ALL-kids

New Treatments for Childhood ALL

I scan journal articles and posts from the ALL-kids email list for new drugs for ALL. To keep track, I'm listing them here. The newest are on top.

Information on cancer vaccines: www.cancer.gov/cancertopics/factsheet/Therapy/cancer-vaccines

If you are looking for a new treatment, especially in situations of relapsed or refractory ALL, your best bet is to contact the COG, or search cancer.gov for clinical trials in phase I or II.

Also see: Targeted treatments

Also see: Recently identified genetic alterations and the TARGET initiative (2011)

2012: Blinatumomab (discussed below) is in a pediatric ALL clinical trial (phase I, II). Clinical trial with blinatumomab.

2012: Survivin is one (among many) protein that inhibit apoptosis (cell-death) proteins (called IAP) and has been found to be overexpressed in relapsed childhood ALL. Quote from the abstract: ". . . silencing of survivin expression in pediatric ALL cell lines as well as primary leukemic blasts reduces viability of these cells. This includes cell lines derived from patients with relapsed disease featuring cytogenetic anomalies such as t(12;21), Philadelphia chromosome t(9;22), t(1;19) as well as a cell line carrying t(17;19) from a patient with de novo ALL." Survivin was "silenced" through "survivin-specific small interfering RNA and survivin-targeted drug, YM155". As of 2012, studies are only with cell lines in culture and cells taken from patients, so it's probably a long way from trials in patients. (I briefly mentioned survivin in my Targeted Treatments article.) Targeting survivin and p53 in pediatric acute lymphoblastic leukemia, J W Tyner, A M Jemal, M Thayer, B J Druker and B H Chang, Leukemia (2012) 26, 623–632. Abstract.

2012: TdT is terminal deoxynucleotidyl transferase (TdT), a DNA polymerase. TdT is a biomarker for ALL; it is overexpressed in ∼90% of ALL patients. Motea, Lee, and Berdis at Case Western University designed a molecule to target TdT, a "non-natural nucleotide" called 5-nitroindolyl-2'-deoxynucleoside triphosphate (5-NITP). This molecule shows activity against TdT in cell cultures and might prove to be a useful targeted therapy for ALL. A Non-natural Nucleoside with Combined Therapeutic and Diagnostic Activities against Leukemia. Motea EA, Lee I, Berdis AJ, ACS Chem Biol. 2012 Mar 13. Abstract.

2012: CD22 is highly expressed in most cases of ALL. Calecheamicin (alternatively spelledcalicheamicin) is an antitumor antibiotic calicheamicin discussed two paragraphs below this one. 49 patients, including some children, were treated at MD Anderson for refractory or relapsed ALL. The overall response rate was 57%, indicating that iInotuzumab ozogamicin shows promise as a treatment for refractory and relapsed ALL. Inotuzumab ozogamicin, an anti-CD22—calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Hagop Kantarjian et al., The Lancet Oncology, epub, 21 February 2012.

2012: CDKs are "cyclin-dependent kinases" - I did not discuss these in my article on targeted therapies for ALL. A group from Singapore and San Diego (CA) describe a novel multi-kinase inhibitor named "TG02) that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3 (see the targeted therapies article). So far, it's being tested in AML cell lines. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. K C Goh et al., Leukemia (2012) 26, 236–243, epub 23 August 2011.

2012: Inotuzumab ozogamicin (CMC-544) is a targeted antibody, consisting of "a humanized CD22 Ab linked to calicheamicin". The calicheamicins are a class of antibiotics that are toxic to all cells, and especially to cancer cells (see Wikipedia). Inotuzumab has been found effective against pediatric primary B-cell ALL cells in culture. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. de Vries JF et al., Leukemia. 2011 Aug 26.

2012: NVP-BEZ235 inhibits both phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). (NVP-BEZ235 is called a dual kinase inhibitor.) In ALL cell lines in culture, NVP-BEZ235 combined with AraC, Doxorubicin or dexamethazone showed more ALL cell line growth stoppage than NVP-BEZ235 alone. Combination with Cytotoxic Drugs Exerts Anti-proliferative Activity towards Acute Lymphoblastic Leukemia Cells, Catrin Schult et al., Anticancer Research February 2012 vol. 32 no. 2 463-474.

2011: TOR, target of rapamycin, and T-cell ALL. From the abstract: "mTORC1 activity can be downmodulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation." AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications. C Grimaldi et al., Leukemia (2012) 26, 91–100. Note: Rapamycin and mTOR is the subject of a Scientific American article on aging, A New Path to Longevity, Jan 2012.

2011: BiTE antibody (Bi-specific T-cell engaging) blinatumomab (also named MT103). Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leukemia. 2011 Jan;25(1):181-4. Epub 2010 Oct 14. Handgretinger R et el. Blinatumomab has been in adult ALL and lymphoma trials; this is an instance of pediatric trials in Germany. Blinatumomab is one subject of Solving Kids Cancer TWiPO podcast #12, Aug. 2011. As reported by both the TWiPO presenters and members of the ALL-kids-relapsed group, blinatumomab is given as "compassionate use" to pediatric patients in Germany at this time. The podcast reports something like an 80% remission in adults (to negative MRD) with this drug; it is currently used before transplant. It has a short half life and thus must be given continually; side effects are fever and flu-like symptoms; it attacks all B lymphocytes, not specifically leukemic lymphocytes; it only attacks B lymphocytes that have the CD19 antigen.

2011: Microarray-based genomic profiling as a diagnostic tool in acute lymphoblastic leukemia. Annet Simons et al., Genes, Chromosomes and Cancer, epub 31 AUG 2011. Abstract. This article does not describe a new targeted therapy; however, it reports how genomic profiling can be used to find genetic alterations, important in the recently identified genetic alterations article that I wrote. "Microarray-based genomic profiling resulted in a CNA detection rate of 90%, whereas for conventional karyotyping this was 61%. In addition, many small (<5 Mb) genetic lesions were encountered, frequently harboring clinically relevant ALL-related genes such as CDKN2A/B, ETV6, PAX5, and IKZF1." Note that of these four CNAs, ETV6 is related to the tel-AML-1 fusion, and the other three are more recently found mutations. A CNA is a copy number aberration.

2011: Targeting survivin and p53 in pediatric acute lymphoblastic leukemia. J W Tyner et al., Leukemia, epub 30 September 2011. Abstract. "Survivin, a member of the inhibitor of apoptosis (IAP) proteins and chromosome passenger complex, is expressed in hematologic malignancies and overexpressed in relapsed pediatric ALL." In vitro cell lines treated with survivin showed lessened viability.

2011: Targeting survivin. Survivin/BIRC5, an inhibitor of apoptosis protein, is associated with drug-resistant ALL. Researchers treated "patient-derived ALL" with shRNA (and chemotherapy) eradicated the ALL. Also, a type of oligonucleotide called EZN-3042 eliminated ALL cells. "These findings show the importance of survivin expression in drug resistance and demonstrate that survivin inhibition may represent a powerful approach to overcome drug resistance and prevent relapse in patients with ALL."

Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Eugene Park et al., Blood, epub June 28, 2011. Abstract.

2011: UCSF Team Discovers Key to Fighting Drug-Resistant Leukemia. Mice with drug resistant ALL can be cured with combination chemotherapy including a compound that disables the BCL6 protein. The compound was initially developed by Ari Melnick, from the Weill Cornell College of Medicine in New York and a co-author of the study. The literature reference is: "BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition." (Nature, May 19, 2011) BCL6 is a transcription factor. The compound used to disable the BCL6 protein was a drug-like peptide; the researchers are searching for ways to block the BCL6 with small molecules, which are generally easier to formulate into oral drugs and and less expensive than peptides.

Related: Investigational drug, RI-BPI, in combination with the drug Gleevec, effective against acute lymphoblastic leukemia. Weill Cornell is developing this drug. Press release (May 2011).

2011: Elevated β-arrestin1 expression correlated with risk stratification in acute lymphoblastic leukemia. Hui Liu et al., International Journal of Hematology Volume 93, Number 4, 494-501, 2011. β-Arrestin1 is "a multifunctional scaffold protein mediating many intracellular signaling networks" - hard for non-professionals to understand this wording, but the bottom line is that it is involved in telling cells whether to grow or die. The authors of the article studied the expression of β-Arrestin1 in 155 newly diagnosed ALL patients, and determined that the expression level might be used as a prognostic factor. Abstract.

2011: Improving outcomes for high-risk ALL: Translating new discoveries into clinical care. Stephen P. Hunger et. al., Pediatric Blood & Cancer, first published online: 15 FEB 2011. Abstract.

Please see my extended discussion of this article.

"High-resolution genomic profiling of genetic alterations and gene expression has revolutionized our understanding of the genetic basis of ALL, and has identified several alterations associated with poor outcome, including mutations of the lymphoid transcription factor gene IKZF1 (IKAROS), activating mutations of Janus kinases, and rearrangement of the lymphoid cytokine receptor gene CRLF2. These data indicated that the genetic basis of HR-ALL is multifactorial, and have also provided a new potential therapeutic option directed at JAK inhibition."

My quick summary: This review paper discusses the paradigm of the success of the addition of the targeted therapeutic imatinib to the chemotherapy cocktail now used in the treatment of BCR-ABL1 (Ph+) childhood ALL; lists recently discovered genetic alterations that are associated with poor outcome, namely, IKZF1 (IKAROS), JAK mutations, and CRLF2; and discusses how recent findings might translate into better treatments for childhood ALL. Of additional interest is the introduction section, which includes a summary of the current prognosis of relapsed and high-risk ALL. In my opinion, the section of the article that covers genomic profiling, or the study of genetic alterations, is very interesting, and is my major focus in this "lay summary".

2011: Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update. Pui et al, JCO, online Jan 10, 2011. Abstract.

This article is a good review of 2011 ALL treatment strategies. Drugs that might become new treatments that are not already listed on the Targeted ALL Treatments page are listed below.

New formulations of old drugs:

Targeted:

2011: Forodesine (BCX-1777, Fodosine, see below) is a nucleoside analogue, an oral purine nucleoside phosphorylase (PNP) inhibitor. Was in clinical trials about 2008-2010. Shows some promise in hematologic malignancies, especially T-cell.

2010: Mitoxantrone shows promise for relapsed ALL. Mitoxantrone compared with idarubicin showed a 20% greater survival rate with the mitoxantrone. There are side effects (but not worse than other drugs) and some reservations of other researchers (small study size), but in general it does sound promising! They stopped the study early and put all patients on the mitoxantrone. The trial was in New Zealand/UK/Ireland/Australia. Mitroxantrone (not an anthracycline drug) is described on Wikipedia.

2010: The farnesyl transferase inhibitor tipifarnib used in a phase I clinical trial. Brigitte C. Widemann et al., Pediatric Blood & Cancer, first published online: 21 SEP 2010. Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2010: Bortezomib is a proteasome inhibitor found to be useful in the treatment for adult multiple myeloma in the early 2000s. In 2010, an active phase I/II clinical trial employs bortezomib in combination with 6 other chemo agents to treat relapsed pediatric ALL. (T2005-003) Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2010: anti-CD22 immunotoxin HA22 (CAT-8015). Currently tested in in vitro cell lines, . . . "HA22, at concentrations achievable in patients, is highly cytotoxic to B-lineage ALL cells. These results provide a strong rationale for clinical testing of this agent in children with drug-resistant ALL and offers the potential to reduce morbidities of treatment while improving outcome." Francis Mussai et al., British Journal of Haematology, June 10, 2010. Abstract. (On the ALL targeted therapies page.)

More on HA22: A clinical trial run by Alan Wayne, M.D., at the NIH Clinical Center to test a second-generation investigational immunotoxin (HA22 or moxetumomab pasudotox) developed by Ira Pastan, M.D., Chief of CCR's Laboratory of Molecular Biology. Lay article.

2010: MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA). In 2010, it has shown promise in adult cancers. In the Pediatric Preclinical Testing Program, it shows promise against ALL. Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2009: Identification of the cells causing T-cell acute lymphoblastic leukaemia (T-ALL). Lay article and another lay article. Lm02 oncogene, McCormack MP. Journal article.

2009: Bacterial proteins as potential drugs in the treatment of leukemia. Formerly used only for solid tumors, Azurin and Laz (bacterial proteins) have shown anticancer effects in leukemia cell lines. The authors recently identified another protein, Pa-CARD, from Pseudomonas aeruginosa that . . . demonstrates cytotoxic activity against leukemia cells. Jennifer Kwan et al., Abtsract. Published in Leukemia Research, 2009.

2009: T-cell ALL: Researchers found a "key protein receptor embedded on the outer surface of leukemic cells is responsible for infiltrating the brain and spinal cord." 2009. Lay article, article in Nature.

2009: Blinatumomab, developed by Micromet. Lay article. PubMed abstract. June 2009: "Micromet announced that its antibody blinatumomab showed a high response rate in a phase 2 clinical study of acute lymphoblastic leukemia patients with minimal residual disease. Blinatumomab is a therapeutic antibody that activates a patient's T cells to seek out and destroy cancer cells." More on Blinatumomab, accessed 2011 on the company's website.

2009: A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. T Ikezoe et al, Leukemia advance online publication 7 May 2009.

2009: Helleborus niger, a plant extract, shows promise in killing leukemia cells in culture. 2009 Pediatric Blood and Cancer article abstract.

2009: "These data indicate silvestrol has efficacy against B-cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias." The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. David M. Lucas et al., Blood First Edition Paper, prepublished online February 3, 2009. Abstract.

2009: Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Roman Crazzolara et al., Blood First Edition Paper, prepublished online February 4, 2009. Abstract. Rapamycin (mTOR) inhibitor, RAD001 (Everolimus). Encouraging results. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2009: Phase I trial for children/adolescents with refractory ALL. CAT-8015 proves promising in a child who failed 3rd remission. Trial information. CAT-8015 is an anti-CD22 immunotoxin (see this NIH page for more information). Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2009: Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia. Charles G. Mullighan et al. NEJM published online January 7, 2009. Abstract. Full text available free online. NCI news release. This comes out of the targeted therapies intiative from NCI. target.cancer.gov Might lead to therapies targeted to the IKAROS gene.

2008: T-cell ALL: "Not The Protein, But Its Location In The Cell, Determines The Onset Of Leukemia". Lay article. Journal article. "...the researchers want to further investigate the therapeutic possibilities of compounds that render binding between the complex and NUP214-ABL1 impossible. This study also indicates that the location of proteins can play an important role in other forms of cancer/leukemia as well." (Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear pore. De Keersmaecker K et al. Mol Cell. 2008 Jul 11;31(1):134-42.

2008: Flavopiridol displays preclinical activity in acute lymphoblastic leukemia. Flavopiridol (FP; Alvocidib) is an agent that affects the expression of cell cycle regulatory proteins. This article shows that FP kills ALL cell lines in culture. The research was funded by STOP cancer. (Ped Blood and Cancer, 2008)

2008: Stem cells for leukemia found. "The new research, published in the journal Science, shows that pre-cancerous stem cells arise from an abnormal fusion of two genes during the mother’s pregnancy to create a hybrid protein ‘TEL-AML1’. This genetic mistake can set in motion a series of events that cause the cells to become leukaemic." Lay article. Journal article: "Initiating and Cancer-Propagating Cells in TEL-AML1-Associated Childhood Leukemia." Dengli Hong et al, Science 18 January 2008: Vol. 319. no. 5861, pp. 336 - 339. Abstract. Another lay article from BBC news.

2008: Immunomodulation against leukemias and lymphomas: A realistic future treatment? S. Mittal et al., Feb. 2008, Critical Reviews in Oncology/Hematology.

2007: NOTCH 1: Oncogene and Achilles' Heel in T-ALL. A good article on possible new ways to treat T-cell ALL on the St. Judes Cure For Kids website. Free registration is required.

2007: DMAPT (dimethylamino-parthenolide). The naturally-occurring compound, parthenolide (PTL), is found in feverfew or bachelor's button (daisies). PTL can induce the death of human leukemia stem cells without killing normal cells. DMAPT is an analog of the naturally-occurring compound with an increased water solubility that shows the same anti-leukemia stem cell action in animal studies. Human trials (in England) are planned for AML and ALL patients. (2007) Link to Blood abstract. Link to lay article. Another lay article. Yet another lay article.

2007: ABT-737 (Abbott Laboratories) acts by inhibiting the Bcl-2 family of proteins (these are expressed in ALL) and inhibit the mechanisms responsible for destroying ALL cells. When used in combination with common drugs administered in ALL therapy, ABT-737 has the ability to enhance the combined toxicity of these drugs against the leukaemia cells with minimal effects on the normal cells of the body. Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2007: Epratuzumab, a humanized monoclonal antibody against CD22. Used in phase II trials by COG. Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2007: Antileukemic and Cytogenetic Activity by Triple Administration of Three Modified Steroidal Derivatives of Nitrogen Mustards. M.A. Fousteris, et al., Chemotherapy, Chemotherapy. 2007;53(2):118-26. Abstract.

2006: Fodosine TM (BioCryst; also called forodesine hydrochloride or BCX-1777 or Immucillin-H) is "a transition-state analog inhibitor of the target enzyme purine nucleoside phosphorylase (PNP)" [from the BioCryst web site]. This means is that it is designed to stop PNP; note that ara G was also designed to inhibit PNP. PubMed abstract of August 2005 article in Blood. In Oct 2005, this drug was given orphan drug status for T-cell ALL (among other leukemias) and is in phase II trials. Fodosine, PNP Inhibitor, on the BioCryst web site Dec 2006.

2006: Researchers Uncover Clues That May Lead To Better Therapies For Children With T-Cell Acute Lymphocytic Leukemia. "Researchers' discovery of clues to the cause of T-cell acute lymphoblastic leukemia (T-ALL) could lead to the development of new targeted therapies for this extremely difficult disease. The researchers, led by Michelle Kelliher, PhD, of the University of Massachusetts Medical School, will report on their findings in the November issue of the journal Molecular and Cellular Biology. The researchers report that abnormal expression of one gene - Notch 1 - activates another gene - c-myc - which is a known cause of leukemia and lymphoma. Recent studies have shown that a majority of T-ALL cases carry mutations that abnormally activate the Notch 1 gene." Online article. Note, 2010: See the developments in the use of NOTCH-related therapies on the ALL targeted therapies page.

2005: Dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2005: Nilotinib. Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2005: Rapamycin, a drug used to prevent rejection in transplant recipients, could show anti-leukemia activity in steroid-resistant cells, as indicated by gene expression connectivity maps. (Dana Farber) Presented at the Dec 2005 ASH meeting. Abstract. Note, 2010: See the developments in the use of this drug on the ALL targeted therapies page.

2005: St. Judes: Genetic trick used to kill leukemia cells, "Natural killer (NK) immune system cells can be genetically modified to brandish a powerful “on” switch that prompts them to aggressively attack and kill leukemic cells, according to St. Jude researchers."

2005: Tipifarnib (ZarnestraTM), a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. T-cell ALL potential. Dasatinib for Ph+ ALL. (Note: 2011 - these drugs are used in trials for ALL, see the targeted ALL treatments article on this web site.)

2005: Annamycin, a novel liposomal drug from the anthracycline family with potentially reduced cardiotoxicity, a patented liposomal formulation, and the potential to circumvent multi-drug resistance in ALL (from Callisto Pharmaceuticals, Inc.). 6/24/2005 -- Callisto Pharmaceuticals, Inc. announced today that the Office of Orphan Products Development of the United States Food and Drug Administration (FDA) has granted orphan drug designation to the company's drug candidate Annamycin for the treatment of acute lymphoblastic leukemia (relapsed). 12/05 -- clinical trial launched.

2005: A couple new drugs have been approved for ALL treatment, ara G (nelarabine, mainly for T-cell) and Clofarabine (Evoltra, made by Bioenvision, Inc; for relapsed ALL) (both on Sea to Ara C).

2005: Evaluation of dendritic cells loaded with apoptotic cancer cells or expressing tumour mRNA as potential cancer vaccines against leukemia. Silvija Jarnjak-Jankovic, Rolf D Pettersen, Stein Sæbøe-Larssen, Finn Wesenberg and Gustav Gaudernack. BMC Cancer 2005, 5:20 Published 18 February 2005.

2005: Targeting FLT3 in primary MLL-gene–rearranged infant acute lymphoblastic leukemia. Ronald W. Stam et. al. Blood, 1 October 2005, Vol. 106, No. 7, pp. 2484-2490. FT3 might turn out to be a good target for targetted chemotherapy: "leukemic cells from infants with MLL were significantly more sensitive to the Fms-like tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than noninfant ALL cells". Abstract.

2005: Oral Aminopterin for relapsed ALL. Aminopterin was used decades ago in ALL treatment but was replaced by methotrexate. Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia. Peter D. Cole et al., Clinical Cancer Research Vol. 11, 8089-8096, November 15, 2005.

2005: Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. Amsacrine intercalates into the DNA; it inhibits topoisomerase activity. Haematologica. 2005 Dec;90(12):1701-3.

2004: Acute Lymphoblastic Leukemia: Time for T. The indolocarbazole derivative CEP-701 selectively and potently kills cells derived from several childhood acute lymphoblastic leukemias (ALL) that overexpress the FLT3 gene, researchers report. (Other treatments listed in article; from ASH 2004 meeting. On MedScape.)

2002: MedScape published an article that discusses current ALL treatment. It's written for the lay person and discusses MRD, new drugs (ara G and clofarabine), and new tactics. This article may not stay online forever (a pre-apology for a potential broken link) and you need to be registered (free) with MedScape to view the article.

 

 

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