280

“Chyliferous vessels,” 2 Chylomicrons, 110 Cisplatin, 264

Cloquet’s lymph node, 74

Colloids. See Radiolabeled colloids Colon cancer, role of SLN procedure, 216 Colorectal cancer, 180, 181, 212, 213, 267 Corynebacterium parvum, 225

Cox regression model, DTC prognosis in, 171

Cricotracheal ligament, 205 Cyclophosphamide, 230 Cytokeratins (CK), 168 Cytostatic drugs, 104

Cytotoxic T lymphocytes (CTLs), 230

D

Dacarbazine (DTIC) monochemotherapy, 282, 284, 285

DC-based immunotherapy strategies, 230 DC-tumor hybrids, 231, 232

Deep inguinal lymph nodes, 68 Deep leg lymph nodes, 71 Deltoideopectoral lymph nodes, 60 Dendritic cells (DCs), 178, 224 Dendritic tumor heterokaryotic hybrid

biological and immunological characteristics, 230–235 by electrofusion, 230 Diacylglycerol (DAG), 260 Dielectrophoresis, 231

Disseminated tumor cells (DTC), 167–173

D5Lacz melanoma, 232 D6 molecule, 42

Dog popliteal lymph node with iodinated oil, 103

Drug carriers, 102 liposomes, 115

oil content reduction of, 107

Drug concentration in lymph nodes, 102 DTC in regional lymph nodes detection,

methods and frequencies, 168 Duodenal carcinoid tumors, 191 Dye-based and radioisotopic tracer

methods, 93

E

Eastern Cooperative Oncology Group (ECOG 5397), 263

E-Cadherin-mediated cell–cell adhesion, 190

ECOG. See Brown University Oncology Group

Edema

pathophysiologic mechanisms underlying, 3

treatment of, 8

ED 11 mouse embryos staining, 20 EGF. See Epidermal growth factor EGFR. See Epidermal growth factor

receptor EGFR-TK, 246

EGFR-TKIs in NSCLC patients, clinical trials with, 267

EGFR tyrosine kinase inhibitors (EGFR-TKIs), 245, 257 EGFR tyrosine kinases, 245, 246 EKB-569, tyrosine kinase inhibitor, 250 Electrofusion technique, 231, 232 Embryoid body

cultures, 34

density slicing of, 35

extracellular matrix and vessels in, 29 lymphangiogenesis, 27–29

lymphatic culture conditions and regulation, 31, 32

Embryoid body vessels, 33

with anti-CD31 and anti-LYVE-1, 29

(4)

Embryonic blood vessels, 26 Embryonic development, 17

Embryonic lymphangiogenesis, 18–20 Embryonic lymph sacs development, 18 EMT. See Epithelial-mesenchymal transition Endolymphatic drug application

experimental basis of, 104 liposomes for, 111

prerequisites and limitations of, 102 therapeutic use of, 103

Endolymphatic therapy drug carriers, 102 Endothelial cell activation, osteopontin

and, 121

Endothelial cells venous and lymphatic, 19 Endothelial markers antibodies, 34 EphrinB2, 27

Epidermal growth factor, 247, 260 Epidermal growth factor receptor, 241,

257, 287

activation and HNSCC cell invasion, 260 autophosphorylation, 262

expression in malignant neopmasms, 258 family receptor, 245

gene copy number, 267 HER-1 receptor, 261

in human cancers, expression of, 240 implication in malignancy, mechanism

of, 260

inhibitors, in treatment of solid cancers, 261–266

ligands, overexpression, 260 members of, 244, 246 mutational activation, 260 pathway activation, 260 signaling network, 261 targeted agents, 244, 245 Epithelial cell adhesion molecule

(EpCAM), 168

Epithelial-mesenchymal transition, 190 Epitroclear lymph nodes, 60

Epstein-Barr virus proteins, 264 ErbB (EGFR) family of receptors, 260 ErbB/HER membrane receptors, 261 ErbB receptor inhibitor, treatment in

metastatic breast cancer, 247 ErbB-1 therapy, 246, 247

Erb tyrosine kinase receptors, 245 Erlotinib, 257, 259

doses of, 248, 249 drug, 248, 249

EGFR tyrosine kinase inhibitor, 262 Esophageal squamous cell carcinoma, 211 Esophogeal carcinoma, 211

European Association of Dermatologic Oncology (EADO), 282

Extracellular signal-regulated kinase (ErK) kinase, 261, 267, 287

Ezrin, 42, 121, 123

F

FACS analysis, 232 Femoral artery, 68 Fibrin, 141 Fibrosarcoma, 217 Fibrous hystiocytoma, 217 Flow cytometry, 168

Fluorescent lymphatic imaging, 86 Fluorescent proteins, 86

5-Fluorouvacil, 241

Food and Drug Administration (FDA), 247 Foot and leg lymphatic bundles of, 67 Forearm deep bundles and lymph

nodes of, 62

Forkhead transcription factor (FKHR), 2, 9, 10, 27, 34, 138

G

Gamma-ray perturbed angular correlation technique, 113

Gastric adenocaricinoma, 212 Gastric cancer

detection of, 195 retrospective analysis, 211 Gastric metastasis, 211

Gastrointestinal stromal tumor (GIST), 217 Gastrointestinal trunk, 57

Gefitinib, EGFR tyrosine kinase inhibitor, 257, 259, 261, 262

Gemcitabine, 265

German Dermatologic Cooperative

Oncology Group (DeCOG),

282, 285

(5)

GL261 glioma, 232

Glioblastoma multiforme (GBM), 230 Gliomas, 260

Glycogen synthase kinase-3 (GSK-3), 261 Glycophosphoprotein, 161

G-protein, 178, 260 Granulocyte-macrophage

colony-stimulating factor (GM-CSF), 223, 224

Growth factor receptor-binding protein 2, 261

Guajazulen, 104

Guajazulen-in-lipiodol solution,

endolymphatic injection, 108, 109 Guajazulen-lecithin emulsion

preparation, 109

Guajazulen-tween emulsions, 109

H

Halsted’s model, 209

Head and neck, anatomy of lymphatics of, 76, 77

Head and neck cancer, 211

Head and neck squamous cell carcinomas (HNSCC), 39, 263, 264

Hematogenic metastasis, 20

Hematogenous (blood-borne) metastasis, 159, 160

Hematogenous dissemination, 211 Hematogenous spread

of distal rectal cancer, 213 from esophageal cancer, 211 Hematoxylin-Eosin (HE), 168

Hepato cellular cancers (HCC), 190, 213 HER-2 signaling pathways, 266

Heterodimerization, 260

High endothelial venules (HEV) of lymph nodes, 178, 187

Histone deacetylation (HDAC) inhibitors, in melanoma, 286, 288

HNSCC cell motility, 260

Human, metastatic specificity in, 190 Hybrid imaging, 83

Hyperamalysemia, 244

Hypersensitivity and role of local LNs, 225 Hypopharynx lymph fluid, 205

Hypothyroidism, 244

Hypoxia-inducible factor (HIF), 242, 243 I IFN-γ secretion by GL261 tumor-specific

T cells, 233 Iliac lymph chain, 75

Immunohistochemical (IHC) staining, 179 Inositol-triphosphate (IP3), 260

Insulin-like growth factor 1(IGF-1), 189 Intercostal trunks, descending, 57 Integrin, 161

Interferon-α, in melanoma

in adjuvant treatment, 278, 281, 282 effects of, 278, 279

pegylated and classic, differences between, 279, 280 Interleukin-2 (IL-2), 243

Internal mammary drainage, of breast cancer, 94, 95

International Union Against Cancer (UICC) TNM classification, 168 Interstitial fluid pressure (IFP), in tumors,

141–143

Interstitium “microcirculatory highway,” 56 Intralymphatic therapy, 87

Intramural metastasis, 211

Intratumoral and peritumoral injections, 93 Intratumoral lymphangiogenesis, 44, 47 Intravascular lymphostasis, 83

Intravital videomicroscopy (IVVM), 145, 160

Intron-A

^®

, 278

In vitro sensitization (IVS) procedure, 227 In vitro sensitized (IVS) LN cells vivo

antitumor reactivity, 228 Irinotecan, 264

Irinotecan-refractory colorectal cancer, 258

Iron ferrumoxtran, 86

Isolated tumor cells (ITCs), 159, 160, 162, 163

J

Jak/Stat pathway, 260

Janus kinases, tyk-2 and JAK-1, 278

(6)

Japan clinical trials, for role of SLNs in esophageal and gastric cancer, 216 Jejunal carcinoid tumors, 191

Jugular trunks, 57 Juguloomohyoid, 77

K

K-Ras mutations in patients, evaluation, 267

L

Laminin α 4 chain, 30 Lancet, 119

Lapatinib, tyrosine kinase inhibitor of EGFR and HER-2, 266 Lapatinib ditosylate, 259 Lecithin, 110

LECs. See Lymphatic endothelial cells Legs

anterior deep bundle and lymph node of, 69

posterior deep bundles of, 70 saphenous bundle of, 65 Leiomyosarcoma, 217 Leucovorin, 241

Lingual lymph nodes, metastatic spread in, 204

Lipid-based endolymphatic drug carriers, 102

Lipiodol ultra-fluid, 107 Lipoprep, 110

Liposarcoma, 217 Liposomat, 111 Liposomes

complications of, endolymphatic administration of, 112 deposition properties of, 113 as drug carriers, 109, 115 for endolymphatic therapy in

humans, 109

experiments using blue dye, objects for, 111–115

for lymph nodes staining, 116 properties of, 110

Liver metastases, 130, 181, 189, 212, 213 Liver transplantation, cause of failure

of, 190

468LN. See MDA-MB-468 human mammary adenocarcinoma cell line 468LN and OPN, role in lymph node

metastases, 161 LNs. See Lymph nodes Lower limb lymphedemas

lymphoscintigraphic image interpretation of, 80

lymphoscintigraphic protocol for, 79 SPECT-CT fusion images of, 81 Lower limbs

anatomy of lymphatics of, 65 anterior and posterior view of, 66, 67 deep and superficial lymph nodes, 68 lymphatic blockage and edema of, 69 lymphatic bundles of, 67

superficial bundles of, 71

superficial inguinal lymph nodes, 71 Low MW proteins cluster, 229 Lumbar aortic lymph nodes, 74 Lumbar trunks, 57

Lung cancer, 167 nonsmall cell, 213 role of SLNs in, 216 Lung metastasis, 213 LV. See Leucovorin Lymph absorption, 56

Lymphangio/adenoscintigraphy (LAS), 6 Lymphangiogenesis, 5, 9, 158, 240

in human cancers, 45 model in vivo, 27

Lymphangiogenesis, animal models of growth factors affecting, 139 VEGF-C, role of, 137, 138 Lymphangiogenic growth factors, 45 Lymphangiosarcoma, 217

Lymphangioscintigraphy, 7 Lymphangiosis carcinomatosa, 20 Lymphatic capillaries, 21, 25 Lymphatic channels, 86

Lymphatic drainage. See also Lymph nodes of breast, 65

from head, 76, 77

of lower limbs, 65

nasopharynx flows, 204

palatine tonsil, 205

(7)

pattern of head and neck, 211 of superior limbs, 58

of upper arms, 59

Lymphatic endothelial cells, 17, 39, 137 of jugular lymph sacs, 18

RNA profile of, 48

transdifferentiation of venous in, 19 Lymphatic endothelial markers, 39

downmodulation, 43 features of, 40

methodological considerations, 43, 44 Lymphatic endothelial-specific growth

factors, 9

Lymphatic endothelium differentiation, 41 Lymphatic imaging, 5

Lymphatic invasion, 158 Lymphatic mapping, 85

for cutaneous melanoma, 90 radiopharmaceuticals for, 90 for sentinel node localization, 87 techniques for, 90

Lymphatic metastasis in breast cancer, 157 biological models of, 160–162

Lymphatic microvessel density (LMVD), 158 Lymphaticovenous communication, 212

“Lymphatic pump,” 5

Lymphatics and lymph circulation, 6 Lymphatic system, 1

biology and pathobiology, 6–8 vs. blood vessels, 55

cancer and, 10–12

evolution and physiology of, 187 function of, 85

imaging, 86 organization of, 56

superficial, deep, and visceral, 56 Lymphatic system dominant model, 197 Lymphatic trafficking, 4, 9

LYVE-1 in, 42

Lymphatic trunks and ducts formation, 57 Lymphatic vascular growth and

development, 9 Lymphatic vascular tubes, 28 Lymphatic vessels

classification of, 56 development of, 26, 27

endothelial hyaluronan receptor-1 (LYVE-1), 158

growth factors in maintenance of, 30 growth in human cancers, 46 hyperplasia, 138

lymph nodes imaging, 5

maturation and differentiation, 27 and non-endothelial structures, 40 Lymphatic vessel-specific markers, 25 Lymph capillaries structure, 56 Lymph channels, 95

Lymph circulation, 2, 8 Lymph collectors, 60 Lymphedema, 7, 8

Lymphedema–angiodysplasia syndromes, 10, 12

Lymphedema–distichiasis (LD) syndrome, 10 Lymphedema–hypotrichosis–telangiectasia

syndrome, 10

Lymph flow rates (LFRs), 143

Lymph fluid velocity, measurement of, 145 Lymph formation physiology, 2

in immunocompromised animals, 45 Lymph node metastasis, 47, 188, 189, 191

occurrence of, 196 treatment, 101, 102

Lymph nodes, 56, 187, 209, 223. See also Sentinel node

of arm, 60, 61

analysis, techniques of, 193 draining significance, in primary

immune responses, 224–227 drug injection to, 102

enlargement of, 106 location of, 187 lymphatic vessel, 189 impregnation, 80 macrometastasis in, 159 metastasis, 159

number of, 57

risk of embolism in, 102 shape of, 57

structure of, 224 tumor-draining, 180

Lymphocyte immunological function

elimination, replication by, 187

(8)

Lymphogenic metastatic spread, 203, 204 Lymphogenous liver metastasis, 212 Lymphology

historic landmarks in, 2–6 translational, 12, 13

Lymphoscintigraphic image interpretation of limbs or sentinel detection, 80 Lymphoscintigraphic protocol

for lower limb lymphedemas, 79 for SN detection, 80

Lymphoscintigraphy and clinical benefits, 6, 89

Lymphostatic elephantiasis, 81

Lymphovascular system, future perspectives, 293–295

“Lymph theory,” 10 Lymphvascular genomics, 9 Lymph vessels cannulation of, 114 LYVE-1

biological function, 42 downregulation in vivo, 43 hyaluronan receptor, 9, 45

LYVE-1

⁺

/CD31

⁻

/ MECA − 32

⁻

structures lymphatic nature of, 28

M

mAbs. See Monoclonal antibodies MAGE (melanoma-associated antigen)

antigens, 173

Magnetic resonance imaging (MRI), 160 Malignant cells spread, 87

Mammalian embryogenesis lymphatic development in, 26

Mammalian embryos lymph sacs, 18 Mammalian target of rapamycin, 261, 287 MAPK. See Extracellular signal-regulated

kinase (ErK) kinase Matrix metalloproteinases, 243 Matuzumab, 259

Maximum tolerated dose (MTD), 262 MCA 205 sarcoma, 232

MCA 105 tumor-draining LN cells, 228 MDA-MB-435 human breast cancer

cells, 161

MDA-MB-468 human mammary adenocarcinoma cell line, 161

Mean metastatic spread, 206 Mediastinal nodal disease, 213 Melanoma, 179, 210, 277

chemosensitivity testing, 282–285 cutaneous lymphoscintigraphy in, 90, 91 identification of lymph channels in, 92 interferon- α

in adjuvant treatment, 278, 281, 282 effects of, 278, 279

pegylated and classic, differences between, 279, 280

Ras-MAPK signal transduction pathway in, 287

sentinel node detection for, issues in, 92 stage IV (see AJCC classification,

melanoma stage IV) targeted therapies, 286–289

Melanoma staging, SLN application in, 215 Mesenchymal lymphangioblasts, 19 Metastases, organ-specific clinical, 189–192 Metastasis

breast cancer, response rates in, 241 cell line growth, 195

cells characteristics, 120, 121

cells and tissue, symbiotic relationship between, 195

colonization, 124

colorectal cancer, pivotal phase III clinical trial of bevacizumab, 241 diseases, immunotherapy and clinical

trials, 230

interstitial fluid pressure (IFP) and, 141–143

osteopontin, role of, 121

patterns for solid cancer in SLN era, 215, 216

premetastatic niche, concept of, 124, 125 process depends on, 192

renal cell carcinoma (RCC), Phase II trial of SU011248, 242

seeds and soil, definition of, 119 spread pathway, 205

stem cells and, 121 stroma, role of, 122 Methotrexate, 263

MHC-peptide complex, 229

(9)

Micrometastasis in SLNs identification by RT-PCR, 215

Micrometastatic tumor cells, 168 MMPs. See Matrix metalloproteinases Mock-transfected cells, 132

Molecular lymphology, 6, 11 and lymphvascular genomics, 9

Monoclonal antibodies, 168, 229, 244, 259 mRNA transcripts for mucin-1 (MUC1),

170 MS-275, in melanoma patients, 288 mTOR. See Mammalian target of

rapamycin

Multicenter sentinel lymphadenectomy trial I (MSLTI), 215

N

Nasopharyngeal carcinoma (NPC), 204, 264 Natural killer cells, 178

Nedd9, overexpression and results, 121 Neovascularization, 158

Neuropilin-2, 27

Nodal metastases, 190, 191, 210–212 Noncolloidal lymphoscintigraphic agents, 90 Non-endothelial structures, 40

Noninvasive lymphatic imaging technology, 8

Non-lymphatic structures, 44

Nonsmall cell lung cancer (NSCLC), 167, 213, 241, 257

Nontyrosine kinase neuropilin receptors (NRP), 239

Notch signaling pathways, 121 NRP-1 expression, 240

NRP-1 and -2 nontyrosine kinase neuropilin receptor, 239 NSCLC, analysis and role, 250, 251

O

Occult oropharyngeal carcinomas, 205 Oil Bleo, 104

dosage of, 105

lymph nodes treated with, 106 Oil emulsions

lipiodol in, 107

in popliteal lymph nodes, 108

Oil suspensions, 104 Oleum ricini, 108

Oral cavity lymph fluid, 204

Osteopontin, and tumor metastasis, 121 Oxaliplatin, 265

P

Paget’s theory. See “Seed and soil” theory, of metastasis

Pancreatic cancer, 266 and EGFR inhibitors, 265 erlotinib role in, 248

Pancreatic endocrine carcinomas, 43 Panitumumab (ABX-EGF) anti-EGFR

IgG2 monoclonal antibody, 257, 259, 265

Papillary thyroid carcinoma, 216 Para-aortal lymph nodes, 106 Parenchymal peritumoral injection, in

breast cancer, 94 Patent Blue V, 104

Pedal lymphography, 103, 106 PEG. See Polyethylene glycol Pelvic lymph nodes, 75

Pelvis anatomy, of lymphatics, 75 Penile cancer SLN concept, 214 Periareolar injections, 94 Peritoneal dissemination, 212 Peritumoral lymphatics, 143–145 Peritumoral lymphangiogenesis, 44 PET scanning and CT/PET in lung

cancer, 214 Peyer’s patches, 178

PFS. See Progression free survival Phophatidylinositol-3-kinase (P13K), 239 Phosphatase and tensin homologue, deleted

on chromosome 10 (PTEN), 261 Phosphatidylinositol biphosphate (PIP2), 260 Phosphatidylinositol-3 kinase (PI-3K),

178, 267

Phosphatidylinositol-3 kinase/Akt molecular pathways, 267 Phospholipase, 178

Phospholipase C (PLC) gamma-1, 260

PI3K-PDK1-AKT pathway, 260

Placebo phase III trial role, 250

(10)

Platelet derived growth factor (PDGF), 243, 260

Platelet-derived growth factor receptor (PDGF-R), 287

Platinum-refractory HNSCC, 263 Podoplanin antibodies, 41, 42 Podoplanin mAb D2-40, 43 Polyethylene glycol, 231 Poor prognosis, 211, 215 Popliteal lymph nodes, 112, 160 Posterior pharyngeal wall, lymphatic

drainage, 205

Pre-sensitized Tcells antigenic stimulation, 229

Primary antigenic contact, significance of local LN draining, 226

Primary immune responses and LNs draining, 224–227

Progression free survival, 244 Protein osteopontin (OPN), 161 Protein tyrosine kinase (PTKs), 247 PROX-1, 41

Prox1 cDNA, 19

Prox1-positive endothelial cells, 18 Prox-1 transcription factor, 9 PTKs, classes, families and role, 247 Pudendum major labia, 68, 72 Pulmonary D5Lacz metastasis

model, 234

Q

Quantitative RT-PCR (qRT-PCR), 169 Quantum dots, 86

R

Radiation safety, 97

Radioactive colloidal materials, 86 Radiocolloid

in inguinal nodes, 88 parenchymal injections of, 93 Radiolabeled colloids, 87

Radiolabeled mannosyl compounds, 86 Radionuclide lymphoscintigraphy, 79, 87

for lower limb lymphedemas assessment, 80, 82

sensitivity and specificity of, 84

Radiopharmaceuticals for lymphatic mapping, 90

Radiosensitive probes, 86 Radiotherapy, advantage of, 243 Raf kinase inhibitor, 242 Raf-Mek-Erk pathway, 239 Ras GTPase-activating protein, 239 Ras-MAPK signal transduction pathway, in

melanoma, 287

Ras/mitogen activated protein kinase (MAPK), 267

Ras/Raf/MEK pathway, 244, 260 Receptor thymidine kinase, 246 Regional lymph node (RLN) metastasis

animal models for, 131–135

biochemical changes associated, 136, 137 drugs for reducing, 148

exogenous and endogenous factors, effects of, 146, 147

syngeneic tumors, role of, 133 VEGF-C, role of, 135 Regional lymph nodes

immunohistochemical methods of detection, 168, 169

molecular methods of detection, 169–171 prognosis of, 171, 172

tumor biology of DTC in, 172, 173 Renal cell cancer (RCC)

drugs used in, 243

molecularly targeted theory, 242–244 pegylated interferon-α and, 280 therapy, 242–244

Renal transplantation, 194

Retroperitoneal lymph nodes, dark blue staining, 109

Retropharyngeal lymph nodes, 205 Retrospective analysis

colorectal cancer, 216 gastric cancer, 211

Reverse transcriptase polymerase chain reaction (RT-PCR), 169, 193 Revlimide, melanoma patients, 289 Rhabdomyosarcoma, 217

Rib flushing sampling, 193 Roferon-A

^®

, 278

RTK. See Receptor thymidine kinase

(11)

S

Sarcoma staging, 217

SCC VII head and neck cancer, 233 SEA. See Staphylococcal enterotoxin A

“Seed and soil” theory, of metastasis, 119, 120

Selected anti-EGFR agents for cancer therapy, 259

Semaxinib tyrosine, 242

Sentinel lymph node (SLNs), 179, 214, 223 anatomical studies of, 188, 189

biopsy, 194, 196

breast cancer detection, 81, 83 for breast caner in ipsilateral axilla

identification, 214 colloidal tracers in, 88

concept validation in solid cancer, 214 definition of, 87

erroneous identification of, 92 localization of, 83, 97 lymphoscintigraphic image

interpretation of, 81

lymphoscintigraphic protocol for, 80 in melanoma and breast cancer, 87, 89, 92 and metastasis, 125

in nodal basin, 214 nonvisualization of, 96 planar images of, 83 SPECT-CT images of, 81

Serum-supplemented lymphatic vessels, 33 Signal transducer and activator of

transcription family of proteins (STAT), 247

Small molecule-targeted agents, 245 Solid cancer

colorectal cancer, 212, 213

head, neck and upper GI cancer, 211 melanoma and breast cancer, 210 nonsmall cell lung cancer, 213, 214 sentinel lymph node concept

validation, 214

in SLN era patterns of metastasis, 215, 216 Solid cancer, metastasis patterns in

pre-SLN era colorectal cancer, 212, 213

head, neck and upper GI cancer, 211, 212

melanoma and breast cancer, 210 nonsmall cell lung cancer, 213, 214 Solid cancer treatments, EGFR inhibition

breast cancer, 266

head and neck cancer, 263, 264 nasopharyngeal and colorectal

carcinoma, 264, 265

nonsmall cell lung cancer, 261, 262 pancreatic cancer, 265

Solid tumors, SEGFR inhibitors in treatment

breast cancer, 266

colorectal carcinoma, 264, 265 head and neck cancer, 263, 264 nasopharyngeal carcinoma (NPC), 264 nonsmall cell lung cancer, 261–263 pancreatic cancer, 265, 266 Sorafenib

drug role of, 242, 244

inhibitor of receptor tyrosine kinases, 244 targeted therapies for melanoma and, 287 SPECT-CT imaging system, 80

limb lymphatic system with, 82 in SN mapping of breast cancer, 83 Spontaneous metastasis, 131

Squamous cell carcinoma of upper aerodigestive tract, 203 Staphylococcal enterotoxin A, 229

“STAT” factors, interferon-α effects on melanoma and, 278

Stem cells and cancer metastasis, 121 SU5416. See Semaxinib tyrosine Subareolar injections, 94 Subclavian trunks, 57

Subglottic lymph fluid flows, 205 SU011248 drug, phase I and II trials for

RCC, 242. See also Renal cell cancer (RCC)

Sunitinib

drug usage of, 243, 244

inhibitor of receptor tyrosine kinase, 243 Superficial bundles

forearm and arm, 58

leg and thigh, 66

lower limb, 71

upper limb, 59

(12)

Superficial inguinal lymph nodes, 68, 69 in feet and left major labium, 72 Superficial lymphatic system, 58

and insufficiency, 83

Superficial popliteal lymph node, 67, 73 Superficial popliteal node, 70

Syngeneic tumors and immunization experiments, 133, 134, 225 Synovial sarcoma, 217

T

TAA. See Tumor-associated antigens T1a/Aggrus/PA2.26/E11 protein, 41 T1a breast cancer, 188

Targeted agents, small molecule, 245 Targeted therapies, for melanoma

Bcl-2 mRNA and, 286 BRAF mutations, 287 HDAC, 286, 288 Revlimide, 289

ubiquitin–proteasome pathway, 287 T1b breast cancer, 188

4T1 breast cancer, 232 T-cell, 178

dependent immune response, 224 receptor, 229

Tc99m particle size of, 90

Tc99m phthalocyanine tetrasulfonate (PCTS), 90

Technetium 99m, 79, 80, 90

TEMs. See Tumor-specific endothelial markers

TGF-α. See Transforming growth factor α Therapeutic T cells, 227, 228

Thoracic duct, 57, 187

Thyroid cancer lymph node metastases, 191 T lymphocytes, 187

Transforming growth factor α, 243, 260 Translational lymphology, 12, 13

Trastuzumab, monoclonal antibody against HER-2, 266

Tumor-associated antigens, 230

Tumor-associated macrophages (TAMs), 158 Tumor cells

basement membrane zone, invasion of, 122

blood vessels, invasion of, 122, 123 characteristics of, 120, 121 and clusters of micrometastases and

metastatic, 192–194 dormancy, 173, 193

motility, requirement of, 121 proliferation of, 146 Tumor-draining LNs, 227–230 Tumor-infiltrating lymphocytes

(TILs), 224

Tumor lymphangiogenesis in avian chorioallantoic membrane, 20–22 Tumor microvessels, 20

Tumor-specific transplantation antigens (TSTA), 225

Tumor blood vessel endothelium, 48 Tumor lymphangiogenesis, 40

and relationship to metastasis, 44–47 Tumor lymphatics, 47

Tumor lymph vessel density, 43 Tumor-specific endothelial markers, 48 T-241/VEGF-C fibrosarcoma, 48 Tyrosine kinase inhibitors (TKIs), 247,

248, 259

Tyrosine kinase receptor, type I, 257

U

Upper limbs

anterior and posterior view of, 58 cephalic and posterior bundles of, 60 lymph nodes of, 60