Vitry-sur-Seine, France
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His scientific poster was presented at the 2017 American Society of Breast Surgeons annual meeting. Dr. Cross has in previous studies also reported a trend toward shorter courses of radiation therapy in cases where patients were treated through breast-conserving lumpectomy surgery. "If we can deliver less overall radiation with better cosmetic results and just as good survival rates, then it's a win-win-win scenario," said Dr. Cross. This observational, retrospective study encompassed a total of 1,115 patients who underwent breast cancer surgery between 2011 and 2016. The use of lumpectomy in Dr. Cross's practice increased by 27.7% during the study period. In 2011-2013 -- the period before the marker was used routinely in the practice's breast surgeries – Dr. Cross performed 540 breast cancer surgeries and the lumpectomy rate was 37.7%. During 2014-2016 when the device was consistently used, he performed 575 breast cancer surgeries and the lumpectomy rate was 48%. Because Dr. Cross's data is from a single practice with a largely rural patient population, he said further research was needed to see if his results are generalizable to other practices that serve patients with different characteristics. The unique BioZorb implant is sutured into the tumor site and is the first device that identifies where the breast cancer tumor was removed in a fixed, three-dimensional manner. After lumpectomy surgery, the implant helps the radiation oncologist plan treatments more reliably and determine where to aim the radiation in a more targeted fashion. The implant consists of a framework made of a bioabsorbable material that holds six titanium clips.  The framework of the device slowly dissolves in the body over the course of a year or more while the small marker clips remain at the surgical site and can be viewed for long-term monitoring such as mammograms. Studies have reported the rate of complications such as infection (2-3%) is virtually the same as for lumpectomy surgery without the implant. Breast cancer can be treated by mastectomy (breast removal) or by lumpectomy. With lumpectomy, a small amount of tissue containing the tumor is removed. In addition to the surgery, it is important to add radiation treatment to "clean up" any microscopic cancer cells that might remain behind in the breast. The addition of radiation allows surgeons to safely conserve the breast tissue, while decreasing the chances of cancer recurring in the same location. The favorable cosmetic results with the device are due in part to its advantages for oncoplastic surgery (OPS), Dr. Cross said. OPS emphasizes both cancer control and a better cosmetic outcome. It reconstructs and reshapes the breast to avoid deformities that can occur after healing from surgery and radiation. "Because of the BioZorb's shape, it helps me use the patients' own tissue for reconstruction at the time of lumpectomy – so I like to use the term 'reconstructive lumpectomy' when I explain what the surgery will entail," Dr. Cross said. "In my practice, this is now the routine standard with appropriately selected patients." The marker enhances oncoplastic surgery because it helps fill the space left by the tumor removal, while also providing a sort of scaffold for the breast tissue as it heals. In addition, the implant clearly delineates the tumor's previous location. This enables follow-up radiation therapy to be delivered more precisely, according to previous studies of the device. Better-targeted radiotherapy can have a positive impact on cosmetic outcomes and can help protect healthy body structures such as the heart and lungs from radiation exposure. Dr. Cross said the ability to deliver shorter, hypofractionated radiation therapy provides a substantial benefit for his patient population. This shorter course of radiation allows women to receive their radiation therapy over three to four weeks, instead of the usual five to six weeks. Many of his patients live far from Fayetteville and have to travel several hours to the city. Patients who receive hypofractionated radiation therapy have to travel far less often for treatment. The ability to get a shorter course of radiation may lead more women to choose breast-conserving surgery (BCS) instead of a mastectomy. (BCS is usually followed up with radiation therapy, while a mastectomy normally is not.) The BioZorb device is now widely used by breast surgeons and general surgeons throughout the U.S. The data was presented as a scientific poster at the annual meeting of the American Society of Breast Surgeons annual meeting held April 26-30 in Las Vegas. Focal Therapeutics, which makes the BioZorb device, provided writing and research support for Dr. Cross's presentation. About Dr. Cross and Breast Treatment Associates in Fayetteville Michael J. Cross, M.D., F.A.C.S., is a surgical oncologist who practices at Breast Treatment Associates in Fayetteville, Ark. His practice is focused on the diagnosis and treatment of medical and surgical diseases of the breast. He is widely published in the medical literature and participated in the nationally prominent American College of Surgeons Oncology Group (ACOSOG) breast cancer trials. He is a member of the faculty of the School of Oncoplastic Surgery and teaches both nationally and internationally. For more information about Breast Treatment Associates, call (479) 582-1000 or access www.breasttreatment.com. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/local-surgeon-reports-positive-findings-from-use-of-3d-marker-in-breast-cancer-treatment-300453838.html


Most of the children who had suffered from childhood cancer also risk heart failure later in life. While the effects of chemotherapy are harsh and can endanger the children's lives, new trial hopes to increase the childhood cancer survivors who surpass this health issue. The reason why chemotherapy treatment has such a high potential to affect the children's hearts is that their bodies are developing, and it represents a common concern among cancer researchers. A new research, which is being conducted by a team from the Children's Oncology Group on a national level, trials a drug that could potentially minimize the effects of chemotherapy on children's hearts. "You go through terrible chemotherapy, achieve remission, have a new lease on life and then your heart fails," Dr. Todd Cooper, director of the Pediatric Leukemia/Lymphoma Program, noted the irony. As part of the research, children and adolescents who relapsed into acute myelogenous leukemia are being subjected to trialing a new drug. The medicine, called CPX-351, is especially created to kill the cells responsible for leukemia in the patients while also not being invasive on the hearts of the young people. According to Cooper, who is also lead researcher in the study, approximately 30 percent of the people who suffer from AML and are treated with chemotherapy have a higher risk of suffering from heart diseases later in life. The medicine has been tested before the trial stared, and it showed astonishingly promising results. "CPX-351 should be considered standard first-line treatment for older patients with high-risk AML," explained Jeffrey E. Lancet, MD, main investigator for the study. Due to the fact that the AML affection is subjected to complicated treatment in order not to pose any danger to patients, multiple chemotherapy sessions are required in order to make sure that the cancer cells are fought properly. However, this comes with the risk of complications later in life, especially when it is the case of children, whose bodies are still developing. The CPX-351 drug is essentially different than previous treatment methods. The medication is contained as part of a liposomal formulation, which — it is believed — raises less heart risks. The container is employed to transport the drugs into the body, thus fighting against the cells that cause leukemia in the bone marrow. The packaging should improve the overall safety of the treatment, which may result in less side effects of chemotherapy used to treat cancer, especially in younger people who are more prone to complications. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


News Article | February 16, 2017
Site: www.eurekalert.org

Bottom Line: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) who were not treated at specialized cancer centers had significantly worse five-year survival compared with children with these cancers who were treated at specialized cancer centers, whereas AYAs treated at specialized cancer centers had outcomes comparable to children treated at specialized cancer centers. Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research. Author: Julie Wolfson, MD, MSHS, assistant professor in the Division of Pediatric Hematology-Oncology and member of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham. Background: AYAs, meaning those ages 15 to 39, with ALL and AML have significantly worse survival outcomes compared with children ages 14 and under, according to Wolfson. "A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer," she added. "We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes." How the Study Was Conducted and Results: Wolfson and colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39. Patients were considered to have been treated at a specialized cancer center if at any age they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers in Los Angeles County or if at the age of 21 or younger they were cared for at any of the Children's Oncology Group sites not designated a Comprehensive Cancer Center. Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA. Among these groups, 70 percent, 30 percent, 74 percent, and 22 percent were treated at a specialized cancer center, respectively. Five-year relative survival rates declined with age for both ALL and AML. Wolfson explained that the researchers excluded data from children with ALL ages 1 to 9 in subsequent analysis because these patients have significantly improved survival compared with other groups, likely as a result of different disease biology. They found that AYAs diagnosed at ages 15 to 21 and 22 to 29 who were treated at specialized cancer centers had comparable overall and leukemia-specific survival to children diagnosed with ALL from ages 10 to 14 and treated at a specialized cancer center. Using the same referent population, AYAs in these age groups who were not treated at specialized cancer centers had an approximately two-fold increased risk of death. AYAs diagnosed at ages 30 to 39 had an approximately three-fold increased risk of death irrespective of where they received care. For AML, AYAs diagnosed at ages 15 to 21 who were treated at specialized cancer centers had comparable overall and leukemia-specific survival to children diagnosed from ages 1 to 14 and treated at a specialized cancer center. AYAs diagnosed at ages 15 to 21 who were not treated at a specialized cancer center had a 1.7-fold increased risk for death. AYAs diagnosed at ages 22 to 39 had an approximately three-fold increased risk of death irrespective of where they received care. Among AYAs ages 21 to 39, those who were uninsured or publicly insured had a more than 70 percent lower likelihood of being treated at a specialized cancer center compared with those who had private health insurance. Author Comment: "We found that AYAs diagnosed with ALL from age 15 to 29 or diagnosed with AML from age 15 to 21 who were treated at specialized cancer centers had better outcomes than their peers who were not treated at specialized cancer centers when each group was compared with children treated at specialized cancer centers," said Wolfson. "These data suggest that treatment at a specialized cancer center can mitigate the poor outcomes in younger AYAs compared with children. We were also able to identify some barriers to being treated at specialized cancer centers for AYAs, which we hope can be used to address the gap in provision of high-quality cancer care to a vulnerable population." "The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals," continuedd Wolfson. "The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy." Limitations: According to Wolfson, the main limitation of the study is that the data were obtained from a cancer registry, which does not provide detailed information about each patient's treatment regimen or the features of their disease. Funding & Disclosures: The study was supported by grants from the National Institutes of Health and the St. Baldrick's Foundation. Wolfson declares no conflicts of interest. About the American Association for Cancer Research Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 37,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 108 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with nearly 19,500 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www. . To interview Julie Wolfson, contact Julia Gunther at julia.gunther@aacr.org or 215-446-6896.


News Article | February 22, 2017
Site: www.nature.com

Pre-B acute lymphoblastic leukaemia (ALL) cells were obtained from patients who gave informed consent in compliance with the guidelines of the Internal Review Board of the University of California San Francisco (Supplementary Table 2). Leukaemia cells from bone marrow biopsy of patients with ALL were xenografted into sublethally irradiated NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice via tail vein injection. After passaging, leukaemia cells were collected. Cells were cultured on OP9 stroma cells in minimum essential medium-α (MEMα; Invitrogen), supplemented with 20% fetal bovine serum (FBS), 2 mM l-glutamine, 1 mM sodium pyruvate, 100 IU/ml penicillin and 100 μg/ml streptomycin. Primary chronic myeloid leukaemia (CML) cases were obtained with informed consent from the University Hospital Jena in compliance with institutional internal review boards (including the IRB of the University of California San Francisco; Supplementary Table 3). Cells were cultured in Iscove’s modified Dulbecco’s medium (IMDM; Invitrogen) supplemented with 20% BIT serum substitute (StemCell Technologies); 100 IU/ml penicillin and 100 μg/ml streptomycin; 25 μmol/l β-mercaptoethanol; 100 ng/ml SCF; 100 ng/ml G-CSF; 20 ng/ml FLT3; 20 ng/ml IL-3; and 20 ng/ml IL-6. Human cell lines (Supplementary Table 2) were obtained from DSMZ and were cultured in Roswell Park Memorial Institute medium (RPMI-1640; Invitrogen) supplemented with GlutaMAX containing 20% FBS, 100 IU/ml penicillin and 100 μg/ml streptomycin. Cell cultures were kept at 37 °C in a humidified incubator in a 5% CO atmosphere. None of the cell lines used was found in the database of commonly misidentified cell lines maintained by ICLAC and NCBI Biosample. All cell lines were authenticated by STR profiles and tested negative for mycoplasma. BML275 (water-soluble) and imatinib were obtained from Santa Cruz Biotechnology and LC Laboratories, respectively. Stock solutions were prepared in DMSO or sterile water at 10 mmol/l and stored at −20 °C. Prednisolone and dexamethasone (water-soluble) were purchased from Sigma-Aldrich and were resuspended in ethanol or sterile water, respectively, at 10 mmol/l. Stock solutions were stored at −20 °C. Fresh solutions (pH-adjusted) of methyl pyruvate, OAA, 3-OMG (an agonist of TXNIP), d-allose (an agonist of TXNIP) and recombinant insulin (Sigma-Aldrich) were prepared for each experiment. DMS was obtained from Acros Organics, and fresh solutions (pH-adjusted) were prepared before each experiment. For competitive-growth assays, 5 mmol/l methyl pyruvate, 5 mmol/l dimethyl succinate (DMS) and 5 mmol/l OAA were used. The CNR2 agonist HU308 was obtained from Cayman Chemical. To avoid inflammation-related effects in mice, bone marrow cells were extracted from mice (Supplementary Table 4) younger than 6 weeks of age without signs of inflammation. All mouse experiments were conducted in compliance with institutional approval by the University of California, San Francisco Institutional Animal Care and Use Committee. Bone marrow cells were obtained by flushing cavities of femur and tibia with PBS. After filtration through a 70-μm filter and depletion of erythrocytes using a lysis buffer (BD PharmLyse, BD Biosciences), washed cells were either frozen for storage or subjected to further experiments. Bone marrow cells were cultured in IMDM (Invitrogen) with GlutaMAX containing 20% fetal bovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin and 50 μM β-mercaptoethanol. To generate pre-B ALL (Ph+ ALL-like) cells, bone marrow cells were cultured in 10 ng/ml recombinant mouse IL-7 (PeproTech) and retrovirally transformed by BCR–ABL1. BCR–ABL1-transformed pre-B ALL cells were propagated only for short periods of time and usually not for longer than 2 months to avoid acquisition of additional genetic lesions during long-term cell culture. To generate myeloid leukaemia (CML-like) cells, the myeloid-restricted protocol described previously30 was used. Bone marrow cells were cultured in 10 ng/ml recombinant mouse IL-3, 25 ng/ml recombinant mouse IL-6, and 50 ng/ml recombinant mouse SCF (PeproTech) and retrovirally transformed by BCR–ABL1. Immunophenotypic characterization was performed by flow cytometry. For conditional deletion, a 4-OHT-inducible, Cre-mediated deletion system was used. For retroviral constructs used, see Supplementary Table 5. Transfection of retroviral constructs (Supplementary Table 5) was performed using Lipofectamine 2000 (Invitrogen) with Opti-MEM medium (Invitrogen). Retroviral supernatant was produced by co-transfecting HEK 293FT cells with the plasmids pHIT60 (gag-pol) and pHIT123 (ecotropic env). Lentiviral supernatant was produced by co-transfecting HEK 293FT cells with the plasmids pCDNL-BH and VSV-G or EM140. 293FT cells were cultured in high glucose Dulbecco’s modified Eagle’s medium (DMEM, Invitrogen) with GlutaMAX containing 10% fetal bovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, 25 mmol/l HEPES, 1 mmol/l sodium pyruvate and 0.1 mmol/l non-essential amino acids. Regular medium was replaced after 16 h by growth medium containing 10 mmol /l sodium butyrate. After incubation for 8 h, the medium was changed back to regular growth medium. After 24 h, retroviral supernatant was collected, filtered through a 0.45-μm filter and loaded by centrifugation (2,000g, 90 min at 32 °C) onto 50 μg/ml RetroNectin- (Takara) coated non-tissue 6-well plates. Lentiviral supernatant produced with VSV-G was concentrated using Lenti-X Concentrator (Clontech), loaded onto RetroNectin-coated plates and incubated for 15 min at room temperature. Lentiviral supernatant produced with EM140 was collected, loaded onto RetroNectin-coated plates and incubated for 30 min at room temperature. Per well, 2–3 × 106 cells were transduced by centrifugation at 600g for 30 min and maintained for 48 h at 37 °C with 5% CO before transferring into culture flasks. For cells transduced with lentiviral supernatant produced with EM140, supernatant was removed the day after transduction and replaced with fresh culture medium. Cells transduced with oestrogen-receptor fusion proteins were induced with 4-OHT (1 μmol/l). Cells transduced with constructs carrying an antibiotic-resistance marker were selected with its respective antibiotic. For loss-of-function studies, dominant-negative variants of IKZF1 (DN-IKZF1, lacking the IKZF1 zinc fingers 1–4) and PAX5 (DN-PAX5; PAX5–ETV6 fusion) were cloned from patient samples. Expression of DN-IKZF1 was induced by doxycycline (1 μg/ml), while activation of DN-PAX5 was induced by 4-OHT (1 μg/ml) in patient-derived pre-B ALL cells carrying IKZF1 and PAX5 wild-type alleles, respectively. Inducible reconstitution of wild-type IKZF1 and PAX5 in haploinsufficient pre-B ALL cells carrying deletions of either IKZF1 (IKZF1∆) or PAX5 (PAX5∆) were also studied. Lentiviral constructs used are listed in Supplementary Table 5. A doxycycline-inducible TetOn vector system was used for inducible expression of PAX5 in mouse BCR–ABL1 pre-B ALL. The retroviral constructs used are listed in Supplementary Table 5. To study the effects of B-cell- versus myeloid-lineage identity in genetically identical mouse leukaemia cells, a doxycycline-inducible TetOn-CEBPα vector system31 was used to reprogram B cells. Mouse BCR–ABL1 pre-B ALL cells expressing doxycycline-inducible CEBPα or an empty vector were induced with doxycycline (1 μg/ml). Conversion from the B-cell lineage (CD19+Mac1−) to the myeloid lineage (CD19−Mac1+) was monitored by flow cytometry. For western blots, B-lineage cells (CD19+Mac1−) and CEBPα-reprogrammed cells (CD19−Mac1+) were sorted from cells expressing an empty vector or CEBPα, respectively, following doxycycline induction. For metabolic assays, sorted B-lineage cells and CEBPα-reprogrammed cells were cultured (with doxycycline) for 2 days following sorting, and were then seeded in fresh medium for measurement of glucose consumption (normalized to cell numbers) and total ATP levels (normalized to total protein). To study Lkb1 deletion in the context of CEBPα-mediated reprogramming, BCR–ABL1-transformed Lkb1fl/fl pre-B ALL cells expressing doxycycline-inducible CEBPα were transduced with 4-OHT(1 μg/ml) inducible Cre-GFP (Cre-ERT2-GFP). Without sorting for GFP+ cells, cells were induced with doxycycline and 4-OHT. Viability (expressed as relative change of GFP+ cells) was measured separately in B-lineage (gated on CD19+ Mac1−) and myeloid lineage (gated on CD19− Mac1+) populations. To study whether Lkb1 deletion causes CEBPα-dependent effects on metabolism and signalling, Lkb1fl/fl BCR–ABL1 B-lineage ALL cells expressing doxycycline-inducible CEBPα or an empty vector were transduced with 4-OHT-inducible Cre-GFP. After sorting for GFP+ populations, cells were induced with doxycycline. B-lineage cells (CD19+ Mac1−) and CEBPα-reprogrammed cells (CD19− Mac1+) were sorted from cells expressing an empty vector or CEBPα, respectively. Sorted cells were cultured with doxycycline and induced with 4-OHT. Protein lysates were collected on day 2 following 4-OHT induction. For metabolomics, sorted cells were re-seeded in fresh medium on day 2 following 4-OHT induction and collected for metabolite extraction. For CRISPR/Cas9-mediated deletion of target genes, all constructs including lentiviral vectors expressing gRNA and Cas9 nuclease were purchased from Transomic Technologies (Supplementary Table 5; see Supplementary Table 6 for gRNA sequences). In brief, patient-derived pre-B ALL cells transduced with GFP-tagged, 4-OHT-inducible PAX5 or an empty vector were transduced with pCLIP-hCMV-Cas9-Nuclease-Blast. Blasticidin-resistant cells were subsequently transduced with pCLIP-hCMV-gRNA-RFP. Non-targeting gRNA was used as control. Constructs including lentiviral vectors expressing gRNA and dCas9-VPR used for CRISPR/dCas9-mediated activation of gene expression are listed in Supplementary Table 5. Nuclease-null Cas9 (dCas9) fused with VP64-p65-Rta (VPR) was cloned from SP-dCas9-VPR (a gift from G. Church; Addgene plasmid #63798) and then subcloned into pCL6 vector with a blasticidin-resistant marker. gRNA sequences (Supplementary Table 6) targeting the transcriptional start site of each specific gene were obtained from public databases (http://sam.genome-engineering.org/ and http://www.genscript.com/gRNA-database.html)32. gBlocks Gene Fragments were used to generate single-guide RNAs (sgRNAs) and were purchased from Integrated DNA Technologies, Inc. Each gRNA was subcloned into pCL6 vector with a dsRed reporter. Patient-derived pre-B ALL cells transduced with either GFP-tagged inducible PAX5 or an empty vector were transduced with pCL6-hCMV-dCas9-VPR-Blast. Blasticidin-resistant cells were used for subsequent transduction with pCL6-hCMV-gRNA-dsRed, and dsRed+ cells were further analysed by flow cytometry. For each target gene, 2–3 sgRNA clones were pooled together to generate lentiviruses. Non-targeting gRNA was used as control. To elucidate the mechanistic contribution of PAX5 targets, the percentage of GFP+ cells carrying gRNA(s) for each target gene was monitored by flow cytometry upon inducible activation of GFP-tagged PAX5 or an empty vector in patient-derived pre-B ALL cells in competitive-growth assays. Cells were lysed in CelLytic buffer (Sigma-Aldrich) supplemented with a 1% protease inhibitor cocktail (Thermo Fisher Scientific). A total of 20 μg of protein mixture per sample was separated on NuPAGE (Invitrogen) 4–12% Bis-Tris gradient gels or 4–20% Mini-PROTEAN TGX precast gels, and transferred onto nitrocellulose membranes (Bio-Rad). The primary antibodies used are listed in Supplementary Table 7. For protein detection, the WesternBreeze Immunodetection System (Invitrogen) was used, and light emission was detected by either film exposure or the BioSpectrum Imaging system (UPV). Approximately 106 cells per sample were resuspended in PBS blocked using Fc blocker for 10 min on ice, followed by staining with the appropriate dilution of the antibodies or their respective isotype controls for 15 min on ice. Cells were washed and resuspended in PBS with propidium iodide (0.2 μg/ml) or DAPI (0.75 μg/ml) as a dead-cell marker. The antibodies used for flow cytometry are listed in Supplementary Table 7. For competitive-growth assays, the percentage of GFP+ cells was monitored by flow cytometry. For annexin V staining, annexin V binding buffer (BD Bioscience) was used instead of PBS and 7-aminoactinomycin D (7AAD; BD Bioscience) instead of propidium iodide. Phycoerythrin-labelled annexin V was purchased from BD Bioscience. For BrdU staining, the BrdU Flow Kit was purchased from BD Bioscience and used according to the manufacturer’s protocol. Methylcellulose colony-forming assays were performed with 10,000 BCR–ABL1 pre-B ALL cells. Cells were resuspended in mouse MethoCult medium (StemCell Technologies) and cultured on 3-cm dishes, with an extra water supply dish to prevent evaporation. Images were taken and colony numbers were counted after 14 days. Cell viability upon the genetic loss of function of target genes and/or inducible expression of PAX5 was monitored by flow cytometry using propidium iodide (0.2 μg/ml) as a dead-cell marker. To study the effects of an AMPK inhibitor (BML275), glucocorticoids (dexamethasone and prednisolone), CNR2 agonist (HU308), or TXNIP agonists (3-OMG and d-allose), 40,000 human or mouse leukaemia cells were seeded in a volume of 80 μl in complete growth medium on opaque-walled, white 96-well plates (BD Biosciences). Compounds were added at the indicated concentrations giving a total volume of 100 μl per well. After culturing for 3 days, cells were subjected to CellTiter-Glo Luminescent Cell Viability Assay (Promega). Relative viability was calculated using baseline values of cells treated with vehicle control as a reference. Combination index (CI) was calculated using the CalcuSyn software to determine interaction (synergistic, CI < 1; additive, CI = 1; or antagonistic, CI > 1) between the two agents. Constant ratio combination design was used. Concentrations of BML275, d-allose, 3-OMG and HU308 used are indicated in the figures. Concentrations of Dex used were tenfold lower than those of BML275. Concentrations of prednisolone used were twofold lower than those of BML275. To determine the number of viable cells, the trypan blue exclusion method was applied, using the Vi-CELL Cell Counter (Beckman Coulter). ChIP was performed as described previously33. Chromatin from fixed patient-derived Ph+ ALL cells (ICN1) was isolated and sonicated to 100–500-bp DNA fragments. Chromatin fragments were immunoprecipitated with either IgG (as a control) or anti-Pax5 antibody (see Supplementary Table 7). Following reversal of crosslinking by formaldehyde, specific DNA sequences were analysed by quantitative real-time PCR (see Supplementary Table 8 for primers). Primers were designed according to ChIP–seq tracks for PAX5 antibodies in B lymphocytes (ENCODE, Encyclopedia of DNA Elements, GM12878). ChIP–seq tracks for PAX5, IKZF1, EBF1 and TCF3 antibodies in a normal B-cell sample (ENCODE GM12878, UCSC genome browser) on INSR, GLUT1, GLUT3, GLUT6, HK2, G6PD, NR3C1, TXNIP, CNR2 and LKB1 gene promoter regions are shown. CD19 and ACTA1 served as a positive and a negative control gene, respectively. The y axis represents the normalized number of reads per million reads for peak summit for each track. The ChIP–seq peaks were called by the MACS peak-caller by comparing read density in the ChIP experiment relative to the input chromatin control reads, and are shown as bars under each wiggle track. Gene models are shown in UCSC genome browser hg19. Extracellular glucose levels were measured using the Amplex Red Glucose/Glucose Oxidase Assay Kit (Invitrogen), according to the manufacturer’s protocol. Glucose concentrations were measured in fresh and spent medium. Total ATP levels were measured using the ATP Bioluminescence Assay Kit CLS II (Roche) according to the manufacturer’s protocol. In fresh medium, 1 × 106 cells per ml were seeded and treated as indicated in the figure legends. Relative levels of glucose consumed and total ATP are shown. All values were normalized to cell numbers (Figs 1b, c, 2c (glucose uptake), 3a and Extended Data Figs 2c, 4f, 6d) or total protein (Fig. 2c, ATP levels). Numbers of viable cells were determined by applying trypan blue dye exclusion, using the Vi-CELL Cell Counter (Beckman Coulter). Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured using a Seahorse XFe24 Flux Analyzer with an XF Cell Mito Stress Test Kit and XF Glycolysis Stress Test Kit (Seahorse Bioscience) according to the manufacturer’s instructions. All compounds and materials were obtained from Seahorse Bioscience. In brief, 1.5 × 105 cells per well were plated using Cell-Tak (BD Biosciences). Following incubation in XF-Base medium supplemented with glucose and GlutaMAX for 1 h at 37 °C (non-CO incubator) for pH stabilization, OCR was measured at the resting stage (basal respiration in XF Base medium supplemented with GlutaMax and glucose) and in response to oligomycin (1 μmol/l; mitochondrial ATP production), mitochondrial uncoupler FCCP (5 μmol/l; maximal respiration), and respiratory chain inhibitor antimycin and rotenone (1 μmol/l). Spare respiratory capacity is the difference between maximal respiration and basal respiration. ECAR was measured under specific conditions to generate glycolytic profiles. Following incubation in glucose-free XF Base medium supplemented with GlutaMAX for 1 h at 37 °C (non-CO incubator) for pH stabilization, basal ECAR was measured. Following measurement of the glucose-deprived, basal ECAR, changes in ECAR upon the sequential addition of glucose (10 mmol/l; glycolysis), oligomycin (1 μmol/l; glycolytic capacity), and 2-deoxyglucose (0.1 mol/l) were measured. Glycolytic reserve was determined as the difference between oligomycin-stimulated glycolytic capacity and glucose-stimulated glycolysis. All values were normalized to cell numbers (Extended Data Fig. 2c) or total protein (Extended Data Figs 3a, 7a, b 8f) and are shown as the fold change relative to basal ECAR or OCR. Metabolite extraction and mass-spectrometry-based analysis were performed as described previously34. Metabolites were extracted from 2 × 105 cells per sample using the methanol/water/chloroform method. After incubation at 37 °C for the indicated time, cells were rinsed with 150 mM ammonium acetate (pH 7.3), and 400 μl cold 100% methanol (Optima* LC/MS, Fisher) and then 400 μl cold water (HPLC-Grade, Fisher) was added to cells. A total of 10 nmol norvaline (Sigma) was added as internal control, followed by 400 μl cold chloroform (HPLC-Grade, Fisher). Samples were vortexed three times over 15 min and spun down at top speed for 5 min at 4 °C. The top layer (aqueous phase) was transferred to a new Eppendorf tube, and samples were dried on Vacufuge Plus (Eppendorf) at 30 °C. Extracted metabolites were stored at −80 °C. For mass spectrometry-based analysis, the metabolites were resuspended in 70% acetonitrile and 5 μl used for analysis with a mass spectrometer. The mass spectrometer (Q Exactive, Thermo Scientific) was coupled to an UltiMate3000 RSLCnano HPLC. The chromatography was performed with 5 mM NH AcO (pH 9.9) and acetonitrile at a flow rate of 300 μl/min starting at 85% acetonitrile, going to 5% acetonitrile at 18 min, followed by an isocratic step to 27 min and re-equilibration to 34 min. The separation was achieved on a Luna 3u NH2 100A (150 × 2 mm) (Phenomenex). The Q Exactive was run in polarity switching mode (+3 kV/−2.25 kV). Metabolites were detected based on retention time (t ) and on accurate mass (± 3 p.p.m.). Metabolite quantification was performed as area-under-the-curve (AUC) with TraceFinder 3.1 (Thermo Scientific). Data analysis was performed in R (https://www.r-project.org/), and data were normalized to the number of cells. Relative amounts were log -transformed, median-centred and are shown as a heat map. To generate a model for pre-leukaemic B cell precursors expressing BCR–ABL1, BCR–ABL1 knock-in mice were crossed with Mb1-Cre deleter strain (Mb1-Cre; Bcr+/LSL-BCR/ABL) for excision of a stop-cassette in early pre-B cells. Bone marrow cells collected from Mb1-Cre; Bcr+/LSL-BCR/ABL mice cultured in the presence of IL-7 were primed with vehicle control or a combination of OAA (8 mmol/l), DMS (8 mmol/l) and insulin (210 pmol/l). Following a week of priming, cells were maintained and expanded in the presence of IL-7, supplemented with vehicle control or a combination of OAA (0.8 mmol/l) and DMS (0.8 mmol/l) for 4 weeks. Pre-B cells from Mb1-Cre; Bcr+/LSL-BCR/ABL mice expressed low levels of BCR–ABL1 tagged to GFP, and were analysed by flow cytometry for surface expression of GFP and CD19. The methylcellulose colony-forming assays were performed with 10,000 cells treated with vehicle control or metabolites. Cells were resuspended in mouse MethoCult medium (StemCell Technologies) and cultured on 3-cm diameter dishes, with an extra water supply dish to prevent evaporation. Images were taken and colony numbers counted after 14 days. For in vivo transplantation experiments, cells were treated with vehicle control or metabolites (OAA/DMS) for 6 weeks. One million cells were intravenously injected into sublethally irradiated (250 cGy) 6–8-week-old female NSG mice (n = 7 per group). Mice were randomly allocated into each group, and the minimal number of mice in each group was calculated by using the ‘cpower’ function in R/Hmisc package. No blinding was used. Each mouse was killed when it became terminally sick and showed signs of leukaemia burden (hunched back, weight loss and inability to move). The bone marrow and spleen were collected for flow cytometry analyses for leukaemia infiltration (CD19, B220). After 63 days, all remaining mice were killed and bone marrow and spleens from all mice were analysed by flow cytometry. Statistical analysis was performed using the Mantel–Cox log-rank test. All mouse experiments were in compliance with institutional approval by the University of California, San Francisco Institutional Animal Care and Use Committee. Following cytokine-independent proliferation, BCR–ABL1-transformed Lkb1fl/fl or AMPKa2fl/fl pre-B ALL cells were transduced with 4-OHT-inducible Cre or an empty vector control. For ex vivo deletion, deletion was induced 24 h before injection. For in vivo deletion, deletion was induced by 4-OHT (0.4 mg per mouse; intraperitoneal injection). Approximately 106 cells were injected into each sublethally irradiated (250 cGy) NOD/SCID mouse. Seven mice per group were injected via the tail vein. We randomly allocated 6–8-week-old female NOD/SCID or NSG mice into each group. The minimal number of mice in each group was calculated using the ‘cpower’ function in R/Hmisc package. No blinding was used. When a mouse became terminally sick and showed signs of leukaemia burden (hunched back, weight loss and inability to move), it was killed and the bone marrow and/or spleen were collected for flow cytometry analyses for leukaemia infiltration. Statistical analysis was performed by Mantel–Cox log-rank test. In vivo expansion and leukaemia burden were monitored by luciferase bioimaging. Bioimaging of leukaemia progression in mice was performed at the indicated time points using an in vivo IVIS 100 bioluminescence/optical imaging system (Xenogen). d-luciferin (Promega) dissolved in PBS was injected intraperitoneally at a dose of 2.5 mg per mouse 15 min before measuring the luminescence signal. General anaesthesia was induced with 5% isoflurane and continued during the procedure with 2% isoflurane introduced through a nose cone. All mouse experiments were in compliance with institutional approval by the University of California, San Francisco Institutional Animal Care and Use Committee. Data are shown as mean ± s.d. unless stated. Statistical significance was analysed by using Grahpad Prism software or R software (https://www.r-project.org/) by using two-tailed t-test, two-way ANOVA, or log-rank test as indicated in figure legends. Significance was considered at P < 0.05. For in vitro experiments, no statistical methods were used to predetermine the sample size. For in vivo transplantation experiments, the minimal number of mice in each group was calculated through use of the ‘cpower’ function in the R/Hmisc package. No animals were excluded. Overall survival and relapse-free survival data were obtained from GEO accession number GSE11877 (refs 35, 36) and TCGA. Kaplan–Meier survival analysis was used to estimate overall survival and relapse-free survival. Patients with high risk pre-B ALL (COG clinical trial, P9906, n = 207; Supplementary Table 10) were segregated into two groups on the basis of high or low mRNA levels with respect to the median mRNA values of the probe sets for the gene of interest. A log-rank test was used to compare survival differences between patient groups. R package ‘survival’ Version 2.35-8 was used for the survival analysis and Cox proportional hazards regression model in R package for the multivariate analysis (https://www.r-project.org/). The investigators were not blinded to allocation during experiments and outcome assessment. Experiments were repeated to ensure reproducibility of the observations. Gel scans are provided in Supplementary Fig. 1. Gene expression data were obtained from the GEO database accession numbers GSE32330 (ref. 12), GSE52870 (ref. 37), and GSE38463 (ref. 38). Patient-outcome data were derived from the National Cancer Institute TARGET Data Matrix of the Children’s Oncology Group (COG) Clinical Trial P9906 (GSE11877)35, 36 and from TCGA (the Cancer Genome Atlas). GEO accession details are provided in Supplementary Tables 9 and 10. ChIP–seq tracks for PAX5, IKZF1, EBF1 and TCF3 antibodies in a normal B-cell sample (ENCODE GM12878, UCSC genome browser) on INSR, GLUT1, GLUT3, GLUT6, HK2, G6PD, NR3C1, TXNIP, CNR2 and LKB1 gene promoter regions are shown in UCSC genome browser hg19. All other data are available from the corresponding author upon reasonable request.


News Article | November 3, 2016
Site: www.eurekalert.org

PORTLAND, OR - For the second year, SWOG, the cancer clinical trials network, and its charity, The Hope Foundation, are providing $125,000 to five U.S. Department of Veterans Affairs medical centers to expand access to cancer clinical trials. Under the VA Integration Support Program, medical centers receive $25,000 in seed funding to help them enroll veterans in trials run by SWOG and other members of the National Cancer Institute's National Clinical Trials Network (NCTN). This means more veterans can enroll in research studies featuring cutting-edge medicines. The publicly funded NCTN offers well over 200 open trials at any given time, trials testing prevention and treatment strategies for a variety of cancers, including lung, prostate, and colorectal cancers - the most common forms in veterans. Clinical trials are an important option for any cancer patient managing their disease. Trials test new treatments, and are sometimes the only way to access immunotherapies or precision medicines. For many reasons, most stemming from a lack of time and money, veterans' ability to join trials sponsored by the National Cancer Institute and other groups has decreased dramatically. SWOG and The Hope Foundation are working to turn that trend around, and their efforts are paying off. Winners of the 2015 VA Integration Support Program grants have expanded the hours of current research staff or hired new staff to process paperwork, screen patients, or collect tissue or other biological samples needed to take part in trials. As a result, 13 NCTN trials are now open to veterans at these sites, including the landmark Lung-MAP precision medicine trial testing new drugs for squamous cell lung cancer. Soon, the NCI-MATCH trial will also be available at some sites. Veterans are responding to the increasing access. About 50 have been screened for trial participation, and 12 have enrolled. One is Jerry Valentino, a lung cancer patient who joined SWOG's Lung-MAP trial through the VA Connecticut Healthcare System. Valentino, a 70-year-old Vietnam War veteran, has experienced no side effects from his trial drug and is responding well to treatment. Scans show his cancer is gone - and hasn't returned. "Trials are the only way we know if drugs work or they don't," Valentino said. "It feels good to be part of the system that is moving medicine forward. This program is really helping veterans - and by all means they deserve it." Dr. Charles Blanke, SWOG group chair, agrees. Blanke created the VA Integration Support Program to help veterans and support the NCTN. Groups in the NCTN - SWOG, Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, and Children's Oncology Group - are a major part of the nation's cancer research infrastructure and enroll tens of thousands of patients each year. All five groups are funded by the National Cancer Institute, and constitute the oldest and largest cancer research network in the nation. "I am pleased with our progress and impact one year into this new program," Blanke said. "We are doing what we'd hoped to do - make great cancer trials available to veterans. Consideration of a clinical trial is a hallmark of excellent cancer care, and our veterans deserve the very best." For information on the VA Integration Support Program, contact Morgan Cox at The Hope Foundation at (734) 998-6887 or morgan@thehopefoundation.org. SWOG is part of the National Cancer Institute's National Clinical Trials Network, the nation's oldest and largest cancer research network, and is a major part of the cancer research infrastructure in the U.S. and the world. SWOG has over 12,000 members in 46 states and six foreign countries who design and conduct cancer clinical trials to improve the lives of people with cancer. Founded in 1956, SWOG's 1,300 trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 2 million years of human life. Learn more at swog.org. The Hope Foundation is a public charity that supports SWOG's work by providing funds for research grants and fellowships, physician education, clinical trial support, and patient advocacy.


News Article | December 6, 2016
Site: www.eurekalert.org

(San Diego, December 6, 2016) - A late-breaking abstract being presented today during the 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego identifies inherited genetic mutations in the gene IKZF1 that confer a higher likelihood of developing pediatric acute lymphocytic leukemia (ALL). The findings are among the latest evidence to point to a strong inherited genetic basis of ALL risk in children. Some of the variants identified also appear to reduce cancer cells' sensitivity to a chemotherapy drug used to treat some types of ALL, potentially contributing to drug resistance. "The genetic variants help explain why these children develop leukemia and also inform potential risk for ALL in family members who carry the same defective version of IKZF1," said lead study author Michelle L. Churchman, PhD, of St. Jude Children's Research Hospital in Memphis. "If patients are identified as having one of these deleterious IKZF1 mutations, then that could potentially inform their treatment, whether family members need to get screened, or other clinical decisions." Overall, about 85 percent of children survive for at least five years after being diagnosed with ALL, a cancer affecting the lymphocytes, a type of white blood cell. Only a handful of other genes have been identified that appear to be associated with a predisposition to the disease. The new study was initiated after multiple cases of pediatric ALL were reported in a single family in Germany and a genetic analysis of the family members pointed to an inherited mutation in IKZF1 as a possible contributor. The IKZF1 gene encodes Ikaros, a protein with essential roles in lymphocyte development. Previous studies have found defects in IKZF1 in leukemia cells linked with some high-risk forms of ALL that respond poorly to treatment, such as BCR-ABL1 (Philadelphia chromosome) ALL. The researchers sequenced the IKZF1 gene in germline DNA from normal blood samples of more than 5,000 children with ALL treated by St. Jude Children's Research Hospital and other collaborating institutions in the Children's Oncology Group and identified 28 gene variants. They then introduced these variant forms of IKZF1 into cultured cells to gauge their effects on activity of the Ikaros protein, cell growth and behavior, and response to chemotherapeutic agents. The results showed that most of the gene variants caused abnormalities conducive to the development of leukemia, such as increased cellular aggregation and "stickiness" of cells in the bone marrow. Several variants significantly reduced the sensitivity of leukemic cells to the chemotherapy drug dasatinib, a drug commonly used to treat high-risk forms of ALL such as BCR-ABL1. "Leukemia running in families may be more common than was previously appreciated," said Dr. Churchman. "This is now a very active area of research, and I think we're looking at the tip of the iceberg in terms of genetic predisposition to this type of leukemia, and maybe other types as well. We now have a handful of genes identified, and I think that there will be more to come." The team plans to continue to study the clinical outcomes of patients with IKZF1 variants, further assess the degree to which these mutations increase the risk of ALL in families, and integrate different types of genomic studies for a more complete picture of how these mutations are inherited. This study was funded by ALSAC of St. Jude, the National Cancer Center and National Institute for General Medical Science of the National Institutes of Health, and grants from the Leukemia & Lymphoma Society and St. Baldrick's Foundation. Michelle L. Churchman, PhD, St. Jude Children's Research Hospital, Memphis, Tenn. will present this study, titled "Germline Genetic Variation in IKZF1 and Predisposition to Childhood Acute Lymphoblastic Leukemia," as a late-breaking abstract (LBA-2) on Tuesday, December 6 in Hall AB of the San Diego Convention Center. For the complete annual meeting program and abstracts, visit http://www. . Follow @ASH_hematology and #ASH16 on Twitter and like ASH on Facebook for the most up-to-date information about the 2016 ASH Annual Meeting. The American Society of Hematology (ASH) (http://www. ) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The Society publishes Blood (http://www. ), the most cited peer-reviewed publication in the field, as well as the newly launched, online, open-access journal, Blood Advances.


News Article | December 22, 2016
Site: www.eurekalert.org

Portland, Oregon, Dec. 21, 2016 - The addition of bortezomib to a standard two-drug regimen for multiple myeloma patients significantly lengthened the time before their cancer returned, and significantly lengthened their lives, according to clinical trial results in The Lancet. Investigators from SWOG, the international cancer clinical trials network funded by the National Cancer Institute (NCI), compared the effectiveness of two drug regimens in newly diagnosed patients undergoing their first round of treatment for multiple myeloma, a type of bone marrow cancer. One regimen used in the study was lenalidomide with dexamethasone, a standard first-line treatment. The other drug regimen also included bortezomib, a second-line drug typically given to myeloma patients whose cancer progresses after initial therapy. SWOG researchers found that the addition of bortezomib made a significant difference for myeloma patients, giving them about another year of remission and another year of life. Patients receiving bortezomib, along with lenalidomide and dexamethasone, in their first six months of treatment had a median remission time of 43 months compared to a median remission of 30 months for patients who received lenalidomide and dexamethasone alone. Researchers also found that patients who received bortezomib lived a median of 75 months, or about six years, after their initial treatment. Patients who received the standard two-drug treatment lived a median of 64 months, or about five years, after initial treatment. "There's a lot of excitement about these research findings and this treatment option, which helps myeloma patients stay healthier longer and gives them more time to spend with people they love," said SWOG study principal investigator Brian G.M. Durie, M.D., a physician at Cedars-Sinai Outpatient Cancer Center in Los Angeles and chairman of the board at the International Myeloma Foundation. "Because the research was so solid, and the findings so strong, we're looking at a potential new standard of care." Results of the SWOG study, S0777, first gained attention in December 2015 at the 57th Annual Meeting of the American Society of Hematology (ASH) held in Orlando, Florida. Myeloma is the second most common blood cancer in the world. According to NCI statistics, in 2016 an estimated 30,330 new cases of myeloma will be diagnosed and 12,650 people will die of the disease in the U.S. In recent years, new drugs have brought new hope, and life expectancy for people diagnosed with multiple myeloma is slowly rising. SWOG researchers enrolled 471 eligible and consented adult patients in S0777 between February 2008 and February 2012 at 139 institutions throughout the National Cancer Trials Network (NCTN), the nation's oldest and largest publicly funded cancer research network. The NCTN includes SWOG, the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, and NRG Oncology, which all enrolled patients to S0777, as well as the Children's Oncology Group, which focuses on pediatric cancers. S0777 patients ranged in age from 28 to 87, had active myeloma, and had not had a stem-cell transplant or any prior treatment for their disease. Patients were randomized into two groups. One group received the standard two-drug treatment for six cycles over six months. That includes lenalidomide, an immunomodulating therapy marketed as Revlimid by Celegene Corporation. The other group received a three-drug combination that included bortezomib, a proteasome inhibitor marketed as Velcade by Millennium Pharmaceuticals. These patients received the triple combination therapy for eight cycles over six months. Despite the increased remission and longevity, the three-drug combination did have a drawback: Patients who received bortezomib were much more likely to experience sensory neuropathy, or tingling, pain, numbness or weakness in their hands and feet. The NCI provided primary grant funding for S0777 and was the sponsor of the study. Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, and Celgene Corporation provided the study drugs under their respective Cooperative Research and Development Agreements with the NCI. A national team of SWOG researchers led S0777. Along with Durie, they include: Antje Hoering, Ph.D, of Cancer Research And Biostatistics; S. Vincent Rajkumar, M.D., of Mayo Clinic; Muneer H. Abidi, M.D., of Spectrum Health and Michigan State University; Joshua Epstein, DS.c, of University of Arkansas for Medical Sciences; Stephen P. Kahanic, M.D., of Souixland Regional Cancer Center; Mohan C. Thakuri, M.D., of Southeast Clinical Oncology Research Consortium NCORP; Frederic J. Reu, M.D., of Cleveland Clinic; Christopher M. Reynolds, M.D., of Michigan Cancer Research Consortium NCORP; Rachael Sexton, M.S., of Cancer Research And Biostatistics; Robert Z. Orlowski, M.D., Ph.D, of MD Anderson Cancer Center; Bart Barlogie, M.D., Ph.D, of University of Arkansas for Medical Sciences; and Angela Dispenzieri, M.D., of Mayo Clinic. SWOG is a global network of researchers that design and conduct cancer clinical trials, and, as part of the Nation Cancer Institute's National Clinical Trials Network, is a major part of the cancer research infrastructure in the U.S. and the world. The group's goal is to change medical practice so it improves the lives of people with cancer. Founded in 1956, SWOG's 1,300 trials have led to the approval of 14 cancer drugs, changed the standard of cancer care more than 100 times, and saved more than 2 million years of human life. Learn more at swog.org.


RESEARCH TRIANGLE PARK, NORTH CAROLINA--(Marketwired - Dec. 1, 2016) - Fennec Pharmaceuticals Inc. (TSX:FRX) (OTCQB:FENCF), a specialty pharmaceutical company focused on the development of Sodium Thiosulfate (STS) for the prevention of platinum-induced ototoxicity in pediatric patients, today announced The Lancet Oncology published the results from the Children's Oncology Group, "Effects of Sodium Thiosulfate versus Observation on Development of Cisplatin-Induced Hearing Loss and Survival in Children with Cancer: Results from the Children's Oncology Group ACCL0431 Randomised Cohort Trial". "Through the successful completion of ACCL0431, identification of sodium thiosulfate as an effective otoprotectant is an important development in supportive care research for children with cancer," said David R. Freyer, DO, MS: Study Chair, ACCL0431, and Director of the Survivorship & Supportive Care Program, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles. "Through supporting and stimulating additional studies in this area, these results will contribute substantially to the ultimate goal of preventing cisplatin-induced hearing loss and its devastating consequences." "I would like to thank Dr. David Freyer and contributing authors as well as all participating investigators and patients in COG ACCL0431 for their dedication and support of STS as a potential treatment in cisplatin-induced hearing loss," said Rosty Raykov, Chief Executive Officer of Fennec. "We look forward to the results of SIOPEL 6 anticipated in 2017 for further enlightenment of the potential future role for STS." Cisplatin and other platinum compounds are essential chemotherapeutic components for many pediatric malignancies. Unfortunately, platinum-based therapies cause ototoxicity in many patients and are particularly harmful to the survivors of pediatric cancer. In the U.S., Europe and Japan it is estimated that up to 10,000 children are diagnosed with local cancers that may receive platinum based chemotherapy. Localized cancers that receive platinum agents may have overall survival rates of greater than 80% further emphasizing the need for quality of life treatments. The incidence of hearing loss in these children depends upon the dose and duration of chemotherapy and many of them require hearing aids for life. There is currently no established preventive agent for cisplatin-induced hearing loss and expensive and technically difficult cochlear (inner ear) implants provide suboptimal benefit. As a result, infants and young children at critical stages of development lack speech language development and literacy, while older children and adolescents lack social-emotional development and educational achievement. STS has been studied by cooperative groups in two Phase 3 clinical studies of reduction of ototoxicity, the COG Protocol ACCL0431 and SIOPEL 6. Both studies are closed to recruitment. COG ACCL0431 final results were published in the Lancet Oncology. SIOPEL 6 initial results will be available in the fourth quarter of 2017. Fennec Pharmaceuticals, Inc., is a specialty pharmaceutical company focused on the development of Sodium Thiosulfate (STS) for the prevention of platinum-induced ototoxicity in pediatric patients. STS has received Orphan Drug Designation in the US in this setting. For more information, please visit www.fennecpharma.com. Except for historical information described in this press release, all other statements are forward-looking. Forward-looking statements are subject to certain risks and uncertainties inherent in the Company's business that could cause actual results to vary, including such risks that regulatory and guideline developments may change, scientific data may not be sufficient to meet regulatory standards or receipt of required regulatory clearances or approvals, clinical results may not be replicated in actual patient settings, protection offered by the Company's patents and patent applications may be challenged, invalidated or circumvented by its competitors, the available market for the Company's products will not be as large as expected, the Company's products will not be able to penetrate one or more targeted markets, revenues will not be sufficient to fund further development and clinical studies, the Company may not meet its future capital requirements in different countries and municipalities, the proposed sale to Elion may not be completed and other risks detailed from time to time in the Company's filings with the Securities and Exchange Commission including its Annual Report on Form 10-K for the year ended December 31, 2015. Fennec Pharmaceuticals, Inc. disclaims any obligation to update these forward-looking statements except as required by law. For a more detailed discussion of related risk factors, please refer to our public filings available at www.sec.gov and www.sedar.com.


— Global Cancer Immunotherapies Market to 2022 - Immune Checkpoint Inhibitors and Therapeutic Cancer Vaccines to Characterize Increasingly Competitive Market The cancer immunotherapies market is forecast to rise from a value of $16.9 billion in 2015 to $75.8 billion in 2022, at a compound annual growth rate of 23.9%. The cancer immunotherapies pipeline is vast, with a significant degree of diversity in terms of molecule types and targets. The company landscape is growing increasingly competitive. Complete report on Global Cancer Immunotherapies Market to 2022 - Immune Checkpoint Inhibitors and Therapeutic Cancer Vaccines to Characterize Increasingly Competitive Market spread across 63 pages available at: http://www.reportsnreports.com/contacts/discount.aspx?name=799564 Understand the current clinical and commercial landscape through a comprehensive study of disease epidemiology, pathogenesis, symptoms, diagnosis and prognosis for the key indications covered in the report, which includes breast cancer, melanoma, NSCLC and ovarian cancer. • Cancer Immunotherapies Key Marketed Products • Cancer Immunotherapies Pipeline Landscape Assessment • Cancer Immunotherapies Multi-scenario Market Forecast to 2022 • Cancer Immunotherapies Company Analysis and Positioning • Cancer Immunotherapies Strategic Consolidations • Cancer Immunotherapies Market, Global, Epidemiology of Key Oncology Indications, 2016 • Cancer Immunotherapies Market, Global, Regional Lymph Node and Metastasis Staging, • Cancer Immunotherapies Market, Global, Eastern Co-operative Oncology Group Criteria, 2016 • Cancer Immunotherapies Market, Global, Breast Cancer Histopathological and Molecular Classification, 2016 • Cancer Immunotherapies Market, US, Breast Cancer Stage at Diagnosis and Five-Year Relative Survival (%), 2016 • Cancer Immunotherapies Market, US, Ovarian Cancer Stage and Survival Rates (%), 2016 • Cancer Immunotherapies Market, US, Lung Cancer Stage at Diagnosis and Five-Year Relative Survival (%), 2016 • Cancer Immunotherapies Market, US, Ovarian Cancer Stage at Diagnosis and Five-year Relative Survival Get Discount on Report at: http://www.reportsnreports.com/contacts/discount.aspx?name=799564 Companies Discussed In Report: Celgene, Bristol-Myers Squibb, Roche , Merck & Co, AstraZeneca , Novartis , Amgen , Pfizer, Kite Pharma Scope: The cancer immunotherapies market already consists of some commercially successful products. • Which classes of drug dominate the market? • What additional benefits have newly approved therapies brought to the market? The cancer immunotherapies pipeline is vast, with a significant degree of diversity in terms of molecule types and targets. • Which molecular targets appear most frequently in the pipeline? • What are the commercial prospects for the most promising late-stage pipeline products? The cancer immunotherapies market is forecast to rise from a value of $16.9 billion in 2015 to $75.8 billion in 2022, at a compound annual growth rate of 23.9%. • Which products are forecast to drive this substantial degree of growth? • Will generic competition have a significant impact on the market over the forecast period? The company landscape is growing increasingly competitive. • What are the leading companies in terms of market share? • Which companies are forecast to experience the greatest growth in market share? • What are the drivers of growth for key companies in the market? • How dependent are the key companies on this disease cluster for revenue? • Which companies rely heavily on this disease cluster for revenue? Get This Report at: http://www.reportsnreports.com/purchase.aspx?name=799564 Reasons to Buy • Understand the current clinical and commercial landscape through a comprehensive study of disease epidemiology, pathogenesis, symptoms, diagnosis and prognosis for the key indications covered in the report, which includes breast cancer, melanoma, NSCLC and ovarian cancer. • Assess the current treatment landscape, with product profiles covering prominent marketed therapies, including revenue forecasts. • Analyze the cancer immunotherapies pipeline and stratify by stage of development, molecule type, and molecular target. The most promising late-stage therapies are profiled and assessed in terms of clinical performance and competitiveness, alongside a single-product forecast. • Predict growth in market size, with in-depth market forecasting from 2015 to 2022. The forecasts will provide an understanding of how epidemiology trends, new drug entries, and patent expirations will influence market value. • Identify the leading companies in the market, in terms of market share and growth. Company analysis determines how dependent the key companies in the market are on revenue derived from cancer immunotherapy products. In addition, analysis determines the primary factors that will drive market growth for the key companies in the market. • Identify commercial opportunities in the cancer immunotherapies deals landscape by analyzing trends in licensing and co-development deals About Us: Reportsnreports.com is an online database of market research reports offer in-depth analysis of over 5000 market segments. The library has syndicated reports by leading market research publishers across the globe and also offer customized market research reports for multiple industries. For more information, please visit http://www.reportsnreports.com/reports/799564-global-cancer-immunotherapies-market-to-2022-immune-checkpoint-inhibitors-and-therapeutic-cancer-vaccines-to-characterize-increasingly-competitive-market.html


— Global Cancer Immunotherapies Market to 2022 - Immune Checkpoint Inhibitors and Therapeutic Cancer Vaccines to Characterize Increasingly Competitive Market The cancer immunotherapies market is forecast to rise from a value of $16.9 billion in 2015 to $75.8 billion in 2022, at a compound annual growth rate of 23.9%. The cancer immunotherapies pipeline is vast, with a significant degree of diversity in terms of molecule types and targets. The company landscape is growing increasingly competitive. Complete report on Global Cancer Immunotherapies Market to 2022 - Immune Checkpoint Inhibitors and Therapeutic Cancer Vaccines to Characterize Increasingly Competitive Market spread across 63 pages available at: http://www.reportsnreports.com/contacts/discount.aspx?name=799564 Understand the current clinical and commercial landscape through a comprehensive study of disease epidemiology, pathogenesis, symptoms, diagnosis and prognosis for the key indications covered in the report, which includes breast cancer, melanoma, NSCLC and ovarian cancer. • Cancer Immunotherapies Key Marketed Products • Cancer Immunotherapies Pipeline Landscape Assessment • Cancer Immunotherapies Multi-scenario Market Forecast to 2022 • Cancer Immunotherapies Company Analysis and Positioning • Cancer Immunotherapies Strategic Consolidations • Cancer Immunotherapies Market, Global, Epidemiology of Key Oncology Indications, 2016 • Cancer Immunotherapies Market, Global, Regional Lymph Node and Metastasis Staging, • Cancer Immunotherapies Market, Global, Eastern Co-operative Oncology Group Criteria, 2016 • Cancer Immunotherapies Market, Global, Breast Cancer Histopathological and Molecular Classification, 2016 • Cancer Immunotherapies Market, US, Breast Cancer Stage at Diagnosis and Five-Year Relative Survival (%), 2016 • Cancer Immunotherapies Market, US, Ovarian Cancer Stage and Survival Rates (%), 2016 • Cancer Immunotherapies Market, US, Lung Cancer Stage at Diagnosis and Five-Year Relative Survival (%), 2016 • Cancer Immunotherapies Market, US, Ovarian Cancer Stage at Diagnosis and Five-year Relative Survival Get Discount on Report at: http://www.reportsnreports.com/contacts/discount.aspx?name=799564 Companies Discussed In Report: Celgene, Bristol-Myers Squibb, Roche , Merck & Co, AstraZeneca , Novartis , Amgen , Pfizer, Kite Pharma Scope: The cancer immunotherapies market already consists of some commercially successful products. • Which classes of drug dominate the market? • What additional benefits have newly approved therapies brought to the market? The cancer immunotherapies pipeline is vast, with a significant degree of diversity in terms of molecule types and targets. • Which molecular targets appear most frequently in the pipeline? • What are the commercial prospects for the most promising late-stage pipeline products? The cancer immunotherapies market is forecast to rise from a value of $16.9 billion in 2015 to $75.8 billion in 2022, at a compound annual growth rate of 23.9%. • Which products are forecast to drive this substantial degree of growth? • Will generic competition have a significant impact on the market over the forecast period? The company landscape is growing increasingly competitive. • What are the leading companies in terms of market share? • Which companies are forecast to experience the greatest growth in market share? • What are the drivers of growth for key companies in the market? • How dependent are the key companies on this disease cluster for revenue? • Which companies rely heavily on this disease cluster for revenue? Get This Report at: http://www.reportsnreports.com/purchase.aspx?name=799564 Reasons to Buy • Understand the current clinical and commercial landscape through a comprehensive study of disease epidemiology, pathogenesis, symptoms, diagnosis and prognosis for the key indications covered in the report, which includes breast cancer, melanoma, NSCLC and ovarian cancer. • Assess the current treatment landscape, with product profiles covering prominent marketed therapies, including revenue forecasts. • Analyze the cancer immunotherapies pipeline and stratify by stage of development, molecule type, and molecular target. The most promising late-stage therapies are profiled and assessed in terms of clinical performance and competitiveness, alongside a single-product forecast. • Predict growth in market size, with in-depth market forecasting from 2015 to 2022. The forecasts will provide an understanding of how epidemiology trends, new drug entries, and patent expirations will influence market value. • Identify the leading companies in the market, in terms of market share and growth. Company analysis determines how dependent the key companies in the market are on revenue derived from cancer immunotherapy products. In addition, analysis determines the primary factors that will drive market growth for the key companies in the market. • Identify commercial opportunities in the cancer immunotherapies deals landscape by analyzing trends in licensing and co-development deals About Us: Reportsnreports.com is an online database of market research reports offer in-depth analysis of over 5000 market segments. The library has syndicated reports by leading market research publishers across the globe and also offer customized market research reports for multiple industries. For more information, please visit http://www.reportsnreports.com/reports/799564-global-cancer-immunotherapies-market-to-2022-immune-checkpoint-inhibitors-and-therapeutic-cancer-vaccines-to-characterize-increasingly-competitive-market.html

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