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1.  Assessment of the Hematopoietic Cell Transplantation Comorbidity Index in Non-Hodgkin Lymphoma Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation 
The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell–replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy (P = .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor (P < .0001) relative to OS, and there was a trend (P = .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.
PMCID: PMC2842937  PMID: 19167682
Comorbidity index; Non-Hodgkin lymphoma; Reduced intensity conditioning; Allogeneic
2.  Cediranib for Metastatic Alveolar Soft Part Sarcoma 
Journal of Clinical Oncology  2013;31(18):2296-2302.
Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs).
Patients and Methods
We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.
Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis.
In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.
PMCID: PMC3677840  PMID: 23630200
3.  Phase II Study of Bevacizumab in Patients With HIV-Associated Kaposi's Sarcoma Receiving Antiretroviral Therapy 
Journal of Clinical Oncology  2012;30(13):1476-1483.
Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti–VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS.
Patients and Methods
Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately.
Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T1), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2).
Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients.
PMCID: PMC3383119  PMID: 22430271
4.  Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies  
Journal of Clinical Oncology  2012;30(8):830-836.
There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R).
Patients and Methods
One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4+ count < 200/μL) or progressive disease.
Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3+ (P < .001), CD4+ (P < .001), and CD8+ (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001).
DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.
PMCID: PMC3295571  PMID: 22312100
5.  Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma 
Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.
Experimental Design
We conducted a phase I/II trial of vandetanib for children (5–12 years) and adolescents (13–18 years) with MTC to define a recommended dose and assess anti-tumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28 day treatment cycles. The dose could be escalated to 150 mg/m2/d after 2 cycles. Radiographic response to vandetanib was quantified using RECIST(v1.0), biomarker response was measured by comparing post-treatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient reported outcome was used to assess clinical benefit.
Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2–52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n=15) the confirmed objective partial response rate was 47% (exact 95%CI, 21%, 75%). Biomarker partial response was confirmed for calcitonin in twelve subjects and for CEA in eight subjects.
Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.
PMCID: PMC4274128  PMID: 23766359
MEN2B; Medullary Thyroid Carcinoma; Phase 1/2 Trial; Rare Disease; Vandetanib
6.  Pre-immature dendritic cells (PIDC) pulsed with HPV16 E6 or E7 peptide are capable of eliciting specific immune response in patients with advanced cervical cancer 
The protein products of the early genes E6 and E7 in high-risk HPV types 16 and 18 have been implicated in the oncogenic capability of these viruses. Therefore, these peptides represent attractive vaccine therapy targets.
Thirty-two patients with advanced cervical cancer (HPV16 or 18 positive) were treated with HPV16 E6 (18–26) (Arm A) or HPV16 E7 (12–20) peptide (Arm B) pulsed on PBMCs in order to illicit immune response against the relevant peptide on both arms. These PBMCs were cultured for a short time (48 hours only) and in the presence of GM- CSF, accordingly, they were identified as “Pre-Immature Dentritic Cells”.
51Cr release assay and ELISPOT demonstrated evidence of specific immune response against the relevant peptide in 10/16 (63%) evaluable patients in arm A and 7/12 (58%) in arm B. HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro. The median overall survival (OS) and progression free survival (PFS) for the full cohort was 10.0 and 3.5 months, respectively. There were no RECIST responses in any patient. The majority of toxicities were grade I and II.
We demonstrated the feasibility and ability of Pre-Immature Dentritic Cells pulsed with HPV16 E6 (18–26) or HPV16 E7 (12–20) to induce a specific immune response against the relevant peptide despite the advanced disease of the cervical cancer patients treated on this trial. We believe that this observation deserves further investigations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0353-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4269078  PMID: 25510844
Dendritic cells; HPV16; E6; E7; Vaccine; Cervical cancer
7.  Active thrombopoiesis is associated with worse severity and activity of chronic graft-versus-host disease 
Bone marrow transplantation  2013;48(12):1569-1573.
Chronic graft-versus-host disease (cGvHD) is a major complication of allogeneic hematopoietic stem cell transplantation. Post-transplant thrombocytopenia in patients with cGvHD has been associated with poor outcome and its etiology is unclear. We investigated whether thrombopoiesis, assessed via measurement of the absolute immature platelet number (AIPN) in the blood, is impaired in cGVHD, and whether the level of thrombopoiesis correlates with the severity and activity of cGvHD as assessed via the NIH organ scoring system. We utilized a cohort of 110 well-characterized cGVHD patients, including 83 (75%) with severe cGVHD per NIH global score. Higher AIPN was associated with active therapeutic intent (p=0.026), lower Karnofsky score (p=0.0013), worse joint/fascia cGVHD (p=0.0005) and worse skin cGVHD (p=0.0044). AIPN correlated with platelet counts and was not correlated with ANC, WBC, CRP, ALC, albumin, total and average NIH scores, or number of prior systemic therapies. AIPN values for cGvHD patients substantially overlapped those of the normal population. Higher AIPN, as marker of active thrombopoiesisis, was associated with worse severity and activity of cGVHD, especially skin and joints/fascia manifestations. Among patients with stable moderate or severe cGVHD, there was no evidence of hypo production of platelets. Future studies should further investigate the role of thrombopoiesis in cGVHD.
PMCID: PMC4166478  PMID: 23832091
Chronic GVHD; NIH score; platelets; AIPN
8.  Phase II Study of Satraplatin and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer: A Pharmacogenetic Assessment of Outcome and Toxicity 
Clinical genitourinary cancer  2013;11(3):229-237.
Genetic polymorphisms in DNA repair enzymes (excision repair cross-complementing group 1 [ERCC1] and x-ray cross-complementing group 1 [XRCC1]) may predict treatment outcome and response to platinum-based treatment. Twenty-four patients were enrolled in this single-arm study to assess the association between ERCC1 and XRCC1 gene variants and treatment outcomes with satraplatin in patients with docetaxel-refractory metastatic castration-resistant prostate cancer.
We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy.
Patients and Methods
Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity.
After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS.
To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin.
PMCID: PMC3758779  PMID: 23684781
ERCC1; Genotyping; Prostate cancer; Satraplatin; XRCC1
9.  Effects of Rapid Donor T-lymphocyte Engraftment on Disease Control and Graft versus Host Disease in Persons Undergoing Reduced-Intensity Conditioning Allotransplantation for Advanced CLL 
Experimental hematology  2013;41(9):772-778.
Eradication of minimal residual disease (MRD) after allotransplantation in persons with chronic lymphocytic leukemia (CLL) is associated with lower rates of relapse. Rapid engraftment of donor lymphocyte elements may contribute to MRD control but it remains unclear if this strategy will benefit patients. Here we report incidence of MRD eradication and graft versus host disease (GvHD) in persons with rapid versus later donor T-lymphocyte engraftment after lymphodepleting chemotherapy and reduced intensity conditioning (RIC) allotransplantation. Twenty-seven subjects received lymphodepleting chemotherapy to facilitate donor engraftment followed by fludarabine and cyclophosphamide RIC and a blood cell allograft. MRD was monitored by multicolor flow cytometry post transplantation. Complete donor T-lymphoid (TLC) and myeloid (MC) chimerism were achieved in 25 subjects at a median of 28 days (range 14–60 days) and 21 days (range 14–180 days). Achieving complete donor TLC by day 14 versus day ≥28 correlated with occurrence of ≥grade-2 acute GvHD (90% [95% confidence interval (CI), 78–100%] versus 35% [95% CI, 16–54%], P=0.014) and better control of minimal residual disease in the bone marrow at day 100, median 0% (range, 0–0.1%) versus 8.5% (range, 0–92%; P=0.016). Among 11 persons with early donor TLC none had progressive disease (PD) and 7 died of treatment related mortality (TRM). In persons with later development of TLC 8 of 16 had PD and 2 died of TRM. Time to donor myeloid chimerism had no impact on outcomes. Rapid establishment of donor TLC results in more complete eradication of early MRD but greater incidence of acute GvHD and TRM in persons with CLL undergoing RIC allotransplantation.
PMCID: PMC3769491  PMID: 23689118
Chronic lymphocytic leukemia; allogeneic transplantation; chimerism; reduced intensity conditioning
10.  Response after Surgical Resection of Metastatic Pheochromocytoma and Paraganglioma: Can Postoperative Biochemical Remission Be Predicted? 
Aggressive surgical resection with intent to cure and surgical debulking procedures are commonly recommended in patients with metastatic pheochromocytoma and paraganglioma. To date there are no data on operative outcomes of patients after surgical resection of metastatic pheochromocytoma and paraganglioma to determine if such an approach is appropriate and what factors may be associated with a favorable outcome.
Study Design
Retrospective analysis of 30 patients with metastatic pheochromocytoma/paraganglioma who underwent surgical treatment. Clinical characteristics and genetic factors were analyzed as predictors of biochemical response to surgery.
Thirty patients underwent a total of 42 operations with a median follow-up time of 24 months (range, 1 to 114). Complete disease resection (R0/R1) was achieved in 18 (42.9%) cases, while 24 cases (57.1%) were debulking (R2) procedures without intent to cure. Complete biochemical remission was achieved in 10 (23.8%) cases and partial biochemical response was achieved in 23 (54.8%) cases. Patients with disease confined to the abdomen were more likely to achieve and maintain a biochemical response postoperatively than those with extra-abdominal disease (P = 0.0003). Debulking operations were significantly less likely to achieve or maintain biochemical palliation, with only 1 patient maintaining a biochemical response 12 months postoperatively (P < 0.0001). Patients were less likely to obtain pharmacologic independence following debulking (P = 0.0003), with only 2 (8.3%) not requiring pharmacotherapy six months after the intervention. Factors not associated with biochemical response to surgery include gender, family history, SDHB mutation status, systemic therapy, and preoperative biochemical profile.
Depending on the extent of disease, patients with metastatic pheochromocytoma/paraganglioma can benefit from aggressive operative intervention and resection with intent to cure. Debulking procedures are unlikely to achieve clinically significant biochemical response, with any biochemical response achieved being very short-lived.
PMCID: PMC3770940  PMID: 23891076
pheochromocytoma; paraganglioma; surgery; outcome; metastatic
11.  A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors 
Oncotarget  2014;5(18):8161-8172.
Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
PMCID: PMC4226674  PMID: 25327558
Nelfinavir; phase I clinical trial; AKT; endoplasmic reticulum stress; neuroendocrine
12.  Operative Management for Recurrent and Metastatic Adrenocortical Carcinoma 
Journal of surgical oncology  2011;105(7):709-713.
A review of all resections for recurrent or metastatic ACC was performed to identify patients who might benefit from a surgical approach, and to identify factors that might aid in prognosis among patients with metastatic disease.
Summary Background Data
Adrenocortical carcinoma (ACC) is a rare tumor, with frequent recurrences and metastases even after complete resection. Chemotherapy has limited efficacy, and surgical resection of metastatic ACC remains controversial.
A retrospective review was performed of all patients who underwent surgical intervention for metastatic ACC in a single tertiary center from 1977 to 2009. All available clinicopathologic data were analyzed to determine potential factors associated with response to treatment and survival.
Fifty-seven patients underwent 116 procedures for recurrent or metastatic disease. Twenty-three resections were for liver metastases, 48 for pulmonary metastases, 22 for abdominal disease including local recurrences, and 13 were for metastases at other sites. Median and 5-year survivals from time of first metastasectomy were 2.5 years, and 41%, respectively. The median survival of patients with DFI <12 months was 1.7 years, compared to 6.6 years for patients with DFI >12 months (P = 0.015). Median survival for right versus left-sided primaries was 1.9 years versus 3.8 years (P = 0.03). Liver metastases were more common with right-sided primaries (67% vs. 41%, P = 0.05). Chemotherapy had no impact on survival.
Resection of recurrent or metastatic ACC is safe, and may result in prolongation of survival in selected patients with DFI greater than 1 year.
PMCID: PMC4136651  PMID: 22189845
metastatic adrenocortical carcinoma; liver resection; lung resection
13.  Soluble CD27-pool in humans may contribute to T-cell activation and tumor immunity 
The interaction between CD27 and its ligand CD70 has been implicated in regulating cellular immune responses to cancer. Here we report on the role of soluble CD27 (sCD27) in T-cell activation and its elevation in the serum of cancer patients after immunotherapy. In vitro, sCD27 is preferentially derived from activated CD4+ T cells. Adding sCD27 to stimulated peripheral blood mononuclear cells increases T-cell activation and proliferation, and is associated with the immunological synapse-related proteins myosin IIA, HMGB1, and the TCR Vβ chain. The pool of serum sCD27 is shown to be greater in healthy donors than in cancer patients. However, metastatic cancer patients treated with immunotherapy showed a significant increase in the serum sCD27-pool post-therapy (p < 0.0005); there was also an increased trend towards an association between enhanced sCD27-pool post-therapy and overall survival (p = 0.022). The identification of sCD27 as an immune modulator associated with enhanced human T-cell activation in vitro and in vivo provides a rationale for developing new immunotherapeutic strategies aimed at enhancing sCD27 for treating cancer and potentially other diseases.
PMCID: PMC4084782  PMID: 23677477
Soluble CD27 (sCD27); CD27/CD70; T-cell activation; soluble factors; cancer vaccine; prostate cancer; immunotherapy; ipilimumab (anti-CTLA4); PROSTVAC
14.  Randomized Selection Design Trial Evaluating CD8+-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma 
Journal of Clinical Oncology  2013;31(17):2152-2159.
Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown.
Patients and Methods
Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points.
Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8+-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8+-enriched TILs responded.
A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8+-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.
PMCID: PMC3731980  PMID: 23650429
15.  Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer 
BJU international  2013;111(8):1269-1280.
To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy.
Patients and Methods
The study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months.
We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily.
In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib.
Endpoints included tumour response, progression-free survival (PFS), overall survival (OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and toxicity.
A total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens.
Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response.
At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively.
We found that the DCE-MRI variables baseline transport constant (Ktrans) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly.
The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities.
This study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy.
PMCID: PMC3660464  PMID: 23419134
castration-resistant prostate cancer; angiogenesis inhibitors; cediranib; AZD2171
16.  Low-Intensity Therapy in Adults with Burkitt’s Lymphoma 
The New England journal of medicine  2013;369(20):1915-1925.
Burkitt’s lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children.
We studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitt’s lymphoma. Two EPOCH-R regimens were tested: a standard dose-adjusted combination in human immunodeficiency virus (HIV)–negative patients (DA-EPOCH-R group) and a lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR group).
A total of 30 consecutive patients were treated; 19 patients were in the DA-EPOCH-R group, and 11 in the SC-EPOCH-RR group. The overall median age of the patients was 33 years, and 40% were 40 years of age or older; 73% of the patients had intermediate-risk disease, and 10% had high-risk disease. The principal toxic events, fever and neutropenia, were observed during 22% of the DA-EPOCH-R treatment cycles and 10% of the SC-EPOCH-RR treatment cycles. The tumor lysis syndrome developed in 1 patient; no treatment-related deaths occurred. The median cumulative doses of doxorubicin–etoposide and cyclophosphamide administered in the SC-EPOCH-RR group were 47% and 57% lower, respectively, than those administered in the DA-EPOCH-R group. With median follow-up times of 86 months in the DA-EPOCH-R group and 73 months in the SC-EPOCH-RR group, the rates of freedom from progression of disease and overall survival were, respectively, 95% and 100% with DA-EPOCH-R and 100% and 90% with SC-EPOCH-RR. None of the patients died from Burkitt’s lymphoma.
In this uncontrolled prospective study, low-intensity EPOCH-R–based treatment was highly effective in adults with sporadic or immunodeficiency-associated Burkitt’s lymphoma. (Funded by the National Cancer Institute; numbers, NCT00001337 and NCT00006436.)
PMCID: PMC3901044  PMID: 24224624
17.  The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors 
Mutant Ras oncogenes produce proteins that are unique to cancer cells and represent attractive targets for vaccine therapy. We have shown previously that vaccinating cancer patients with mutant ras peptides is feasible and capable of inducing a specific immune response against the relevant mutant proteins. Here, we tested the mutant ras peptide vaccine administered in combination with low dose interleukin-2 (IL-2) or/and granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to enhance the vaccine immune response.
5000μg of the corresponding mutant ras peptide was given subcutaneously (SQ) along with IL-2 (Arm A), GM-CSF (Arm B) or both (Arm C). IL-2 was given SQ at 6.0 million IU/m2/day starting at day 5, 5 days/week for 2 weeks. GM-CSF was given SQ in a dose of 100μg/day one day prior to each ras peptide vaccination for 4 days. Vaccines were repeated every 5 weeks on arm A and C, and every 4 weeks on arm B, for a maximum of 15 cycles or until disease progression.
We treated 53 advanced cancer patients (38 with colorectal, 11 with pancreatic, 1 with common bile duct and 3 with lung) on 3 different arms (16 on arm A, 18 on arm B, and 19 on arm C). The median progression free survival (PFS) and overall survival (OS) was 3.6 and 16.9 months, respectively, for all patients evaluable for clinical response (n = 48). There was no difference in PFS or OS between the three arms (P = 0.73 and 0.99, respectively). Most adverse events were grade 1-2 toxicities and resolved spontaneously. The vaccine induced an immune response to the relevant ras peptide in a total of 20 out of 37 evaluable patients (54%) by ELISPOT, proliferative assay, or both. While 92.3% of patients on arm B had a positive immune response, only 31% of patients on arm A and 36% of patients on arm C had positive immune responses (P = 0.003, Fisher’s exact test).
The reported data showed that IL-2 might have a negative effect on the specific immune response induced by the relevant mutant ras vaccine in patients with advanced cancer. This observation deserves further investigations.
Trial registration
PMCID: PMC3942063  PMID: 24565030
Ras; Peptide; Vaccine; IL-2; GM-CSF; Immune response
18.  The Statistics of Phase 0 Trials 
Statistics in medicine  2010;29(10):1072-1076.
The PD-driven phase 0 trial is a new form, designed to be a first-in-man study, often of a new agent, conducted to assess drug effect on a molecular target, by means of a pharmacodynamic (PD) assay, in a very small number (10–15) of patients. Such a study is meant to be a proof of principle trial to determine whether the agent yields the PD effect predicted by pre-clinical studies. The dosage is meant to be pharmacologically active, but neither toxic nor likely to yield clinical benefit. Such a trial may be used to serve as a very early test of an agent’s biologic effect, allowing for early weeding out of ineffective agents, or as an early means of determining the most promising of competing analogue agents. This manuscript will present designs for such PD-driven studies which are statistically efficient and rigorous, focusing on non-comparative trials. The phase 0 trial promises to become an increasingly important tool for facilitating and speeding the development of new therapeutic agents, particularly in oncology.
PMCID: PMC3902019  PMID: 20419759
19.  Interferon Regulatory Factor-8 Modulates the Development of Tumor-Induced CD11b+Gr-1+ Myeloid Cells 
Journal of cellular and molecular medicine  2009;13(0):10.1111/j.1582-4934.2009.00685.x.
Tumor-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumor progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b+ and Gr-1+ cell surface markers remains unclear. Because CD11b+Gr-1+ cells expand during progressive tumor growth, this suggests that tumor-induced events alter signaling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-γ regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumor-induced CD11b+Gr-1+ cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumor growth. In the 4T1 model, both splenic and bone marrow-derived CD11b+Gr-1+ cells of tumor-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumor-induced CD11b+Gr-1+ cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumor growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b+Gr-1+ cells were significantly lower in dTg mice when compared with single transgenic tumor-bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumor-induced development and/or accumulation of CD11b+Gr-1+ cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy.
PMCID: PMC3858838  PMID: 20196788
IRF-8; myeloid-derived suppressor cells; tumor progression; hematopoiesis
20.  Survey of Nursing Integration of Genomics Into Nursing Practice 
Translating clinically valid genomic discoveries into practice is hinged not only on technologic advances, but also on nurses—the largest global contingent of health providers—acquiring requisite competencies to apply these discoveries in clinical care. The study aim was to assess practicing nurse attitudes, practices, receptivity, confidence, and competency of integrating genomics into nursing practice.
A convenience sample of practicing nurses was recruited to complete an online survey that assessed domains from Roger’s Diffusion of Innovations Theory and used family history utilization as the basis for competency assessment.
Results were tabulated and analyzed using descriptive statistical techniques.
Two-hundred-thirty-nine licensed registered nurses, 22 to 72 years of age, with a median of 20 years in practice, responded, for an overall response rate of 28%. Most were White (83%), female (92%), and held baccalaureate degrees (56%). Seventy-one percent considered genetics to be very important to nursing practice; however, 81% rated their understanding of the genetics of common diseases as poor or fair. Per-question response rates varied widely. Instrument assessment indicated that modifications were necessary to decrease respondent burden.
Respondents’ perceived genomic competency was inadequate, family history was not routinely utilized in care delivery, and the extent of family history varied widely. However, most nurses indicated interest in pursuing continuing genomic education.
Clinical Relevance
Findings from this study can lead to the development of targeted education that will facilitate optimal workforce preparation for the ongoing influx of genetics and genomics information, technologies, and targeted therapies into the healthcare arena. This pilot study provides a foundation on which to build the next step, which includes a national nursing workforce study.
PMCID: PMC3515630  PMID: 23205780
21.  Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer 
Previous studies identified the human nonmetastatic gene 23 (NME1, hereafter Nm23-H1) as the first metastasis suppressor gene. An inverse relationship between Nm23-H1 and expression of lysophosphatidic acid receptor 1 gene (LPAR1, also known as EDG2 or hereafter LPA1) has also been reported. However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated.
The LPA1 inhibitor Debio-0719 or LPA1 short hairpinned RNA (shRNA) was used. Primary tumor size and metastasis were investigated using the 4T1 spontaneous metastasis mouse model and the MDA-MB-231T experimental metastasis mouse model (n = 13 mice per group). Proliferation and p38 intracellular signaling in tumors and cell lines were determined by immunohistochemistry and western blot to investigate the effects of LPA1 inhibition on metastatic dormancy. An analysis of variance-based two-tailed t test was used to determine a statistically significant difference between treatment groups.
In the 4T1 spontaneous metastasis mouse model, Debio-0719 inhibited the metastasis of 4T1 cells to the liver (mean = 25.2 liver metastases per histologic section for vehicle-treated mice vs 6.8 for Debio-0719-treated mice, 73.0% reduction, P < .001) and lungs (mean = 6.37 lesions per histologic section for vehicle-treated mice vs 0.73 for Debio-0719-treated mice, 88.5% reduction, P < .001), with no effect on primary tumor size. Similar results were observed using the MDA-MB-231T experimental pulmonary metastasis mouse model. LPA1 shRNA also inhibited metastasis but did not affect primary tumor size. In 4T1 metastases, but not primary tumors, expression of the proliferative markers Ki67 and pErk was reduced by Debio-0719, and phosphorylation of the p38 stress kinase was increased, indicative of metastatic dormancy.
The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor sites.
PMCID: PMC3611817  PMID: 22911670
22.  Molecular imaging of pediatric brain tumors: comparison of tumor metabolism using 18F-FDG-PET and MRSI 
Journal of neuro-oncology  2012;109(3):521-527.
Magnetic resonance spectroscopic imaging (MRSI) and 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) are non-invasive imaging techniques routinely used to evaluate tumor malignancy in adults with brain tumors. We compared the metabolic activity of pediatric brain tumors using FDG-PET and MRSI.
Children (n=37) diagnosed with a primary brain tumor underwent FDG-PET and MRSI within two weeks of each other. Tumor metabolism was classified as inactive, active or highly active using the maximum choline:N-acetyl-asparate (Cho:NAA) on MRSI and the highest tumor uptake on FDG-PET. A voxel-wise comparison was used to evaluate the area with the greatest abnormal metabolism. Agreement between methods was assessed using the percent agreement and the kappa statistic (κ).
Pediatric brain tumors were metabolically heterogeneous on FDG-PET and MRSI studies. Active tumor metabolism was observed more frequently using MRSI compared to FDG-PET, and agreement in tumor classification was weak (κ=0.16, p=0.12), with 42% agreement (95% CI= 25 – 61%). Voxel-wise comparison for identifying the area of greatest metabolic activity showed overlap in the majority (62%) of studies, though exact agreement between techniques was low (29.4%, 95% CI = 15.1 – 47.5%).
These results indicate that FDG-PET and MRSI detect similar but not always identical regions of tumor activity, and there is little agreement in the degree of tumor metabolic activity between the two techniques.
PMCID: PMC3482688  PMID: 22760419
pediatric; brain tumor; 18F-FDG-PET; MR spectroscopy; metabolism
23.  Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients 
Bone marrow transplantation  2012;48(2):269-277.
To enhance the therapeutic index of allogeneic hematopoietic stem cell transplantation (HSCT), we immunized ten HLA-matched sibling donors prior to stem cell collection with recipient-derived clonal myeloma immunoglobulin, idiotype (Id), as a tumor antigen, conjugated with keyhole limpet hemocyanin (KLH). Vaccinations were safe in donors and recipients. Donor-derived KLH- and Id-specific humoral and central and effector memory T cell responses were detectable by day 30 after HSCT and were boosted by post-transplant vaccinations at 3 months in most recipients. One patient died prior to booster vaccinations. Specifically, after completing treatment 8/9 myeloma recipients had persistent Id-specific immune responses and 5/9 had improvement in disease status. Although regulatory T cells increased after vaccination, they did not impact immune responses. At a median potential follow-up period of 74 months, six patients are alive, the 10 patients have a median progression-free survival of 28.5 months, and median overall survival has not been reached. Our results provide proof of principle that neoantigen and tumor antigen-specific humoral and cellular immunity could be safely induced in HSCT donors and passively transferred to recipients. This general strategy may be used to reduce relapse of malignancies and augment protection against infections after allogeneic HSCT.
PMCID: PMC3469751  PMID: 22773122
myeloma; transplantation; allogeneic; donor vaccination; idiotype
24.  A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients 
Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine.
Experimental design
Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer over-expressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles.
Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively.
We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials.
PMCID: PMC3708463  PMID: 21927947
p53; IL-2; Ovarian cancer; Cancer vaccine
25.  Reduced Intensity Allogeneic Stem Cell Transplantation in Children and Young Adults with Ultra-High Risk Pediatric Sarcomas 
Some subsets of pediatric sarcoma patients have very poor survival rates. We sought to determine the feasibility and efficacy of allogeneic HSCT (alloHSCT) in pediatric sarcoma populations with <25% predicted overall survival. Patients with ultra-high risk Ewing’s sarcoma family of tumors (ESFT), alveolar rhabdomyosarcoma or desmoplastic small round cell tumor received EPOCH-fludarabine induction, a cyclophosphamide/fludarabine/melphalan preparative regimen and HLA matched related peripheral blood stem cells. Thirty patients enrolled; 7 did not undergo alloHSCT due to progressive disease with diminishing performance status during induction. All 23 alloHSCT recipients experienced rapid full donor engraftment, with no peri-transplant mortality. Five of 23 alloHSCT recipients (22%) remain alive (overall survival of 30% by Kaplan-Meier analysis at 3 years), including 3 of 7 (42%) transplanted without overt disease (median survival 14.5 vs. 29.0 months from alloHSCT for patients transplanted with vs. without overt disease, respectively). Among the 28 patients who progressed on the study, the median survival from date of progression was 1.9 months for the 7 who did not receive a transplant compared to 11.4 months for the 21 transplanted (p=0.0003). We found prolonged survival after post-transplant progression with several patients exhibiting indolent tumor growth. We also saw several patients with enhanced anti-tumor effects from post-transplant chemotherapy (objective response to pre-transplant EPOCH-F was 24% vs. 67% to post-transplant EOCH), however this was associated with increased toxicity. This largest reported series of alloHSCT in sarcomas demonstrates that alloHSCT is safe in this population, and that patients undergoing alloHSCT without overt disease show higher survival rates than reported using standard therapies. Enhanced chemo- and radio-sensitivity of tumors and normal tissues was observed post-transplant.
PMCID: PMC3262116  PMID: 21896345

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