Publications by authors named "Rupa Narayan"

15 Publications

  • Page 1 of 1

Incidence of Invasive Fungal Infections in Acute Myeloid Leukemia Without Antifungal Prophylaxis.

Clin Lymphoma Myeloma Leuk 2020 Nov 26;20(11):e883-e889. Epub 2020 Jun 26.

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA.

Background: Antifungal prophylaxis during induction for acute myeloid leukemia (AML) varies according to local rates of invasive fungal infections (IFIs). We evaluated fluconazole prophylaxis and no antifungal prophylaxis, as a natural interrupted time-series study to assess survival and infection complications.

Patients And Methods: We identified patients with AML ≥ 18 years old undergoing induction chemotherapy during 2 time periods: period 1, fluconazole prophylaxis from August 1, 2013 to September 30, 2015, and period 2, no prophylaxis from October 1, 2015 to December 31, 2017. The primary outcome was incidence of proven or probable IFI. Secondary outcomes included types of IFIs and 60-day overall survival (OS). IFI was defined by the 2002 European Organization for Research and Treatment of Cancer/Mycoses Study Group Consensus criteria.

Results: One hundred forty-four patients received induction chemotherapy over the 2 time periods. In the prophylaxis versus no-prophylaxis groups, the rate of proven or probable IFIs was 4 (5%) of 87 versus 12 (21%) of 57 (P = .01). The total number of proven IFIs was 3 (3%) of 87 versus 4 (7%) of 57 (P = .44), whereas probable IFIs were 1 (1%) of 87 versus 8 (14%) of 57 (P < .01). No difference was observed in fungemia. Incidence of IFIs was too low to detect resistance patterns. OS at 60 days was improved in with fluconazole prophylaxis compared with no prophylaxis (hazard ratio, 0.329; 95% confidence interval, 0.12-0.89; P = .028).

Conclusion: Observed rates of proven or probable IFI were lower in the fluconazole prophylaxis group versus the no-prophylaxis group. Sixty-day OS was higher with fluconazole prophylaxis. Further study is required to evaluate how fluconazole may impart the differences in survival seen in this analysis.
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http://dx.doi.org/10.1016/j.clml.2020.06.008DOI Listing
November 2020

Modified Hyper-CVAD With Proteasome Inhibition for Multiple Myeloma: A Single-Center Retrospective Analysis.

Clin Lymphoma Myeloma Leuk 2020 Dec 29;20(12):e961-e985. Epub 2020 Jul 29.

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA. Electronic address:

Background: Although novel agents have changed the treatment landscape of multiple myeloma (MM), cytotoxic chemotherapy regimens continue to have a role in aggressive or rapidly progressive disease. In such cases, our institution has utilized a hyperfractionated cyclophosphamide regimen (termed mCAD), similar to hyper-CVAD, in which vincristine is omitted or replaced with a proteasome inhibitor (PI), either bortezomib or carfilzomib. On occasion, doxorubicin is also omitted because of patient history and provider preference.

Patients And Methods: We retrospectively reviewed the charts of adult patients with MM receiving mCAD regimens at our institution between 2012 and 2016 and analyzed utilization patterns, toxicity profiles, and clinical outcomes.

Results: A total of 131 patients received mCAD, including 9% for newly diagnosed MM (NDMM), 18% attempting to optimize response to frontline therapy (OPT-MM), and 73% for treatment of relapsed/refractory MM (RRMM). Renal dysfunction was common; 31% had estimated glomerular filtration rate < 50 mL/min and 14% were dialysis dependent. The overall response rate was 83%, 63%, and 67% with a median progression-free survival of 17.4, 23.7, and 4.2 months, respectively, for NDMM, OPT-MM, and RRMM. Median overall survival was not reached for NDMM or OPT-MM, and was 15.2 months for RRMM. Most patients (90%) bridged to subsequent therapy, including 32% who proceeded to autologous transplantation. Hematologic, infectious, and cardiac toxicities were common and were similar to those expected for cytotoxic chemotherapy.

Conclusion: mCAD regimens were safe and active across patient groups, including patients with renal dysfunction. Most patients were able to bridge to subsequent therapy.
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http://dx.doi.org/10.1016/j.clml.2020.07.015DOI Listing
December 2020

Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangement.

Blood Adv 2020 01;4(1):106-111

Harvard Medical School, Boston, MA.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subtype of Ph-negative ALL that molecularly resembles Ph-positive ALL. It shares the adverse prognosis of Ph-positive ALL, but lacks the BCR-ABL1 fusion oncogene. Instead, Ph-like ALL is associated with alternative mutations in signaling pathways. We describe a case of Ph-like ALL that harbored 2 genomic alterations, which activated signaling, an NRASGly12Asp mutation, and an ETV6-NTRK3 rearrangement. Initially, the NRAS mutation was detected at high frequency, whereas the gene fusion was only detectable with a targeted next-generation sequencing-based fusion assay, but not by fluorescence in situ hybridization analysis. The disease failed to respond to multiagent chemotherapy but investigational CD19-directed chimeric antigen receptor T-cell therapy resulted in a complete remission. However, the leukemia relapsed after 6 weeks. Intriguingly, the NRAS mutation was extinguished during the chimeric antigen receptor T-cell therapy and did not contribute to the relapse, which was instead associated with a rise in ETV6-NTRK3. The relapsed leukemia progressed with further chemo- and immunotherapy but was controlled for 6 weeks with substantial leukemic cytoreduction using the TRK inhibitor larotrectinib. Unfortunately, recovery of normal hematopoiesis was only marginal and the patient eventually succumbed to infections. These results demonstrate that larotrectinib has clinical activity in ETV6-NTRK3-associated Ph-like ALL.
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http://dx.doi.org/10.1182/bloodadvances.2019000769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960464PMC
January 2020

A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

Cancer 2020 03 20;126(6):1264-1273. Epub 2019 Dec 20.

Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML.

Methods: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7.

Results: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion.

Conclusions: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777).

Lay Summary: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.
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http://dx.doi.org/10.1002/cncr.32657DOI Listing
March 2020

Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin.

PLoS One 2019 10;14(7):e0219547. Epub 2019 Jul 10.

Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, United States of America.

Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219547PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619824PMC
February 2020

Cardiac and genetic predictors of cardiovascular risk in patients with myelodysplastic syndromes.

Leuk Lymphoma 2019 12 23;60(12):3058-3062. Epub 2019 May 23.

Center for Leukemia, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1080/10428194.2019.1617863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001765PMC
December 2019

Donor-Derived Cytokine-Induced Killer Cell Infusion as Consolidation after Nonmyeloablative Allogeneic Transplantation for Myeloid Neoplasms.

Biol Blood Marrow Transplant 2019 07 3;25(7):1293-1303. Epub 2019 Apr 3.

Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, California. Electronic address:

Non-myeloablative conditioning, such as with total lymphoid irradiation and antithymocyte globulin (TLI-ATG), has allowed allogeneic hematopoietic cell transplantation (allo-HCT) with curative potential for older patients and those with comorbid medical conditions with myeloid neoplasms. However, early achievement of full donor chimerism (FDC) and relapse remain challenging. Cytokine-induced killer (CIK) cells have been shown to have antitumor cytotoxicity. Infusion of donor-derived CIK cells has been studied for hematologic malignancies relapsed after allo-HCT but has not been evaluated as post-transplant consolidation. In this phase II study, we prospectively studied whether a one-time infusion of 1 × 10/kg CD3 donor-derived CIK cells administered between day +21 and day +35 after TLI-ATG conditioning could improve achievement of FDC by day +90 and 2-year clinical outcomes in patients with myeloid neoplasms. CIK cells, containing predominantly CD3CD8NKG2D cells along with significantly expanded CD3CD56 cells, were infused in 31 of 44 patients. Study outcomes were compared to outcomes of a retrospective historical cohort of 100 patients. We found that this one-time CIK infusion did not increase the rate of FDC by day +90. On an intention-to-treat analysis, 2-year non-relapse mortality (6.8%; 95% confidence interval [CI], 0-14.5%), event-free survival (27.3%; 95% CI, 16.8-44.2%), and overall survival (50.6%; 95% CI, 37.5-68.2%) were similar to the values seen in the historical cohort. The cumulative incidence of grade II-IV acute graft-versus-host disease at 1-year was 25.1% (95% CI, 12-38.2%). On univariate analysis, the presence of monosomal or complex karyotype was adversely associated with relapse-free survival and overall survival. Given the favorable safety profile of CIK cell infusion, strategies such as repeat dosing or genetic modification merit exploration. This trial was registered at ClinicalTrials.gov (NCT01392989).
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http://dx.doi.org/10.1016/j.bbmt.2019.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662740PMC
July 2019

Zoledronic acid-induced orbital inflammation in a patient with multiple myeloma.

J Oncol Pharm Pract 2019 Jul 13;25(5):1253-1257. Epub 2018 Jul 13.

3 Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA, USA.

Multiple myeloma is a cancer of malignant plasma cells which stimulates osteoclasts and is associated with increased bone turnover and osteolysis. Bisphosphonates including zolendronic acid are used to prevent skeletal complications in patients with multiple myeloma. Orbital inflammation is a rare but serious complication following use of bisphosphonates. The diagnosis is made by excluding other possible causes in patients with myeloma and rapid initiation of therapy is required. Corticosteroids are the mainstay of therapy but the ideal treatment course has not been delineated. This report describes a case of this rare complication and provides a review of the literature.
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http://dx.doi.org/10.1177/1078155218785967DOI Listing
July 2019

T-Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins.

Proteomics 2018 06 18;18(12):e1700410. Epub 2018 Apr 18.

Department of Chemical and Systems Biology, Stanford Medicine, Stanford, CA, USA.

Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 10 were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (T ), conventional T cells (T ), and activated T cells. The combined T cell immunopeptide dataset reported here contains 13 804 unique HLA ligands derived from 5049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from T -enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell subpopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new T -biased ligand candidates; and 3) supports immunopeptidome surveys' value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting T and abrogating their suppressive functions to treat cancer.
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http://dx.doi.org/10.1002/pmic.201700410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021197PMC
June 2018

Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome.

Leuk Lymphoma 2016 13;57(3):609-15. Epub 2015 Oct 13.

a Division of Hematology, Department of Medicine , Stanford University School of Medicine , Stanford , CA , USA .

The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. The median number of treatment cycles on study was two (range = 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.
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http://dx.doi.org/10.3109/10428194.2015.1091930DOI Listing
December 2016

A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

Integr Cancer Ther 2014 Jan 11;13(1):46-53. Epub 2013 Jun 11.

Columbia University, New York, NY, USA.

Purpose: To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction.

Experimental Design: Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks.

Results: Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug.

Conclusion: Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.
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http://dx.doi.org/10.1177/1534735413490798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866213PMC
January 2014

Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1.

Blood 2013 May 11;121(19):3925-35, S1-12. Epub 2013 Mar 11.

Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples, Naples, Italy.

Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34(+) cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.
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http://dx.doi.org/10.1182/blood-2013-02-482489DOI Listing
May 2013

Killed but metabolically active Leishmania infantum as a novel whole-cell vaccine for visceral leishmaniasis.

Clin Vaccine Immunol 2012 Apr 8;19(4):490-8. Epub 2012 Feb 8.

Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California, USA.

There are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach using Leishmania infantum chagasi promastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results in Leishmania organisms termed killed but metabolically active (KBMA). In this report, we characterize the in vitro growth characteristics of both KBMA L. major and KBMA L. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like live L. infantum chagasi, KBMA L. infantum chagasi parasites were able to initially enter liver cells in vivo after intravenous infection. However, whereas live L. infantum chagasi infection leads to hepatosplenomegaly in mice after 6 months, KBMA L. infantum chagasi parasites were undetectable in the organs of mice at this time point. In vitro, KBMA L. infantum chagasi retained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMA L. infantum chagasi correlated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either live L. infantum chagasi or KBMA L. infantum chagasi displayed similar cytokine patterns in vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoan L. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens.
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http://dx.doi.org/10.1128/CVI.05660-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318268PMC
April 2012

Immunomodulation by imiquimod in patients with high-risk primary melanoma.

J Invest Dermatol 2012 Jan 18;132(1):163-9. Epub 2011 Aug 18.

Division of Dermatology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California 90502, USA.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.
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http://dx.doi.org/10.1038/jid.2011.247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229834PMC
January 2012