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1.  Dose Escalation of Total Marrow Irradiation with Concurrent Chemotherapy in Patients with Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation 
Purpose
We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) 16 Gy without chemotherapy or TMI 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This study reports on TMI combined with higher intensity chemotherapy regimens on two phase I trials in patients with advanced AML/ALL who would do poorly on standard intent-to-cure HCT regimens.
Methods
Trial 1: TMI on days -10 to -6, VP16 day -5 (60 mg/kg), and cyclophoshamide (CY) day -3 (100 mg/kg). TMI dose (Gy) was 12 (n=3), 13.5 (n=3) and 15 (n=6) at 1.5 Gy BID. Trial 2: Busulfan (BU) days -12 to -8 (800 uM min), TMI days -8 to -4, and VP16 day -3 (30 mg/kg). TMI dose (Gy) was 12 (n=18) and 13.5 (n=2) at 1.5 Gy BID.
Results
Trial 1: 12 patients; median age 33; 6 induction failure (IF), 6 first relapse (1RL); 9 with marrow blasts (10–98%), 5 with circulating blasts (24–85%) and 2 with chloromas. No dose limiting toxicities were observed. Eleven achieved CR at day 30. With a median follow-up 14.75 months, 5 remain in complete remission from 13.5–37.7 months. Trial 2: 20 patients; median age 41; 13 IF, 5 1RL, 2 in 2nd relapse; 19 with marrow blasts (3–100%) and 13 with peripheral blasts (6–63%). Grade 4 dose limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials.
Conclusions
TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to dose-limiting toxicities. Future efforts will focus on whether further dose escalation with CY/VP16 is safe with the goal of improving disease control in this high risk population.
doi:10.1016/j.ijrobp.2012.03.033
PMCID: PMC4312108  PMID: 22592050
total marrow irradiation; bone marrow transplantation; total body irradiation; tomotherapy; acute leukemia
2.  miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway 
eLife  2014;3:e01977.
MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.
DOI: http://dx.doi.org/10.7554/eLife.01977.001
eLife digest
Messenger RNA molecules take the information encoded in a gene's DNA sequence and turn it into instructions for building a protein. However, if certain smaller molecules of RNA—called microRNAs—bind to a messenger RNA molecule, they ‘silence’ it, which prevents the information in the messenger RNA from being translated to make a protein.
Despite their small size, microRNAs are very powerful. These molecules are able to simultaneously inhibit the translation of hundreds of messenger RNAs and perform many roles, including controlling cell growth and maintaining populations of stem cells. Furthermore, microRNAs have been linked to different aspects of the growth of cancerous cells. Certain microRNAs appear to suppress tumors by regulating the growth of the stem cells found there, while others appear to be ‘hyperactive’ in cancers—including breast cancer, colon cancer, and blood cancer.
In 2009, researchers compared the amount of microRNA in breast cancer stem cells that are highly capable of forming tumors with the amount in other cancer cells within the same tumor. Amongst other differences, two microRNAs (called miR-142 and miR-150) were found to be hyperactive in human breast cancer stem cells. One of them, miR-142, is known to target a gene called APC that inhibits the renewal of normal stem cells. Mutations in the APC gene have been linked to colon cancer, and scientists have suggested that the mutations inactivate APC in cancer cells to promote unregulated cell growth. Breast tumors rarely have mutations in the APC gene, but Isobe et al. wondered whether microRNAs that target this gene might also promote the growth of these tumor cells.
Isobe et al.—including several of the researchers involved in the 2009 work—show that miR-142 does target the APC gene in human breast cancer stem cells, and silences it. With the gene silenced, a cancer-promoting pathway turns on and more miR-150 is made. Increasing the amount of either miR-142 or miR-150 causes excessive cell growth in breast tissue and can form abnormal breast tissue in mice. Reducing the amount of miR-142 in human breast cancer stem cells slows the growth of breast tumors.
Although they only make up a small population of human breast cancer cells, focusing on breast cancer stem cells could uncover the cancer-promoting pathways that are activated in human breast cancers.
DOI: http://dx.doi.org/10.7554/eLife.01977.002
doi:10.7554/eLife.01977
PMCID: PMC4235011  PMID: 25406066
breast cancer; cancer stem cells; miR-142; miR-150; APC; WNT signaling pathway; human; mouse
3.  Barriers to Treatment in Patients With Locally Advanced Breast Cancer 
Delays between presentation and treatment could have a significant effect on breast cancer mortality. The authors hypothesized that patient, physician, and system barriers are all responsible for treatment delays. Therefore, a study was conducted to define prevalent barriers to treatment from the patient’s perspective. A modified 43-item Likert-scale questionnaire was administered to patients with clinical stage III locally advanced breast cancer (LABC) who had experienced a delay in treatment of 3 months or more. Between October 2008 and January 2010, 153 patients presented with LABC; 43 patients (28.1%) met eligibility, and 40 completed the questionnaire. Among the patient barriers reported, 38% of patients delayed care for fear of losing their breast and 47% awaited previously scheduled routine appointments instead of seeking care. Among the physician barriers reported, 20% of physicians of initial contact did not believe the breast lump/symptom was related to cancer and 15% did not believe it needed a biopsy. Among the system barriers reported, the most prevalent were delays in performing diagnostic tests and obtaining insurance authorization for tests, treatment, or physician visits. Substantial delays were seen in 28.1% of patients from presentation to when they sought therapy at City of Hope Comprehensive Cancer Center. The high prevalence of patient barriers versus physician/system barriers suggests that increased educational efforts for patients and health care professionals are needed.
PMCID: PMC4159358  PMID: 24142820
4.  Analysis of Circulating Tumor Cells in Breast Cancer 
Over the past few decades, substantial progress has been made in the diagnosis and treatment of breast cancer. Early identification of relapsed and metastatic disease has been a primary focus of ongoing research. Circulating tumor cells (CTCs) are implicated as harbingers of metastases. With advances in detection technologies, CTCs offer the option for real-time liquid biopsies. Methods to identify CTCs in the bloodstream by physical or biochemical properties, although feasible, still require improvements to promote widespread, reproducible use. Sufficient data support enumeration and assessment of changes in the number of CTCs as prognostic indicators, but controversy around their predictive utility for selecting treatments remains. As the technology to detect CTCs and characterize their heterogeneous molecular profile evolves, additional information will likely be obtained to guide targeted and individualized therapies.
PMCID: PMC4159355  PMID: 23946176
5.  Enrollment onto breast cancer therapeutic clinical trials: A tertiary cancer center experience 
Applied nursing research : ANR  2013;26(3):133-135.
Background
Advances in breast cancer prevention, diagnosis, and treatment are in part the result of patient involvement in clinical trials. Despite increases in new clinical research initiatives and trials open to accrual, only 2–3% of women with breast cancer enroll. There is a need to identify the barriers interfering patient accrual.
Methods
Data were extracted from patients with breast cancer seen for treatment in 2009 retrospectively. Descriptive analysis of patient demographic on enrollment were performed using logistic regression analyses.
Results
Of 418 patients evaluated for treatment, 163 had a trial available; 138 of these were eligible. Eighty (58%) participated in a clinical trial; the remainder declined (24%) or were not presented for a trial by their treating physicians (76%). Age, preferred language, marital status, family history, or race/ethnicity did not predict for enrollment on a therapeutic clinical trial. Patients with stage II or III breast cancer were more likely to be enrolled on a trial compared to patients with stage 0 or I (odds ratio 2.89, 9.17; p=.02, .0005 respectively).
Conclusions
Enrollment of breast cancer patients on therapeutic clinical trials was relatively high (58% eligible, 19% overall). Prospective studies observing breast cancer stage, clinical trial design, and inclusion of community based physician practices would add breadth to the understanding of poor accrual to breast cancer clinical trials.
doi:10.1016/j.apnr.2013.01.003
PMCID: PMC3748286  PMID: 23490340
Breast cancer; Clinical trials; Cancer prevention; Clinical trial accrual; Trial barriers; Accrual
6.  Breast Cancer, Version 3.2013 
These NCCN Guidelines Insights highlight the important updates specific to the management of HER2-positive metastatic breast cancer in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer. These include new first-line and subsequent therapy options for patients with HER2-positive metastatic breast cancer.
PMCID: PMC3991132  PMID: 23847214
7.  Second primary malignancies after autologous hematopoietic cell transplantation for multiple myeloma 
Recent studies demonstrate an increased risk of second primary malignancies (SPM) in multiple myeloma (MM) patients on maintenance lenalidomide following autologous stem cell transplantation (ASCT). There may be other risk factors driving SPM post-ASCT in MM, so we explored this possibility through analysis of our large transplant database in conjunction with our long-term followup program. We conducted a retrospective cohort study of 841 consecutive MM patients who underwent ASCT from 1989–2009 at City of Hope, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during and after ASCT. Median length of follow-up for the entire cohort was 3.4 years (range 0.3–19.9). Sixty cases with seventy SPM were identified. The overall cumulative incidence of SPM was 7.4% at five years and 15.9% at ten years if non-melanoma skin cancers (NMSCs) were included, and 5.3% at 5 years and 11.2% at 10 years if NMSCs were excluded. Multivariate analysis of the entire cohort revealed association of both older age (≥55yrs) (RR 2.3 p<0.004) and race (non-Hispanic white) (RR 2.4 p=0.01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend towards increased risk (OR=3.5, p=0.15); however, not enough patients were treated with lenalidomide to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables, but was accompanied with loss of statistical significance. This large single-institution analysis identified race and older age to be associated with increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that may not be restricted to lenalidomide.
doi:10.1016/j.bbmt.2012.09.023
PMCID: PMC3553262  PMID: 23073267
second primary malignancy; transplantation; myeloma
8.  Image Guided Total Marrow Irradiation (TMI) Using Helical TomoTherapy in Patients with Multiple Myeloma and Acute Leukemia Undergoing Hematopoietic Cell Transplantation (HCT) 
Purpose
TBI plays an important role in patients undergoing HCT, but is associated with significant toxicities. Targeted TBI using helical tomotherapy (HT) results in reduced doses to normal organs, which predict for reduced toxicities compared to standard TBI.
Methods and Materials
Thirteen patients with multiple myeloma (MM) were treated on an autologous tandem transplant Phase I trial with high dose melphalan, followed 6 weeks later by TMI to skeletal bone. Doses levels were 10, 12, 14, and 16 Gy at 2 Gy QD/BID. On a separate allogeneic HCT trial, 8 patients (5 AML, 1 ALL, 1 NHL, 1 MM) were treated with TMI+TLI + splenic RT to 12 Gy (1.5 Gy BID) combined with fludarabine/melphalan.
Results
For the 13 patients on the tandem autoHCT trial, median age was 54 (42–66). Median organ doses were 15–65% that of the GTV dose. Grade 1–2 acute toxicities were primarily observed. Six reported no vomiting, 9 no mucositis, 6 no fatigue, and 8 no diarrhea. For the 8 patients on the alloHCT trial, the median age was 52 (24–61). Grade 2–3 nausea, vomiting, mucositis and diarrhea were observed. On both trials no grade 4 non-hematologic toxicity was observed and all patients engrafted successfully.
Conclusions
This study demonstrates that TMI using HT is clinically feasible. Reduced acute toxicities observed compare favorably to those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI containing regimens to patients unable to tolerate standard approaches.
doi:10.1016/j.ijrobp.2008.04.071
PMCID: PMC3896447  PMID: 18786784
helical tomotherapy; IMRT; bone marrow transplantation; multiple myeloma; leukemia
9.  Late Relapses Following Reduced Intensity Allogeneic Transplantation in Patients with Multiple Myeloma: a long-term follow-up study 
British journal of haematology  2012;160(2):199-206.
SUMMARY
We analysed the long-term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu-mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high-dose melphalan conditioning for autograft followed by low-dose total body irradiation conditioning for allogeneic HCT (auto-allo regimen). Donors included human leucocyte antigen-matched siblings (n=55) or matched unrelated donors (n=5). With a median follow-up of 9.8 years, 7-year overall survival (OS) and progression-free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft-versus-host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post-transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, 5 had normal karyotypes, and 5 were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.
doi:10.1111/bjh.12123
PMCID: PMC3542410  PMID: 23151215
multiple myeloma; reduced intensity; allogeneic; tandem auto-allo; transplantation
10.  A phase II study of docetaxel and vinorelbine plus filgrastim for HER-2 negative, stage IV breast cancer: SWOG S0102 
Docetaxel and vinorelbine have demonstrated Single-agent activity in breast cancer. Preclinical studies suggest potential synergy between these antitubulin chemotherapy agents. This study evaluates these drugs in combination in metastatic breast cancer. Taxane-naive patients with HER-2 negative, stage IV breast cancer without prior chemotherapy for metastatic disease, were eligible. Docetaxel (60 mg/m2) was given intravenously on Day 1, vinorelbine (27.5 mg/m2) intravenously on Days 8 and 15, and filgrastim on Days 2–21 of a 21-day cycle. The primary study outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate (RR), and toxicity. Of 95 patients registered, 92 were eligible and received treatment. One-year OS was 74 % (95 % CI 64–82 %) with a median OS of 22.3 months (95 % CI 18.8–31.4 months). One-year PFS was 34 % (95 % CI 24–43 %) with median of 7.2 months (95 % CI 6.4–10.3). OS at 2 and 3 years were 49 % (95 % CI 38–59 %) and 30 % (95 % CI 21–40 %), respectively. OS was poorer for women with estrogen-receptor negative disease (n = 32) compared to estrogen-receptor positive (n = 60) (log-rank p = 0.031), but PFS was not significantly different (p = 0.11). RR was 59 % among the 74 patients with measurable disease. Grade 3 and 4 adverse events were 48 and 16 %, respectively. Grade 4 neutropenia was 12 % and grade 3/4 febrile neutropenia was 3 %. Common grade 3/4 nonhematologic toxicities were fatigue (14 %), pneumonitis (10 %), and dyspnea (9 %). The combination of docetaxel and vinorelbine is an active first-line chemotherapy in HER-2 nonoverexpressing, metastatic breast cancer. This combination is associated with significant hematologic and nonhematologic toxicity. The safety profile and expense of the filgrastim limit recommendations for routine use.
doi:10.1007/s10549-013-2797-2
PMCID: PMC3889983  PMID: 24352574
Breast cancer; Vinorelbine; Docetaxel; Metastatic
11.  Conditional Survival and Cause-specific Mortality after Autologous Hematopoietic Cell Transplantation for Hematological Malignancies 
Leukemia  2012;27(5):1139-1145.
The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but is not known for aHCT populations. We determined disease-, and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies; and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 and 50% at 10 years from aHCT. On the other hand, 5-year relative survival was 70%, 75%, 81%, and 88% after having survived 1, 2, 5, and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95%CI=13.1–14.8). The risk of death approached that of the general population for 10-year survivors (SMR=1.4, 95%CI=0.9–1.9), with the exception of female Hodgkin lymphoma patients transplanted before 1995 at age 40 years or younger (SMR=6.0, 95%CI=1.9–14.0). Among those who had survived 10 years, non-relapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.
doi:10.1038/leu.2012.311
PMCID: PMC3776451  PMID: 23183426
conditional survival; autologous HCT; cause-specific mortality
12.  Metastatic Breast Cancer, Version 1.2012 
These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option.
PMCID: PMC3753191  PMID: 22773798
13.  Total Marrow Irradiation: A New Ablative Regimen as Part of Tandem Autologous Stem Cell Transplantation for Patients with Multiple Myeloma 
Purpose
To establish feasibility, maximum tolerated dose, and potential efficacy of ablative dose total marrow irradiation (TMI) delivered by helical tomotherapy, in patients with multiple myeloma (MM).
Experimental Design
Patients with responding or stable MM received tandem autologous transplants (TASCT), first with melphalan 200 mg/m2, and ≥ 60 days later, with TMI. TMI doses were to be escalated from 1000 cGy, by increments of 200 cGy. All patients received thalidomide and dexamethasone maintenance.
Results
Twenty two of 25 enrolled patients (79%) received TASCT: TMI was administered a median of 63.5 days (44–119) after melphalan. Dose limiting toxicities at level 5 (1800 cGy) included reversible grade 3 pneumonitis, congestive heart failure, and enteritis (1), and grade 3 hypotension (1). The estimated median radiation dose to normal organs was 11–81% of the prescribed marrow dose. Late toxicities included reversible enteritis (1), and lower extremity deep venous thrombosis during maintenance therapy (2). The complete and very good partial response rates were 55% and 27%, following TASCT and maintenance therapy. At a median of 35 months of follow-up (21-50+ months) progression-free and overall survival for all patients are 49 % (95% CI 0.27-0.71) and 82% (0.67-1.00).
Conclusion
Ablative dose TMI as part of TASCT is feasible, and the complete response rate is encouraging. Careful monitoring of late toxicities is needed. Further assessment of this modality is justified at the 1600 cGy maximum tolerated dose level in MM patients who are candidates for ASCT.
doi:10.1158/1078-0432.CCR-10-1912
PMCID: PMC3717559  PMID: 21047977
multiple myeloma; total marrow irradiation; tandem autologous transplantation
14.  CCL2 mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells 
Cancer Research  2012;72(11):2768-2779.
Cancer stem cells (CSCs) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer (BC) stem cells. We found that compared to normal fibroblasts, primary cancer-associated fibroblasts (CAFs) and fibroblasts activated by co-cultured BC cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in BC cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse BC-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in BC cells, constituting a “cancer-stroma-cancer” signaling circuit. In a xenograft model of paired fibroblasts and BC tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary BCs, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.
doi:10.1158/0008-5472.CAN-11-3567
PMCID: PMC3367125  PMID: 22472119
breast cancer; cancer stem cells; chemokine (C-C motif) ligand 2; tumor microenvironment; stromal fibroblasts
15.  Role of SMC1 in Overcoming Drug Resistance in Triple Negative Breast Cancer 
PLoS ONE  2013;8(5):e64338.
Triple-negative breast cancer (TNBC) is one of the hardest subtypes of breast cancer to treat due to the heterogeneity of the disease and absence of well-defined molecular targets. Emerging evidence has shown the role of cohesin in the formation and progression of various cancers including colon and lung cancer but the role of cohesin in breast cancer remains elusive. Our data showed that structural maintenance of chromosome 1 (SMC1), a subunit of the cohesin protein complex, is differentially overexpressed both at RNA and protein level in a panel of TNBC cell lines as compared to normal epithelial or luminal breast cancer cells, suggesting that the amplified product of this normal gene may play role in tumorigenesis in TNBC. In addition, our results show that induced overexpression of SMC1 through transient transfection enhanced cell migration and anchorage independent growth while its suppression with targeted small interfering RNA (siRNA) reduced the migration ability of TNBC cells. Increased expression of SMC1 also lead to increase in the mesenchymal marker vimentin and decrease in the normal epithelial marker, E-cadherin. Immunocytochemical studies along with flow cytometry and cell fractionation showed the localization of SMC1 in the nucleus, cytoplasm and also in the plasma membrane. The knockdown of SMC1 by siRNA sensitized the TNBC cells towards a PARP inhibitor (ABT-888) and IC50 was approximately three fold less than ABT-888 alone. The cytotoxic effect of combination of SMC1 suppression and ABT-888 was also confirmed by the colony propagation assay. Taken together, these studies report for the first time that SMC1 is overexpressed in TNBC cells where it plays a role in cell migration and drug sensitivity, and thus provides a potential therapeutic target for this highly invasive breast cancer subtype.
doi:10.1371/journal.pone.0064338
PMCID: PMC3661439  PMID: 23717600
16.  Tandem Autologous versus Single Autologous Transplantation Followed by Allogeneic Hematopoietic Cell Transplantation for Patients with Multiple Myeloma: Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial 
The lancet oncology  2011;12(13):1195-1203.
Background
Autologous hematopoietic cell transplantation (HCT) improves survival in patients with multiple myeloma, but disease progression remains a challenge. Allogeneic HCT (alloHCT) has the potential to reduce disease progression through graft-versus-myeloma effects. The aim of the BMT CTN 0102 trial was to compare outcomes of autologous HCT (autoHCT) followed by alloHCT with non-myeloablative conditioning (auto-allo) to tandem autoHCT (auto-auto) in patients with standard risk myeloma. Patients in the auto-auto arm were randomized to one year of thalidomide and dexamethasone (Thal-Dex) maintenance therapy or observation (Obs).
Methods
Patients with multiple myeloma within 10 months from initiation of induction therapy were classified as standard (SRD) or high risk (HRD) disease based on cytogenetics and beta-2-microglobulin levels. Assignment to auto-allo HCT was based on availability of an HLA-matched sibling donor. Primary endpoint was three-year progression-free survival (PFS) according to intent-to-treat analysis.
Results
710 patients were enrolled completed a minimum of 3-year follow up. Among 625 SRD patients, 189 and 436 were assigned to auto-allo and auto-auto, respectively. Seventeen percent (33/189) of SR patients in the auto-allo arm and 16% (70/436) in the auto-auto arm did not receive a second transplant. Thal-Dex was not completed in 77% (168/217) of assigned patients. PFS and overall survival (OS) did not differ between the Thal-Dex (49%, 80%) and Obs (41%, 81%) cohorts and these two arms were pooled for analysis. Three year PFS was 43% and 46% (p=0·671) and three-year OS was 77% and 80 % (p=0·191) with auto-allo and auto-auto, respectively. Corresponding progression/relapse rates were 46% and 50% (p=0·402); treatment-related mortality rates were 11% and 4% (p<0·001), respectively. Auto/allo patients with chronic graft-vs-host disease had a decreased risk of relapse. Most common grade 3 to 5 adverse events in auto-allo was hypebilirubenemia (21/189) and in the auto-auto was peripheral neuropathy (52/436). Among 85 HRD patients (37 auto-allo), three PFS was 40% and 33% (p=0·743) and three-year OS was 59% and 67% (p=0·460) with auto-allo and auto-auto, respectively.
Conclusion
Thal-Dex maintenance was associated with poor compliance and did not improve PFS or OS. At three years there was no improvement in PFS or OS with auto-allo compared to auto-auto transplantation in patients with standard risk myeloma. Decisions to proceed with alloHCT after an autoHCT in patients with standard risk myeloma should take into consideration results of the current trial. Future investigation of alloHCT in myeloma should focus to minimize TRM and maximize graft-versus myeloma effects. This trial was registered in Clinicaltrials.gov (NCT00075829) and was funded by the National Heart, Lung and Blood Institute and National Cancer Institute.
doi:10.1016/S1470-2045(11)70243-1
PMCID: PMC3611089  PMID: 21962393
18.  A Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid, -SAHA) in Metastatic Breast Cancer: A California Cancer Consortium Study 
Purpose
The primary goal of this trial was to determine the response rate of single-agent vorinostat in patients with metastatic breast cancer. The secondary goals included assessment of time to progression, evaluation of toxicities, and overall survival.
Experimental Design
From June 2005 to March 2006, fourteen patients received vorinostat, 200 mg orally, twice daily for 14 days of each 21 day cycle. Response and progression were evaluated using RECIST criteria.
Results
The median age for all patients was 60.5 years (range: 37–88). Eight patients were ER and/or PR positive, four were Her-2 positive. Sites of metastatic disease included brain, liver, lungs, bones, pelvis, pleura, chest wall, and distant lymph nodes. Patients received a median of 1.5 prior (range: 0–2) chemotherapeutic regimens for metastatic disease. Fatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically significant adverse effects. The median number of cycles delivered was two (range: 1–20). There were no complete or partial responses and the study was terminated after the first stage, however 4 patients were observed with stable disease with time to progression of 4,8,9 and 14 months. The median number of months that patients received treatment on this study was 1.7 (range: 0.5–14).
Conclusion
While not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken.
doi:10.1158/1078-0432.CCR-08-0122
PMCID: PMC3543872  PMID: 18981013
19.  Combining Emerging Agents in Advanced Breast Cancer 
The Oncologist  2011;16(6):760-771.
Data and ongoing research on new cytotoxic and targeted therapies for the treatment of patients with metastatic breast cancer are outlined, and new developments regarding approved but relatively new classes of cytotoxic and targeted agents and also new classes of targeted therapy that are undergoing clinical evaluation are highlighted.
Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability.
doi:10.1634/theoncologist.2010-0345
PMCID: PMC3228217  PMID: 21543509
Metastatic breast cancer; Combination therapy; Targeted therapy; Monoclonal antibodies; Small-molecule inhibitors
20.  De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer 
Background
MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome.
Methods
The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers.
Results
More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients.
Conclusions
Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.
doi:10.1186/1479-5876-10-42
PMCID: PMC3342150  PMID: 22400902
Breast cancer; miRNA; Biomarker; Neoadjuvant chemotherapy; Metastasis
21.  Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors 
Purpose
This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.
Methods
Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1–3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.
Results
Seventeen patients received 39 cycles of treatment: median 2, (range 1–5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60–90%) and age: 52 (range 24–75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4% (range 15.1–59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02–3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2–5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.
Conclusions
The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.
doi:10.1007/s00280-010-1242-z
PMCID: PMC3265324  PMID: 20107803
Topotecan; Carboplatin; Tamoxifen; Brain tumors; Chemotherapy
22.  Papillary Carcinoma of the Breast: An Overview 
Papillary carcinoma of the breast represents approximately 0.5% of all newly diagnosed cases of breast cancer. The prevalence of both invasive and in situ papillary carcinoma seems to be greater older postmenopausal women, and -in relative terms-in males. Histologic features of the tumor include cellular proliferations surrounding fibrovascular cores, with or without invasion. In this review, characteristics of both in situ and invasive disease are outlined. Immunohistochemical analyses of papillary carcinoma suggest the utility of markers such as smooth muscle myosin heavy chain, calponin, p63 and high molecular weight keratins, which can characterize the myoepithelial cell layer. With respect to radiographic evaluation of papillary carcinoma, ultrasonography is the most extensively studied imaging modality, though magnetic resonance mammography has potential utility. Available data suggest improved outcome for papillary carcinoma as compared to invasive ductal carcinoma. Treatment-related information for patients with papillary carcinoma is limited, and patterns noted in available series suggest a variable approach to this disease. The scarcity of information underscores the need for further treatment- and outcome-related studies in papillary carcinoma of the breast.
doi:10.1007/s10549-010-0961-5
PMCID: PMC3244819  PMID: 20524058
papillary; breast carcinoma; male breast cancer; breast ultrasonography; breast magnetic resonance mammography
23.  A Pretherapy Biodistribution and Dosimetry Study of Indium-111-Radiolabeled Trastuzumab in Patients with Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer 
Abstract
Purpose
The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of 111Indium (111In)-MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether 90Y-MxDTPA-trastuzumab should be evaluated in subsequent clinical therapy trials.
Experimental Design
Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4–8 mg/kg IV), followed 4 hours later by 5 mCi 111In-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days.
Results
Eight (8) patients received 111In-MxDTPA-trastuzumab, which was well tolerated with no adverse side-effects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No antiantibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with 90Y were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi.
Conclusions
In summary, results from this study indicate that 90Y-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to 111In-MxDTPA-trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other 90Y-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose-limiting cardiotoxicity.
doi:10.1089/cbr.2010.0783
PMCID: PMC2958439  PMID: 20707718
breast cancer; indium-111; radioimmunotherapy; radiolabeled antibody; trastuzumab
24.  Diffuse Large B-Cell Lymphoma with Calf Muscle Localization 
Case Reports in Hematology  2011;2011:292494.
Although diffuse large B-cell lymphoma (DLBCL) usually occurs in the lymph nodes, approximately 30–40% of the time it can have an extranodal site of involvement and it can arise in nearly every body site such as intestine, bone, breast, liver, skin, lung, and central nervous system. Muscle involvement of DLBCL is especially uncommon, comprising 0.5% of extranodal NHL. We report a case of a 72-year-old man with extranodal DLBCL of a unique manifestation in the calf muscle, involving predominantly the gastrocnemius muscle. The patient achieved complete response and remained free of local recurrence or metastasis following diagnosis.
doi:10.1155/2011/292494
PMCID: PMC3420606  PMID: 22937305
25.  Stat3-induced S1PR1 expression is critical for persistent Stat3 activation in tumors 
Nature medicine  2010;16(12):1421-1428.
IL-6/Jak2 signaling is viewed critical for persistent Stat3 activation in cancer. However, IL-6-induced Stat3 activity is transient in normal physiology. Here we identify a mechanism important for persistent Stat3 activation in tumor cells and the tumor microenvironment. We show that sphingosine-1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor for lysophospholipid sphingosine-1-phosphate (S1P), is elevated in Stat3-positive tumors. Stat3 is a transcription factor for the S1pr1 gene. Enhanced S1pr1 expression activates Stat3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis. Conversely, silencing S1pr1 in tumor cells or immune cells inhibits tumor Stat3 activity, tumor growth and metastasis. S1P/S1PR1-induced Stat3 activation is persistent, in contrast to transient Stat3 activation by IL-6. S1PR1 activates Stat3 in part by upregulating Jak2 tyrosine kinase activity. We demonstrate that Stat3-induced S1pr1 expression, as well as S1P/S1PR1 pathway, is important for persistent Stat3 activation in cancer cells and the tumor microenvironment and for malignant progression.
doi:10.1038/nm.2250
PMCID: PMC3088498  PMID: 21102457

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