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Daniel J. Hicklin etc., J Clin Oncol 23 :1011-1027 : **

Larry H. Bernstein et al,"Signaling transduction tutorial", http://: pharmaceuticalintelligence.com/8-10-2014/Signaling transduction tutorial

mitogenic activity,102 while cotransfection of NRP-1 intoVEGFR-2 expressing endothelial cells enhanced the bindingofVEGF165 toVEGFR-2andsubsequentmitogenic andche-motactic activity.96,98 Both NRP-1 and NRP-2 are believedto interact with VEGFR-1, and other members of the VEGFfamily also interact with NRPs, notably VEGF-Bwith NRP-1103 and PlGF2 with NRP-1 and NRP-2.104,105

The role of NRP-1 in vascular development was estab-lished by transgenic mouse studies, where knockout ofNRP-1,106 as well as forced expression of NRP-1,107 ledto embryonic death with vascular and neuronal abnormal-ities. Similar embryonic lethality with markedly abnormalvascular development was shown with knockout of NRP-2and heterozygous expression of NRP-1 or with knockoutof NRP-1 and heterozygous expression of NRP-2.108 Ho-mozygous NRP-2 mutants are viable, although their smalllymphatic vessels and capillaries are reduced in number orabsent,109 implying that the predominant role of NRP-2s isin lymphatic development.

Similar to VEGFR-1, there is a naturally occurring sol-uble isoform of NRP-1 that acts as a natural antagonist.sNRP-1 inhibits VEGF165 binding to endothelial andtumor cells and inhibits VEGF165-induced tyrosinephosphorylation of VEGFR-2 in endothelial cells. Ratprostate carcinoma cells expressing recombinant sNRP-1were characterized by extensive hemorrhage, damaged ves-sels, and apoptotic tumor cells.110

FUNCTIONS OF VEGF ON ENDOTHELIAL CELLS

PermeabilityVEGF is a pleiotropic growth factor that mediates

multiple functions via its stimulation of cognate receptors

on endothelial cells (Fig 2; Table 1). VEGF was originallydiscovered because of its ability to render venules andsmall veins hyperpermeable to circulating macromoleculesand was, therefore, initially termed vascular permeabilityfactor (VPF).6 In fact, VEGF is one of the most potent in-ducers of vascular permeability known50,000-fold morepotent than histamine.28 This ability to enhance microvas-cular permeability remains one of the most importantproperties of VEGF, especially with regards to the hyper-permeability of tumor vessels that is thought to be largelyattributable to tumor cell expression of VEGF. It has beensuggested that the increase in permeability results in theleakage of several plasma proteins, including fibrinogenand other clotting proteins. This can lead to the depositionof fibrin in the extravascular space, which subsequentlyretards the clearance of edema fluid and transforms thenormally antiangiogenic stroma of normal tissues intoa proangiogenic environment.6,28 VEGF increases perme-ability in a variety of vascular beds, including in those ofthe skin, peritoneal wall, mesentery, and diaphragm, andcan lead to pathologic conditions such as malignant asci-tes111 and malignant pleural effusions.112 In fact, there isevidence that inhibition of VEGF can lead to decreasedformation of pleural effusions and that antibodies directedagainst VEGF or VEGFR-2 can lead to decreases in tumorvessel permeability and ascites formation.112,113

The precise mechanisms by which VEGF increases mi-crovascular permeability are not entirely clear. Work fromDvoraks laboratory has shown that macromolecules crossthe endothelium by means of a transendothelial cellpathway involving vesicovascular organelles inducedby VEGF.6,28 Other investigators have proposed thatVEGF induces endothelial fenestrations that provide an

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Fig 2. Model of vascular endothelialgrowth factor (VEGF)/VEGF receptor(VEGFR) role in tumor angiogenesis.VEGF ligands expressed by tumorcells or host stromal cells stimulateVEGFR-1, VEGFR-2 or VEGFR-3 ex-pressed by endothelial, lymphendo-thelial, or hematopoietic cells. VEGFstimulation of VEGFR-1positive andVEGFR-2positive endothelial cellsactivates proliferation, migration,survival, and vascular permeability.VEGF may also stimulate mobilizationand recruitment of endothelial pro-genitor cells (EPCs) and VEGFR-1positive myeloid cells in the bonemarrow to sites of tumor neovasculari-zation. VEGF-C and VEGF-D stimulateVEGFR-3-positive lymphatic endothe-lial cells and lymphangiogenesis.

VEGF Pathway in Tumor Growth and Angiogenesis

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Kellie L Jones Etc.,Lancet Oncl 2009: 1179-87 : **

www.thelancet.com/oncology Vol 10 December 2009 1179

Review

Evolving novel anti-HER2 strategiesKellie L Jones, Aman U Buzdar

The approval of trastuzumab for use in metastatic breast cancer marked a breakthrough in the understanding of the biology of the disease. However, like most cancer therapies, the disease fi nds a way to advance despite the treatments developed to eradicate it. Although trastuzumab has had a large eff ect on the treatment of early and advanced-stage disease, a substantial proportion of patients with HER2-positive breast cancer still progress after receiving the drug. Potential mechanisms of resistance to trastuzumab include bypass mechanisms, mutations of the HER2 target, masking of HER2 proteins, inhibition of insulin-like growth factor, and phosphatase and tensin homologue (PTEN) defi ciency. Many therapies are being developed to target these mechanisms in patients with HER2-positive, trastuzumab-resistant breast cancer. Additionally, treatment strategies other than trastuzumab with unique mechanisms of action are being assessed in this specifi c group of patients. In this review, we discuss the emerging data assessing therapeutic approaches in the management of trastuzumab-resistant HER2-positive disease.

IntroductionTargeted therapy has been used for more than 100 years in the treatment of breast cancer. In 1896, Beatson reported a treatment response after oopherectomy in a premenopausal patient.1 After ovarian ablation, other targeted agents were developed, such as tamoxifen and aromatase inhibitors. Trastuzumab, a monoclonal antibody targeting the HER2 protein, was introduced in 1998. Around 25% of patients with breast cancer have HER2-positive disease, with positivity assessed by immunohistochemistry, which detects overexpression of the HER2 protein, or fl uorescence in-situ hybridisation, which detects amplifi cation of the HER2 gene. Patients with 3+ staining from immuno histo chemistry (from a possible 1+, 2+, or 3+) and patients with a positive result from in-situ hybridisation are considered to benefi t most from trastuzumab.2 Patients with HER2-positive disease have a higher risk of recurrence and death than those with HER2-negative disease. The approval of trastuzumab broadened the scope of targeted therapy and marked the fi rst of many steps toward improved understanding of the biology of breast cancer.

Mechanism of action of trastuzumab Trastuzumab is a recombinant, humanised monoclonal antibody directed against the extracellular domain of the HER2 protein, which is expressed on the surface of epithelial cells in many healthy tissues, including the breast.3 Trastuzumabs mechanisms of action are numerous and complex (fi gure 1).3 One mechanism of action is via antibody-dependent cellular cytotoxicity; the activation of natural killer cells initiates lysis of cancer cells that are bound to trastuzumab. Trastuzumab also inhibits the formation of p95, a truncated membrane-bound fragment that results from cleavage of the extracellular domain of HER2 and has in-vitro kinase activity. Additionally, trastuzumab inhibits the phosphoinositide 3-kinase (PI3K) pathway, which is activated by over expression of HER2. PI3K causes translocation of AKT, resulting in its phosphorylation and activation. Once activated, AKT can phosphorylate many sites, leading to cell proliferation. Activated AKT is

negatively regulated by phosphatase and tensin homologue (PTEN). Trastuzumab inhibits the PI3K pathway, reducing PTEN phosphorylation and AKT dephosphorylation, therefore increasing cell death.4,5 Preclinical studies identifi ed another mechanism of action as the reduction of microvessel density, normalisation of vasculature, or both, which improved tumour response; this occurred only in response to combinations of trastuzumab and chemotherapy.68

Trastuzumabs many mechanisms of action give rise to various mechanisms of resistance (table 1). Although trastuzumab targets HER2, cross-talk among the other extracellular HER proteins (HER1 and HER3) can result in incomplete inhibition and lateral activation, promoting

Lancet Oncol 2009; 10: 117987

Purdue University School of Pharmacy and Pharmaceutical Sciences, Indianapolis, IN, USA (K L Jones PharmD); and University of Texas M D Anderson Cancer Center, Houston, TX, USA (Prof A U Buzdar MD)

Correspondence to: Prof Aman U Buzdar, 1515 Holcombe, Unit 1354, Houston, TX 77030, USA [email protected]

Apoptosis

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HER2

P

Ligand

Ligand

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Figure 1: Mechanism of action of current therapies for HER2-expressing breast cancerConstitutively active HER2 receptors on the surface of HER2-expressing breast-cancer cells dimerise with other HER receptors, activating downstream signalling pathways that mediate tumorigenic cell proliferation, survival, and invasion. Trastuzumab prevents constitutive activation of HER2, induces internalisation and degradation of the protein, and stimulates the immune system to recognise HER2-overexpressing cells. Lapatinib binds to HER2 and HER1 and inhibits tumorigenic receptor signalling.

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References 1. Slamon DJ et al. N Eng J Med. 2001; 344:783-92.

2. Balduzzi S et al. Cochrane Database Syst Rev. 2014 Jun 12; 6.

3. Moja et al. Cochrane Database Syst Rev. 2012 Apr 18; 4.

4. Swain SM et al. N Engl J Med. 2015; 372:724-34.

5. Verma S et al. N Engl J Med. 2012; 367:1783-91.

6. Sequist LV et al. J Clin Oncol. 2013; 31:3327-34.

7. Liang W et al. PLoS One. 2014; 9:e85245.

8. Shaw AT et al. Lancet Oncol. 2011; 12:1004-12.

9. Solomon BJ. N Engl J Med. 2014; 371:2167-77.

10. Shaw AT et al. N Engl J Med. 2014; 371:1963-71.

11. Welch S et al. Ann Oncol. 2010; 21:1152-62.

12. Van Cutsem E et al. J Clin Oncol. 2015; 33:692-700.

13. Stintzing S et al. ESMO conference 2014, abstract LBA11.

14. Heinemann V et al. Lancet Oncol. 2014 Sep;15(10):1065-75.

15. Venook AP et al. ESMO conference, abstract O-0019.

16. Grothey A et al. Lancet. 2013; 381:303-12.

17. McArthur GA et al. Lancet Oncol. 2014; 15(3):323-32.

18. Robert C et al. N Engl J Med. 2015; 372(1):30-9.

19. Hodi FS et al. N Engl J Med. 2010; 363(8):711-23.

20. Maio M et al. J Clin Oncol. 2015; 33:1191-6.

21. Dummer R et al. J Transl Med. 2015; 13:2062.

22. Robert C et al. Lancet. 2014; 384:1109-17.

23. Rizvi NA et al. Lancet Oncol. 2015; 16:257-65.

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, -15% , , - 30%-40% ]7[. , BRCA-1 -BRCA-2. DNA : -60% 80% ) 7 ( - 25%-50% ) 25 ( ]8,9[. ) , , ( . BRCA1/2, . . , , . , , . , .

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References 1. Siegel R, et al. CA Cancer J Clin. 2013; 63:1130.

2. Menczer J et al. Int J Gynecol Cancer. 2006; 16:41-4.

3. Bhoola S et al. Obstet Gynecol. 2006; 107:1399-410.

4. Levanon K et al. J Clin Oncol. 2008; 26:5284-93.

5. Gonzlez-Martn A. Ann Oncol. 2013; 24 Suppl 1(Supplement 10):x4852.

6. Rein BJ et al. J Oncol. 2011; 2011:475983.

7. Modan B et al. JAMA. 1996; 276:1823-5.

8. King MC et al. Science. 2003; 302:643-6.

9. Struewing JP et al. N Engl J Med. 1997; 336:1401-8.

10. NCCN Clinical practice guidelines in oncology. (Accessed on April 01, 2014).

11. Rebbeck TR et al. N Engl J Med. 2002; 346:1616.

12. Kauff ND et al. N Engl J Med. 2002; 346:1609.

13. Erekson EA et al. Menopause. 2013; 20: 1104.

14. Marchetti C et al. Menopause. 2014; 21:763-8.

15. Burger RA et al. N Engl J Med. 2011; 365:2473-83.

16. Perren TJ et al. N Engl J Med. 2011; 365:2484-96.

17. Ledermann J et al. N Engl J Med. 2012; 366:1382-92.

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References 1. Gtzsche PC et al. Cochrane Database Syst Rev. 2009, Oct 7; 4.2. Autier P et al. J Clin Oncol 27:5919-23.3. McPherson CP et al. J Am Geriatr Soc. 2002; 50:1061-8.4. Nelson HG, et al. Ann Intern Med 2009; 151:727-37.5. Metter FA, et al. Cancer 1996; 77:903-9.

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Plasma exchange: concepts, mechanisms, and an overviewof the American Society for Apheresis guidelines

Jeffrey L. Winters1

1Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, Mayo Clinic,

Rochester, MN

Plasma exchange is a therapeutic procedure used to treat a variety of diseases through the bulk removal of plasma. Toapply this treatment to patients appropriately, it is essential to understand the methods to remove plasma, its effectson normal plasma constituents, the role of replacement fluids in the treatment, and the risks associated with theprocedure. To facilitate the appropriate evidence-based use of plasma exchange and to encourage research, theAmerican Society for Apheresis has published guidelines providing practical guidance and information to thoseresponsible for ordering or providing this treatment.

IntroductionThe word apheresis is derived from the Greek word aphairesis,which means to separate, to take away by force, or to remove.This term was originally used by Abel, Rowntree, and Turner todescribe manual plasma exchange, the removal of units of wholeblood anticoagulated with heparin followed by centrifugation toseparate the blood into the cellular elements and plasma.1 Thecellular elements were then mixed with a replacement for thediscarded plasma and reinfused. Since this initial use, the term hasbeen used more broadly to describe several procedures, all of whichinvolve the separation of whole blood into its components withremoval or modification of one or more of these components. Table1 lists the apheresis procedures performed commonly within theUnited States.2

Of the procedures listed in Table 1, therapeutic plasma exchange(TPE) is the procedure that is performed most commonly. Asdefined in Table 1, TPE is a procedure in which a large volume ofplasma is removed from a patient.2 The volume removed is such thatif it were not replaced, significant hypovolemia resulting invasomotor collapse would occur. As a result, the removed plasma

must be replaced with some form of replacement fluid.2 Plasmaphere-sis removes a smaller amount of plasma, usually less than 15% ofthe patients blood volume, and therefore does not require replace-ment of the removed plasma. The most common plasmapheresisprocedures performed in the United States are those in whichplasma is collected from healthy donors for transfusion or manufac-ture into products such as albumin, IVIG, factor concentrates, andlaboratory reagents. In common usage, the terms plasma exchangeand plasmapheresis are used interchangeably, although the 2 proce-dures are different. The lack of clarity in usage of these 2 termscould result in problems when searching the medical literature.Plasmapheresis and plasma exchange are 2 separate MedicalSubject Headings (MeSH) in the National Library of Medicine. Theincorrect usage of the terms by authors has led to incorrectcategorization, meaning that literature searches should include bothterms to identify all relevant literature. For the remainder of thisarticle, only TPE will be discussed, because the devices used toperform therapeutic plasmapheresis procedures, other than thedevices used to perform low-density lipoprotein apheresis, have notbeen approved by the Food and Drug Administration for use in theUnited States.

Table 1. Apheresis procedures performed commonly in the United States2

Procedure name Description

Leukocytapheresis A procedure in which the WBCs are separated from the blood. The cells may be discarded, aswhen used to decrease WBC count in acute leukemia, or used for transfusion, as in the caseof granulocyte collection or the collection of hematopoietic progenitor cells.

Extracorporeal photopheresis (ECP) A type of leukocytapheresis in which the cells collected are treated with a psoralen compound,exposed to ultraviolet A light, and reinfused to induce an immunomodulatory effect.

Platelet apheresis A donor procedure in which platelets are removed to produce a platelet product for transfusion.Thrombocytapheresis A therapeutic procedure in which platelets are removed and discarded from a thrombocythemic

patient.Erythrocytapheresis A donor procedure in which the equivalent of 1 or 2 units of RBCs are removed to produce

RBCs for transfusion.RBC exchange A therapeutic procedure in which abnormal RBCs are removed and replaced by donated RBCs.Plasmapheresis A procedure in which plasma is separated from the blood and retained without replacing the

removed volume.LDL apheresis A type of plasmapheresis procedure in which the removed plasma is modified to remove LDL

cholesterol and then returned to the patient.Plasma exchange A procedure in which a large volume of plasma is removed, usually 1-1.5 plasma volumes. The

removed plasma is replaced with a replacement fluid.

LDL indicates low-density lipoprotein.

3 PS IN A POD

Hematology 2012 7

Table 2. Diseases and disorders treated with plasma exchange2 Disease category * Recommendation grade

ABO-incompatible hematopoietic stem cell transplantation

BM II 1B

Peripheral blood II 2B

ABO-incompatible solid organ transplantation Kidney

II

1B

Heart (age _ 40 mo) II 1C

Liver III 2C

Acute disseminated encephalomyelitis II 2C

Acute inflammatory demyelinating polyradiculopathy (Guillain-Barr Syndrome)

I 1A

ANCA-associated rapidly progressive glomerulonephritis/vasculitis (Wegener granulomatosis) Dialysis independent

I

1A

Alveolar hemorrhage I 1C

Dialysis dependent III 2C

Antiglomerular basement membrane disease (Goodpasture syndrome)

Dialysis independent I 1A

Alveolar hemorrhage I 1B

Dialysis dependent IV 1A

Aplastic anemia III 2C

Autoimmune hemolytic anemia

Warm III 2C

Cold agglutinin disease (life threatening) II 2C

Catastrophic antiphospholipid Ab syndrome II 2C

Chronic focal encephalitis (Rasmussen encephalitis) II 2C

Chronic inflammatory demyelinating polyradiculopathy I 1B

Cryoglobulinemia I 1B

Focal segmental glomerulosclerosis (recurrent) I 1C

Hemolytic uremic syndrome

Complement factor gene mutations II 2C

Autoantibody to factor H I 2C

Diarrhea associated IV 1C



BM II 1B



II

1B


Liver III 2C



I 1A


I

1A









Warm III 2C













BM II 1B



II

1B


Liver III 2C



I 1A


I

1A









Warm III 2C











Hypertriglyceridemic pancreatitis III 2C

Hyperviscosity in monoclonal gamopathies

Symptomatic I 1B

Prophylactic for rituximab treatment I 1C

Multiple sclerosis

Acute CNS demyelination unresponsive to steroids II 1B

Chronic progressive III 2B

Myeloma cast nephropathy II 2B

Neuromyelitis optica II 1C

Paraproteinemic polyneuropathies

IgG/IgA I 1B

IgM I 1C

Multiple myeloma III 2C

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

I 1B

Phytanic acid storage disease (Refsum disease) II 2C

Posttransfusion purpurea III 2C

RBC alloimmunization in pregnancy II 2C

Renal transplantation, Ab-mediated rejection I 1B

Renal transplantation desensitization II 1B

Scleroderma IV 1A

Sepsis with multiorgan failure III 2B

Systemic lupus erythematosus

Severe complications of vasculitis II 2C

Nephritis IV 1B

Thrombotic thrombocytopenic purpura I 1A

Thyroid storm III 2C

American Society of Hematology

Reactions due to TPE

Study Reaction

Shemin Basic-Jukic Couriel and Weinstein

1727

4857 381 No. of TPE procedures

7.3%

2.7% 5.5% Paresthesias



BM II 1B



II

1B


Liver III 2C



I 1A


I

1A









Warm III 2C











21 20

: -



BM II 1B



II

1B


Liver III 2C



I 1A


I

1A









Warm III 2C













Symptomatic I 1B


Multiple sclerosis






IgG/IgA I 1B

IgM I 1C



I 1B






Scleroderma IV 1A




Nephritis IV 1B





Study Reaction


1727


7.3%




Symptomatic I 1B


Multiple sclerosis






IgG/IgA I 1B

IgM I 1C



I 1B






Scleroderma IV 1A




Nephritis IV 1B





Study Reaction


1727


7.3%


7.4%

1.6% 0.26%

Urticaria

NR

NR 3.67% Hypofibrinogenemia

5.6%

NR 2.1% Hypotension

NR

NR 0.5% Vasovagal reactions

3.2%

NR 2.9% Nausea

2.7%

NR 0.5% Vomiting

NR

NR 0.26% Hemothorax

NR

0.0.% 0.26% Catheter site infection

NR

2.46% 0.26% Bleeding/hematoma

NR % 0.00 0.26% Pneumothorax

Fever, 7.7% Pruritus, 5.8% Tachycardia, 5.6%

Clotting, 1.7% NR Other

AMERICAN SOCIETY OF HEMATOLOGY



BM II 1B



II

1B


Liver III 2C



I 1A


I

1A









Warm III 2C











References 1. Abel JJ et al. J Pharmacol Exp Ther. 1914; 5:625-41.2. Szczepiorkowski ZM et al. J Clin Apher. 2010; 25:83-177.3. Shemin D et al. J Clin Apher. 2007; 22:270-6.4. Shehata N et al. Transfus Med Rev. 2002; 16:200-29.5. Jeffrey LW. Hematology 2012; 2012:7-12.

: -



Symptomatic I 1B


Multiple sclerosis






IgG/IgA I 1B

IgM I 1C



I 1B






Scleroderma IV 1A




Nephritis IV 1B





Study Reaction


1727


7.3%


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