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e21693 Background: CHS-1701 is a proposed biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony stimulating factor approved for decreasing infection in patients receiving myelosuppressive anticancer drugs associated with febrile neutropenia. This multi-center, randomized, single-blind, 3-sequence, crossover study in healthy subjects assessed bioequivalence of CHS-1701 to pegfilgrastim with regard to pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Subjects were randomized to 1 of 3 treatment sequences; each included 1 dose of CHS-1701 (6-mg) and 2 doses of pegfilgrastim (6-mg) separated by ≥28 days. Primary PK endpoints were area under the curve from 0 to infinity (AUC0-∞) and maximum concentration (Cmax). PD endpoints were maximum absolute neutrophil count (ANCmax) and ANC area under the curve (ANC AUCs). Bioequivalence was demonstrated if the 90% confidence interval (CI) for the geometric mean ratio (GMR) of CHS-1701 to pegfilgrastim was within 80-125% for the endpoints. Results: 122 subjects were randomized and treated. Baseline characteristics were comparable between treatment groups. Median age was 29.5 (range 18-45). PK bioequivalence criteria were met for Cmax (GMR = 105.0; 90% CI 95.5, 115.4) and AUC0–∞ (GMR = 97.5; 90% CI 88.6, 107.2). PD bioequivalence criteria were met for ANCmax (GMR = 99.6; 90% CI: 96.2, 103.2), ANC AUC0–last (GMR = 96.7; 90% CI: 92.2, 101.4), and ANC AUC0–480 (GMR = 99.8; 90% CI: 97.7, 102.0). Adverse events (AEs) occurred in 76.0%, 76.6%, and 73.1% of subjects during the CHS-1701, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigator-designated treatment-related AEs occurred in 71.9%, 71.2%, and 62.8% of subjects, respectively, and most commonly included back pain (47.9%, 42.3%, 33.3%) and headache (33.3%, 41.4%, 34.6%). There were no treatment-related serious AEs. Conclusions: This study established the bioequivalence of CHS-1701 to pegfilgrastim with respect to PK and PD. There were no unexpected safety findings, and the two treatments displayed similar safety profiles. Clinical trial information: NCT02650973.

Purpose: This is a pilot study combining focal irradiation and systemic TGFβ blockade in metastatic breast cancer. The rationale for using TGFβ blockade was to limit tumor growth and further spread as well as to curb systemic immune suppression. Combining this systemic approach with hypofractionated radiation of selective tumor metastasis aimed at vaccinating each patient in vivo with her own, relevant tumor antigens by local radiation damage and allow T cells to reach their full potential while escaping TGFβ's grip. Experimental Design: Serial blood samples from 22 patients undergoing treatment with 1mg or 10mg Fresolimumab and Radiation at the New York University School of Medicine (n=15) and at the David Geffen School of Medicine, University of California, Los Angeles (n=7) were immunophenotyped based on flow cytometric analysis of 21 surface antigens. Results: There were significant differences between the 1mg and 10mg groups with respect to several immune parameters, especially the rise in circulating central memory CD8s at the higher dose level (relative increase at 2 weeks 10mg vs 1mg, p=0.027). Regulatory networks responded to the 10mg treatment regime with a consistent expansion in CD4 Tregs while mMDSCs declined (ratio Tregs/mMDSC rising in 10mg vs 1mg, p=0.026). An overall survival benefit was seen in the 10mg Fresolimumab arm (median OS 64.1 weeks versus 20 weeks, p=0.015 log rank test) albeit not striking. CART analysis allowed accurate survival classification based on 2-week changes in CD8/mMDSC ratios and plasma Tryptophan (ROC AUC 0.979). Conclusion: Inhibiting TGFβ in the context of focal irradiation seems to create a favorable systemic immune landscape that drives T cell memory differentiation while limiting myeloid suppression. Citation Format: Dörthe Schaue, Michael W. Xie, Josephine A. Ratikan, Ewa D. Micewicz, Lin Hwang, Kym F. Faull, James W. Sayre, Percy P. Lee, John A. Glaspy, Sandra Demaria, Silvia C. Formenti, William H. McBride. Radiation and TGFβ blockade bring back memories in metastatic breast cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B86.

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.

Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.

Anemia is frequently observed in cancer patients and can cause symptoms and result in red cell transfusions. The erythropoiesis stimulating agents (ESAs) have been shown to increase hemoglobin levels and reduce transfusion requirements in anemic subjects with cancer who are receiving chemotherapy. Initially, these benefits motivated broad use of the ESAs in oncology. Over the past 10 years, recognition of the adverse events that can be associated with ESA use in these patients, particularly venous thrombosis, has resulted in a rethinking of the issue of who are the correct candidates for treatment. Different health care systems have come to different conclusions based upon the available data and additional data are still being generated. This article will review the data concerning the safety of ESAs in cancer patients, including the results of additional trials published in the past 2 years. This will include a discussion of the potential of ESAs to impact tumor progression or survival. Thrombosis remains the most important and best documented adverse event associated with ESA therapy in oncology. The mechanism(s) through which ESAs alter thrombosis risk are still very poorly understood.

BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K–PTEN–AKT–upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses. Significance: This study provides critical insights into how human BRAF-mutant melanoma, a malignancy with marked mutational burden, escapes from BRAF inhibitors. Understanding the core resistance pathways as well as tumor heterogeneity, fitness, and mutational patterns, which emerge under drug selection, lays a foundation to rationalize clinical studies and investigate mechanisms of disease progression. Cancer Discov; 4(1); 80–93. ©2013 AACR. See related commentary by Solit and Rosen, p. 27 This article is highlighted in the In This Issue feature, p. 1

Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP), which stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO). NESP has been shown to be safe and efficacious in patients with chronic renal failure. NESP is biochemically distinct from rHuEPO, due to its increased sialic acid content. NESP has an approximately 3-fold greater half-life. rHuEPO has been shown to be safe and effective for the treatment of chemotherapy-induced anaemia. This study assessed the safety and efficacy of NESP administered once per week, under the supervision of a physician, to patients with solid tumours who were receiving multicycle chemotherapy for up to 12 weeks. Three dose cohorts are presented in this sequential, unblinded and dose-escalating study. Thirteen to 59 patients received NESP (0.5, 1.5 or 2.25 mcg kg−1wk−1) in each cohort. Patients were monitored for adverse events, including antibody formation to NESP and for effects on haemoglobin. NESP appeared to be well tolerated. Adverse events were similar across all cohorts and were consistent with the population being studied. No antibody formation was detected over the 16-week study period and follow-up. A dose–response relationship was evident for NESP and multiple measures of efficacy, including proportion of patients responding to NESP and the mean change in haemoglobin by week 4 and end of treatment for NESP 0.5, 1.5 and 2.25 mcg kg−1wk−1cohorts (mean change in haemoglobin at end of treatment was 1.24, 1.73 and 2.15 g dl−1respectively). Controlled studies of this agent at higher doses and less frequent schedules of administration are ongoing. © 2001 Cance Cancer Research Campaign

Anaemia is a common haematologic disorder in patients with cancer and has a multifactorial aetiology, including the effects of the malignancy itself and residual effects from previous therapy. Novel erythropoiesis stimulating protein (NESP, darbepoetin alfa), a protein with additional sialic acid compared with erythropoietin (EPO), stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO) but it is biochemically distinct. NESP, with its approximately 3-fold greater serum half-life, can maintain haemoglobin levels as effectively as rHuEPO in anaemic patients with chronic renal failure and do so with less frequent dosing. We investigated the ability of NESP to safely increase haemoglobin levels of anaemic patients with non-myeloid malignancies not receiving chemotherapy. NESP was administered under the supervision of a physician at doses of 0.5, 1.0, 2.25 or 4.5 mcg kg−1wk−1for a maximum of 12 weeks. This report includes 89 patients completing the study by November 2000. NESP was well tolerated, with no reported dose-limiting toxicities or treatment-related severe adverse events. Increasing doses of NESP corresponded with increased efficacy. The percentage (95% confidence interval) of patients responding ranged from 61% (42%, 77%) in the 1.0 mcg kg−1wk−1group to 83% (65%, 94%) in the 4.5 mcg kg−1wk−1group. © 2001 Cance Cancer Research Campaign

Human alpha-fetoprotein (AFP) is a potentially important target for the immunotherapy of hepatocellular carcinoma (HCC). AFP(542-550) (GVALQTMKQ) is one of several HLA-A2.1-restricted immunodominant AFP peptides that consistently generate AFP-specific T cell responses in human T cell cultures and in HLA-A2.1/K(b) transgenic (A2.1 tg) mice. We performed a fine specificity analysis of this nonamer to determine which amino acid side chains were critical for T cell priming and recognition. Using peptide-pulsed dendritic cells (DC) as an immunization strategy, we characterized the effects of AFP(542-550) amino acid substitutions on priming and recognition in A2.1 tg mice. Replacing the glutamine at anchor position 9 with a leucine enhanced MHC binding and AFP-specific T cell responses. Substitution of leucine at non-anchor position 4 with an alanine did not alter binding but greatly diminished T cell recognition. Computer-generated three-dimensional models provided the structural rationale for these observed effects in MHC binding and T cell responses resulted from the modifications in the AFP(542-550) sequence.

The safety and efficacy of administering ex vivo expanded peripheral blood progenitor cells (PBPC) to patients with breast cancer who undergo high-dose chemotherapy and PBPC transplantation was investigated. Unselected PBPC were cultured in gas-permeable bags containing 1-L serum-free media, granulocyte colony-stimulating factor, stem cell factor, and pegylated megakaryocyte growth and development factor for 9 days. Cell dose cohorts were assigned to have between 2 and 24 × 109 PBPC cultured at 1, 2, or 3 × 106 cells/mL. Twenty-four patients received high-dose chemotherapy followed by infusion of the cultured PBPC and at least 5 × 106 CD34+ uncultured cryopreserved PBPC per kilogram. No toxicities resulted from infusions of the ex vivo expanded PBPC. The study patients had shorter times to neutrophil (P = .0001) and platelet (P = .01) recovery and fewer red cell transfusions (P = .02) than 48 historical controls who received the same conditioning regimen and posttransplantation care and at least 5 × 106CD34+ PBPC per kilogram. Improvements in all these endpoints were significantly correlated with the expanded cell dose. Nine of 24 (38%) patients recovered neutrophil counts above 500/μL by day 5 or 6 after transplantation, whereas none of the controls had neutrophil recovery before the eighth day. Seven (29%) patients had neutropenia for 3 or fewer days, and 9 (38%) patients did not experience neutropenic fevers or require broad-spectrum antibiotics. Therefore, ex vivo expanded PBPC are capable of ameliorating posttransplantation neutropenia, thrombocytopenia, and anemia in patients receiving high-dose chemotherapy.

Forty-seven patients with stage II, III, or IV breast cancer undergoing autologous peripheral blood progenitor cell (PBPC) transplantation were randomized to placebo (n = 13) or to one of five sequential dose cohorts of pegylated (PEG) recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) (1.0, 2.5, 5.0, 7.5, or 10.0 microg/kg/day) (n= 34). Blinded study drug was started on the day of transplantation and was continued until the platelet count was > or =100 x 109/l or a maximum of 21 days. PBPCs were mobilized with filgrastim (r-metHuG-CSF) and all patients received filgrastim starting on day +2 after transplantation. The nadir platelet count was not affected by treatment. The median time to platelet recovery was 11 and 12 days for the placebo and combined PEG-rHuMGDF groups, respectively. No trends in adverse events suggested dose- or treatment-related toxicity. Two patients withdrew from the study because of an adverse event (allergic reaction in the 7.5 microg/kg group) probably related to study drug, and veno-occlusive disease (VOD) (in the 5 microg/kg group) which was felt not to be related to study drug by the investigator. No patients developed neutralizing antibodies to MGDF. Day +21 and day +28 platelet counts were higher in the group receiving PEG-rHuMGDF (246 vs 148 x 109/l and 299 vs 145 x 109/l, respectively; both P < 0. 05). PEG-rHuMGDF up to 10 microg/kg/day was well tolerated. In this study, there was no effect of study drug on initial platelet engraftment at the doses studied. However, the efficacy of other doses is unknown.

Summary: The murine melanoma B16 expresses the murine counterpart of the human MART-1/Melan-A (MART-1) antigen, sharing a 68.6% amino acid sequence identity. In this study, mice were vaccinated with bone marrow–derived murine dendritic cells genetically modified with a replication-incompetent adenoviral vector to express the human MART-1 gene (AdVMART1). This treatment generated a protective response to a lethal tumor challenge of unmodified murine B16 melanoma cells. The response was mediated by major histocompatibility complex class I–restricted cytotoxic T lymphocytes specific for MART-1 antigen, which produced high levels of interferon-γ when reexposed to MART-1 in vitro and lysed targets in a calcium-dependent mechanism suggestive of perforin/granzyme B lysis. MART-1 was presented by the dendritic cells used for vaccination and not by epitopes cross-presented by host antigen-presenting cells. In conclusion, dendritic cells genetically modified to express the human MART-1 antigen generate potent murine MART-1–specific protective responses to B16 melanoma.

Tumor shrinkage induced by tumor immunotherapy may be preceded by inflammatory changes. This confounds the assessment of response rates to tumor immunotherapy. In this issue of Clinical Cancer Research, Wolchok et al. attempt to address this peculiarity by proposing a new set of criteria termed immune-related response criteria. (Clin Cancer Res 2009;15(23):7116–8)

Erythropoiesis-stimulating agents are widely used in patients with cancer; however, uncertainty persists over their effect on survival. This article discusses the results of a meta-analysis of randomized, controlled trials of these agents in patients with cancer.

We have assessed tumor contamination of peripheral blood progenitor cells (PBPC) in 203 high-risk breast cancer patients who were prospectively randomized to mobilization with stem cell factor (SCF) plus granulocyte colony-stimulating factor (G-CSF) versus G-CSF alone. The patients then received high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) with PBPC support. One bone marrow aspirate obtained before treatment, one whole blood specimen obtained before cytokine infusion, and one to five leukapheresis products were tested for the presence of tumor cells by an alkaline phosphatase immunocytochemical technique with a targeted sensitivity of 1.7 tumor cells per 106 hematopoietic cells. Tumor cells were detected in the bone marrow, peripheral blood, and/or PBPC of 21 patients (10%). In 14 patients, bone marrow specimens were tumor-positive; in seven patients, premobilization whole blood specimens were tumor-positive, and in eight patients, leukapheresis products were tumor-positive. In five patients, repetitive or multiple specimens were tumor-positive, and in three cases, marrow, peripheral blood, and PBPC products were all tumor-positive. Nine of the patients in whom tumor cells were found in marrow or peripheral blood were clinical stage II to III and 12 were clinical stage IV. Nine of the tumor-positive patients were in the SCF + G-CSF arm and 12 were in the G-CSF arm. Tumor cells were detected in leukapheresis products of eight patients: three in the G-CSF + SCF arm and five in the G-CSF arm. We conclude that detectable tumor-cell contamination of bone marrow, peripheral blood, and/or PBPC occurred in approximately 10% of patients in this trial and was observed in stage II to III patients, as well as in stage IV patients. No significant difference could be found in the rate of PBPC tumor-cell contamination between patients who received SCF + G-CSF compared with those who received G-CSF alone. Neither mobilization regimen was found to increase the rate of tumor-cell contamination when control premobilization blood samples were compared with leukapheresis products.

Dendritic cells (DC) are potent stimulators of primary T cell responses. In this study, we demonstrate that DC, genetically engineered to express the MART-1/Melan-A (MART-1) tumor-associated Ag, express MART-1 mRNA and protein, correctly process and present the HLA-A2.1-restricted immunodominant MART-1 peptide (MART-127–35), and serve as potent stimulators of MART-1-specific CTL in vitro. A replication-defective E1-deleted adenovirus (AdV) was constructed that expresses MART-1 (AdVMART1). Transduced DC produce full length MART-1 mRNA as well as MART-1 protein. AdVMART1 does not significantly down-regulate cell surface class I expression despite having an intact E3 region. Transduction of an HLA-A2-positive/MART-1-negative cell line with AdVMART1 renders these cells sensitive to lysis by CTL specific for the MART-127–35 immunodominant peptide. In addition, DC transduced with AdVMART1 stimulated MART-127–35-specific tumor-infiltrating lymphocytes to synthesize IFN-γ. Finally, AdVMART1-transduced DC were able to generate MART-127–35 peptide-specific, class I-restricted CTL in PBL cultures from normal donors. This study supports the use of tumor Ag-engineered DC in genetic immunotherapy.

The CD34+ cell surface antigen is expressed on progenitor cells required for blood stem cell transplantation. The number of cells expressing CD34+ can be used to assess the peripheral blood progenitor cell (PBPC) graft quality and predict hematopoietic recovery after engraftment. Because there is considerable variability among centers in the determination of CD34+ cell counts, standardizing flow cytometry methodology is essential. It is necessary to define a minimum safety threshold CD34+ cell dose for hematopoietic cell transplantation. This minimum dose would define a cell number in the graft, below which a proportion of patients would be expected to have delayed hematopoietic recovery or failure to engraft. We reviewed data from numerous studies. Although 1-2 x 10(6) CD34+ cells/kg can be considered an adequate graft, available data suggested that doses >5 x 10(6) CD34+ cells/kg were associated with more rapid engraftment and a lower probability of graft failure. The risk of delayed recovery was inversely related to CD34+ cell dose. Delayed recovery may result in greater transfusion requirements, longer hospitalization, increased antibiotic use and growth factor support, and higher health care costs. The extent of prior chemotherapy and radiation treatment are major risk factors for poor PBPC collection. To achieve an optimal CD34+ cell yield, PBPC collection should be initiated early during therapy. PBPC collection should be coordinated with the anticipated number of chemotherapy cycles, duration of chemotherapy, interval between chemotherapy and apheresis, need for radiotherapy, and exposure to the more progenitor cell-toxic drugs such as carmustine or busulfan. Biol Blood Marrow Transplant 1998;4(2):84-92.

Drug-induced pulmonary toxicity is one of the most frequent non-hematologic toxicities in breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, cisplatin and BCNU (CY/CDDP/BCNU). A non-invasive clinical scoring system was utilized in an attempt to diagnose and treat early lung toxicity in 64 consecutive breast cancer patients undergoing CY/CDDP/BCNU supported by peripheral blood progenitor cells. Following hospital discharge, patients who developed symptoms suggestive of lung toxicity were evaluated with physical examination, DLCO, 2-min walking oximetry and a chest radiograph. Clinically weighted scores were assigned as follows: crackles on lung exam, 2; decrease in corrected DLCO by > 10% from baseline, 3; decrease in O2 saturation by > or = 4% with a 2-min walk, 3; and interstitial infiltrates on chest radiograph, 3. Patients with scores > or = 6 were treated with prednisone (60 mg p.o. twice a day followed by a 2-month taper). Treatment was instituted in 37 patients (58%) a median of 56 days after high-dose chemotherapy. Steroid therapy was associated with rapid clinical improvement in most patients. No fatal complications or chronic pulmonary fibrosis was seen. This non-invasive clinical scoring system can be utilized as a model for the early diagnosis of lung toxicity. Further investigation is warranted for the development of preventative measures against this syndrome.

The safety and optimal dose and schedule of stem cell factor (SCF ) administered in combination with filgrastim for the mobilization of peripheral blood progenitor cells (PBPCs) was determined in 215 patients with high-risk breast cancer. Patients received either filgrastim alone (10 μg/kg/d for 7 days) or the combination of 10 μg/kg/d filgrastim and 5 to 30 μg/kg/d SCF for either 7, 10, or 13 days. SCF patients were premedicated with antiallergy prophylaxis. Leukapheresis was performed on the final 3 days of cytokine therapy and, after high-dose chemotherapy and infusion of PBPCs, patients received 10 μg/kg/d filgrastim until absolute neutrophil count recovery. The median number of CD34+ cells collected was greater for patients receiving the combination of filgrastim and SCF, at doses greater than 10 μg/kg/d, than for those receiving filgrastim alone (7.7 v 3.2 × 106/kg, P < .05). There were significantly (P < .05) more CD34+ cells harvested for the 20 μg/kg/d SCF (median, 7.9 × 106/kg) and 25 μg/kg/d SCF (median, 13.6 × 106/kg) 7-day combination groups than for the filgrastim alone patients (median, 3.2 × 106/kg). The duration of administration of SCF and filgrastim (7, 10, or 13 days) did not significantly affect CD34+ cell yield. Treatment groups mobilized with filgrastim alone or with the cytokine combination had similar hematopoietic engraftment and overall survival after PBPC infusion. In conclusion, the results of this study indicate that SCF therapy enhances CD34+ cell yield and is associated with manageable levels of toxicity when combined with filgrastim for PBPC mobilization. The combination of 20 μg/kg/d SCF and 10 μg/kg/d filgrastim with daily apheresis beginning on day 5 was selected as the optimal dose and schedule for the mobilization of PBPCs.

Polyunsaturated fatty acids of the omega-6 (omega-6) class, as found in corn and safflower oils, can act as precursors for intermediates involved in the growth of mammary tumors when fed to animals, whereas polyunsaturated fatty acids of the omega-3 (omega-3) class, as found in fish oil, can inhibit these effects. The effects of dietary intervention on the ratios of these fatty acids in breast and other adipose tissues have not previously been prospectively studied.The present investigation was conducted to study the impact on the ratio of omega-3 and omega-6 polyunsaturated fatty acid in plasma and in adipose tissue of the breast and buttocks when women with breast cancer consume a low-fat diet and fish oil supplements.Twenty-five women with high-risk localized breast cancer were enrolled in a dietary intervention program that required them to eat a low-fat diet and take a daily fish oil supplement throughout a 3-month period. Breast and gluteal fat biopsy specimens were obtained from each woman before and after dietary intervention. The fatty acid compositions of specimens of plasma, breast fat, and gluteal fat were determined by gas-liquid chromatography. Statistical analysis involved use of a two-sided paired t test.After dietary intervention, a reduction in the level of total omega-6 polyunsaturated fatty acids in the plasma was observed (P.0003); moreover, total omega-3 polyunsaturated fatty acids increased approximately three-fold (P.0001) and the omega-3/omega-6 polyunsaturated fatty acids ratio increased approximately fourfold (i.e., mean values increased from 0.09 to 0.41; P = .0001). An increase in total omega-3 polyunsaturated fatty acids in breast adipose tissue was observed following dietary intervention (P = .04); the omega-3/omega-6 polyunsaturated fatty acid ratio increased from a mean value of 0.05 to 0.07 (P = .0001). An increase in total omega-3 polyunsaturated fatty acids was observed in gluteal adipose tissue following the intervention (P = .05); however, the ratio of omega-3 to omega-6 polyunsaturated fatty acids (mean ratio values of 0.036-0.045; P = .06) was unchanged.Short-term dietary intervention can lead to statistically significant increases in omega-3/omega-6 polyunsaturated fatty acid ratios in plasma and breast adipose tissue. Breast adipose tissue changed more rapidly than gluteal adipose tissue in response to the dietary modification tested in this study. Therefore, gluteal adipose tissue may not be a useful surrogate to study the effect of diet on breast adipose tissue.

Hematopoietic growth factors (CSFs) are now available for use in patients with myelosuppression due to congenital, acquired and therapy-induced conditions. Variations in the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in different countries are due to differences in approved indications by national regulatory agencies, varying opinions on the importance of certain treatment outcomes, differences in the selection of published and unpublished evidence of efficacy and the impact of the cost of these agents in different health care systems. Through Medline searches and personal files, we have reviewed the published literature on the efficacy and cost of GM-CSF and G-CSF in patients with severe chronic neutropenia and those receiving standard dose chemotherapy or high-dose chemotherapy requiring bone marrow reconstitution. Guidelines were established with regard to (1) the relative merits of different types of clinical studies and (2) the relative importance of different clinical outcomes as reported in these studies. The cost implications of these agents as they apply to the different clinical settings are also reviewed. Recommendations for the use of G-CSF and/or GM-CSF include: (1) the prevention of recurrent, debilitating infections in patients with severe chronic neutropenia; and (2) the maintaining of dose-intensity of potentially curative, standard-dose chemotherapy. While G-CSF and/or GM-CSF have been shown to improve secondary outcomes in higher-than-standard dose-intensive therapy, further studies are needed to test whether such improvements also lead to significant improvements in survival and/or quality of life. These recommendations are based on the collective interpretation of the presented evidence by an international group of investigators in this area. (C) 1997 Elsevier Science B.V.

Despite its high prevalence, anemia often does not receive proper clinical attention, and detection, evaluation, and management of iron deficiency anemia and iron-restricted erythropoiesis can possibly be an unmet medical need. A multidisciplinary panel of clinicians with expertise in anemia management convened and reviewed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various patient populations and made recommendations on the detection, diagnostic approach, and management of anemia. The available evidence confirms that the prevalence of anemia is high across all populations, especially in hospitalized patients. Anemia is associated with worse clinical outcomes including longer length of hospital stay, diminished quality of life, and increased risk of morbidity and mortality, and it is a modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Iron deficiency is usually present in anemic patients. An algorithm for detection and management of anemia was discussed, which incorporated iron study (with primary emphasis on transferrin saturation), serum creatinine and glomerular filtration rate, and vitamin B12 and folic acid measurements. Management strategies included iron therapy (oral or intravenous), erythropoiesis-stimulating agents, and referral as needed.

Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.

Background. This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone. Methods. Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy. Results. Compliance rates for the EORTC questionnaires were acceptable at 72%–93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up. Conclusion. HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.

Oncologic patients constitute a population whose susceptibility to infections is conditioned by a broad variety of factors. Advances in antineoplastic treatments have resulted in significant prevalence of severe immunosuppression among such patients. Although impairment of more than one distinct effector limb of host defenses occurs in each patient, infections can usually be attributed to a particular deficiency. Major risk factors for infections include granulocytopenia and defects of cell-mediated immunity or of humoral immunity. In the extreme situation of allogeneic bone marrow transplantation, the multitude and the timing of infections can be explained by significant dysfunction of all types of specific immune deficiencies. Treatment of bacterial infections has become more effective with the advent of broad-spectrum antibiotics; however, the dreadful emergence of polyresistant strains may be a serious problem in the near future. Prevention strategies have reduced the risk posed by important pathogens such as CMV or PCP, whereas we still lack reliable treatment against invasive mycoses. The advent of growth factors is a useful adjunct in our armamentarium; in addition to shortening the neutropenic periods after chemotherapy, they may restore qualitative defects of phagocytes. Their exact usefulness and role in managing infections remains to be defined.

Article abstract-Chronic lymphocytic leukemia is the most common human leukemia but infrequently causes neurologic symptoms. We have reviewed all previously reported cases of chronic lymphocytic leukemia in the CNS along with three new cases; one patient was diagnosed antemortem and treated with immediate improvement and 4-year survival. In addition, we reviewed all autopsy cases since 1972 and available lumbar puncture data on patients with chronic lymphocytic leukemia admitted to the Massachusetts General Hospital. Invasion of the CNS by chronic lymphocytic leukemia often leads to confusional state, meningitis with cranial nerve abnormalities, optic neuropathy, or cerebellar dysfunction. Lumbar puncture shows a lymphocytosis consisting of monoclonal B cells, but CSF cytology studies are of limited value in establishing the diagnosis. Long-term survival may be related to the stage of chronic lymphocytic leukemia at the time of CNS disease and may be associated with intrathecal chemotherapy. A mild, asymptomatic infiltration of the brain, frequently noted in late-stage chronic lymphocytic leukemia in autopsy series, may explain the CSF lymphocytosis in some patients with late-stage chronic lymphocytic leukemia.NEUROLOGY 1996;46: 19-25

189 Background: Stomatitis is a frequent adverse event (AE) associated with mTOR inhibition. In BOLERO-2 patients (pts) receiving EVE/EXE, all grade (Gr) stomatitis was 67%; 33% had Gr ≥ 2 and 8% Gr 3. Median time to ≥ Gr 2 onset was 15.5 days; incidence of new stomatitis (Gr ≥ 2) plateaued at 6 wks. In a meta-analysis, 89% of first stomatitis events occurred within 8 wks. Topical steroids are used to treat aphthous ulcers; anecdotal use as prophylaxis has been reported. Methods: Eligibility included PM women with HR+ MBC prescribed EVE/EXE. Treatment included EVE 10 mg and EXE 25 mg QD, with 10 mL of commercially available 0.5 mg/5 mL dexamethasone oral solution to swish x 2 min and spit QID for 8 wks starting day 1. Pts completed a daily adherence log, including an oral pain (range 0-10) and normalcy of diet score. The primary endpoint was to compare the incidence of Gr ≥ 2 stomatitis at 8 wks with BOLERO-2 results. Secondary endpoints included MW use by average times/day, EVE/EXE dose intensity, incidence of all Gr stomatitis and time to resolution to Gr ≤ 1. Results: 92 women were enrolled; 86 were evaluable for efficacy. Median age was 61 yrs (range 34-87); median dose intensity was 10 (range 3-10) and 25 mg (range 8-25) for EVE and EXE, respectively. 95% of pts used the MW 3-4 times/day (median MW use/day = 3.95, range 1.9-4). At 8 wks, the rate of ≥ Gr 2 stomatitis was 2.4% (2 pts) with a Gr 1 rate of 18.8%. A comparison of stomatitis incidence by grade between BOLERO-2 and SWISH is shown in the table. In the 75 patients with complete ECOG scores, 88% maintained/improved ECOG status. Mean pain scale score was < 1 at all visits; 88% of pts reported a normal diet at 8 wks. 13% discontinued EVE/EXE due to suspected related AEs (most common: rash, 2%; hyperglycemia, 2%; stomatitis, 2%; and pneumonitis, 1%). Conclusions: Prophylactic use of 0.5 mg/5 mL dexamethasone oral solution markedly decreases the incidence and severity of stomatitis in patients receiving EVE/EXE for MBC and should be considered a new standard of oral care in this setting. Clinical trial information: NCT02069093. [Table: see text]

We investigated, via multicolor flow cytometry, the in vivo effects of colony-stimulating factors (CSFs) on cell size, frequencies, and expression of surface antigens on peripheral blood monocytes from melanoma patients treated concurrently with CSFs and tumor-specific monoclonal antibody (mAb) R24. Recombinant human macrophage colony-stimulating factor (rhM-CSF) increased cell size, relative percentages of monocytes, percentages of CD14+, HLA-DQ+, CD11b+, and CD16+ monocytes, and cell-surface expressions of HLA-DR and CD11b; rhM-CSF also up-regulated cell-surface expression of CD14 on CD14brightCD16- monocytes. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) increased cell size, percentages of CD14+, HLA-DQ+, and CD11b+ monocytes, and cell-surface expressions of HLA-DR, HLA-DQ, CD11b, and CD58. Relative percentages of monocytes and CD16+ cells and cell-surface expression of CD14 on CD14brightCD16- monocytes decreased. In addition, monocytes derived from patients treated with rhM-CSF showed functional activity when assayed in vitro for antibody-dependent cellular cytotoxicity (ADCC). During treatment and coincident with increased CD16 expression, monocytes derived from rhM-CSF patients had enhanced levels of cytotoxicity towards melanoma target cells compared to healthy controls and to patients treated with rhGM-CSF.

Background: Talazoparib is the most potent PARP inhibitor in clinical development (IC50 = 0.57 nMol/L). When talazoparib is combined with DNA damaging agents a synergistic effect mediated through enhanced PARP inhibition and PARP trapping is seen. Here we report first in human combination studies of talazoparib with temozolomide (TEM) or irinotecan (IRI) with biomarker correlates of response. Methods: A phase I dose escalation study evaluated escalating doses of talazoparib (? 0.5 mg PO QD) with either TEM (? 25 mg/m2 PO days 1-5) (Arm A) or IRI (? 25 mg/m2 IV q2 weeks) (Arm B) every 28 days in patients with advanced malignancies. In both arms the dose of talazoparib was escalated first up to the single agent maximum tolerated dose (MTD) of 1.0 mg before the dose of chemotherapy was increased. The primary endpoint was the determination of the maximum tolerated dose (MTD), and secondary endpoints included pharmacokinetics, tumor response, and biomarkers. DLTs were assessed during the 1st cycle of each dose level. RECIST version 1.1 assessment was done every 8 weeks. Prior TEM or IRI was permitted. A subset of patients had tumor assessment using next generation sequencing (NGS) to identify genomic aberrations distinct from BRCA mutations. Results: 41 patients received escalating doses (0.5-1.0 mg) of talazoparib and either TEM or IRI: 19 patients in Arm A and 22 in Arm B. Median age was 57 (21-77), all PS were 0 or 1 and the median number of prior chemotherapy regimens was 6 (1-15). The MTD for each arm was talazoparib 1.0 mg and 37.5 mg/m2 for either TEM or IRI. Confirmed partial responses (PR) were seen in 4/7 (57%) germline BRCA wild-type platinum-resistant ovarian cancer patients, and PRs were seen in one patient each with Ewing's Sarcoma, cervical adenocarcinoma, small cell lung cancer and triple negative breast cancer. There was a correlation between response and the presence of deleterious somatic mutations in non-BRCA DNA repair genes (e.g. PALB2, RAD51D, MSH2). In the ovarian patients, Homologous Recombination Deficiency (HRD) scores ?42 was correlated with response. The most common grade 3/4 AE's (?5%) related to the treatment combination talazoparib + TEM were neutropenia (28%), anemia (33%) and thrombocytopenia (33%), and for the combination talazoparib + IRI were thrombocytopenia (13%), anemia (27%) and neutropenia (31%). No significant PK interactions were seen between talazoparib and either TEM or IRI. Conclusions: The combination of talazoparib with either TEM or IRI is generally well tolerated in patients with heavily pre-treated advanced malignancies. Regardless of histology, there was a correlation with the presence of specific genomic alterations (not confined to DNA repair) and a PR by RECIST. These data support further evaluation of talazoparib in combination with TEM or IRI in tumors to evaluate efficacy and safety with a focus on relevant somatic mutations, pathway predictors and/or response/resistance biomarkers. Citation Format: Zev A. Wainberg, J. Randolph Hecht, Gottfried E. Konecny, Jonathan W. Goldman, Saeed Sadeghi, Bartosz Chmielowski, Arun Singh, Richard S. Finn, Diego Martinez, Lisa Yonemoto, John Glaspy, Dennis J. Slamon. Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor talazoparib in combination with either temozolomide or irinotecan in patients with advanced malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT011.

5557Background: Deregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6) – p16 – Rb signaling pathway is commonly found in ovarian cancer (OC). Palbociclib is an inhibitor of CDK4/6 and was re...

Background CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. Methods A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. Results No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. Conclusions This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).

Patients with cancer frequently develop a multifactorial anemia. The past decade has seen a dramatic improvement in understanding of the biology of the anemia of chronic disease, which has increased interest in studies of parenteral iron or antihepcidin strategies in these patients. Randomized trials have shown that therapy with erythropoiesis-stimulating agents (ESAs) is associated with a reduction in transfusion rates in patients with cancer undergoing chemotherapy. More recently, some studies have suggested that ESA therapy may increase the risk of tumor progression or reduce survival in patients with cancer. This topic was extensively reviewed previously. This update supplements prior reviews with data generated over the past 4 years. During this interval, interest in thrombosis and its role in cancer biology has increased, and concerns about the thrombotic risks of ESAs has moved to the fore-front. Until additional safety data are forthcoming, ESAs should be used only to treat chemotherapy-induced anemia, with the goal of preventing transfusions. Patients and physicians should be aware of the safety data for these products.

Patients with HIV infection frequently develop clinically significant anemia, either as a manifestation of the HIV or as a result of therapy with medications such as zidovudine. Therapy with recombinant human erythropoietin can increase hemoglobin levels in these patients, decreasing transfusion requirements and improving some aspects of the quality of life. Once erythropoietin therapy is started, it is important to monitor patients carefully for the development of iron deficiency and erythrocytosis.

Positron emission tomography (PET) is an imaging technique that can produce high-quality tomographic images reflective of the metabolic characteristics of imaged tissue. Among the many positron-emitting tracers utilized in conjunction with PET is [18F]fluoride ion; it is actively taken up in bone in proportion to bone metabolic activity, analogous to standard nuclear medicine bone scanning agents such as technetium methylenediphosphonate ([99mTc]MDP). Whole-body imaging with PET and [18F]fluoride ion generates tomographic images that are useful in mapping patterns of bone metabolism, as well as identifying extraosseous site of bone formation or calcification. We report the case of a patient with polyostotic fibrous dysplasia, metastatic osteogenic sarcoma, and a breast mass, who presented with pulmonary nodules, in whom [18F] fluoride ion/PET imaging was useful in confirming the nature of the pulmonary nodules.

(1994). Positron Emission Tomography Scanning in Cancer. Cancer Investigation: Vol. 12, No. 1, pp. 74-87.

There is increasing clinical interest focused on ex vivo manipulation and expansion of hematopoietic cells. In this study, we demonstrate that a simple combination of growth factors can expand progenitors to yield functional myeloid cells. Furthermore, this system can produce mature, functionally competent cells in the absence of fetal bovine serum (FBS), which will enhance the clinical utility of this approach. Hematopoietic progenitor cells obtained from normal bone marrow and from leukapheresis products were studied. The mononuclear fraction was enriched for CD34 cells using the Ceprate CD34 biotin kit (CellPro #LC34-1 or LC34-2). The selected cells were expanded for two weeks in Iscove's medium supplemented with 20% FBS and various combinations of interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF) and interleukin-6 (IL-6) added either simultaneously or sequentially. The optimal combination of these factors identified for myeloid expansion was simultaneous addition of IL-3, SCF and G-CSF (at 50 ng/ml each), resulting in an average 773 ± 133-fold expansion of nucleated cells (n = 5). When corrected for the purity of CD34 cells in the starting population, the mean fold expansion with IL-3, SCF and G-CSF was 2,265 ± 729. A mean of 74.7 ± 10.5% (n = 3) of the expanded cells was positive for CD11b; 86-91% (n = 2) of the cells were promyelocytes or more mature granulocytes. Functional assays demonstrated normal phagocytosis and intracellular killing of Staphylococcus aureus (S. aureus) by the expanded cell population. Studies performed using cells expanded in defined serum-free media demonstrated that fold expansion was decreased and that the cells produced were less mature and functionally less competent than cells expanded with FBS. The decreased expansion could be partially reversed, and the functionality almost completely restored by the addition of autologous plasma.

Novel erythropoiesis-stimulating protein (AranespTM; darbepoetin alfa) is a glycoprotein hormone with a longer serum half-life than recombinant human erythropoietin (rHuEPO) (1). The polypeptide backbone of the human EPO molecule has an invariant amino acid sequence; however, the carbohydrate side chains exhibit microheterogeneity in sugar content and structure (2)(3)(4). A negatively charged sialic acid molecule typically caps the end of each arm of a carbohydrate chain. As a consequence, the variable nature of the sialic acid content gives rise to EPO isoforms with differences in charge (3). After purifying isoforms of rHuEPO, Egrie and coworkers (5)(6) discovered a direct correlation between the number of sialic acid groups on the carbohydrate part of rHuEPO and both its serum half-life and biological activity, as well as an inverse relationship with receptor binding. These data showed that pharmacokinetic factors have a greater influence on biological activity than receptor binding affinity. These principles explain the increased half-life and increased in vivo activity of darbepoetin alfa, which contains 5 N-linked carbohydrate chains and up to 22 sialic acids (5)(7). In contrast, rHuEPO has 3 N-linked carbohydrate chains and a maximum of 14 sialic acids (5)(7). Similar clinical responses can be achieved by administering darbepoetin alfa once a week or rHuEPO three times a week (8)(9). The efficacy of darbepoetin alfa in the treatment of anemia associated with chronic renal failure has been shown (10), and in 2001 it was approved by the US Food and Drug Administration for that indication. Darbepoetin alfa is under investigation for the treatment of anemia in cancer patients (11) and other applications. Although darbepoetin alfa was approved only recently, we detected darbepoetin alfa in the urine of three athletes competing in the 2002 Winter Olympic Games …

In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate ESA benefits and risks in lung cancer, we conducted meta-analyses of data from controlled ESA trials conducted in lung cancer patients. Study-level analyses included controlled ESA trials reporting lung cancer mortality, identified from the 2006 Cochrane ESA report and from a systematic search for studies published through December 2010. Patient-level analyses included data from lung cancer patients receiving chemotherapy in Amgen studies evaluating darbepoetin alfa (DA) vs placebo. Study-level and patient-level analyses examined deaths, progression, and transfusion incidence. Patient-level analyses also examined adverse events (AEs) and fatigue.In a study-level meta-analysis of nine ESA studies of 2342 patients receiving chemotherapy, the ESA odds ratio (OR) was 0.87 (95% confidence interval [CI] 0.69–1.09) for mortality; the overall random-effects risk difference (95% CI) for mortality was −0.02 (−0.06, 0.02). The ESA OR (95% CI) for disease progression in five chemotherapy studies reporting progression was 0.84 (0.65–1.09). The ESA odds ratio (95% CI) was 0.34 (0.28–0.41) for transfusion incidence.In a patient-level meta-analysis of four studies evaluating 1009 patients through follow-up, the median survival time was 41 weeks with DA and 38 weeks with placebo. During the combined study and follow-up periods, 80% of placebo-group patients and 74% of DA patients died (mortality hazard ratio [HR] 0.90 [95% CI, 0.78–1.03] for DA); results were similar for small cell lung cancer and non-small cell lung cancer. Overall, 87% of placebo patients and 84% of DA patients progressed or died. Fewer DA patients had transfusions (week 5 through end-of-study, DA 19%, placebo 43%). AEs included thrombotic/embolic events (DA 10.5%, placebo 7.2%), cerebrovascular disorders (DA 3.7%, placebo 4.2%), pulmonary edema (DA 0.4%, placebo 1.0%) and pulmonary embolism (DA 1.8%, placebo 0.6%).These meta-analyses suggest that ESAs reduce transfusions without increasing mortality or disease progression in lung cancer patients undergoing chemotherapy.

Background A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines. Materials and methods The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin were tested against a panel of human melanoma cell lines with defined BRAF and NRAS mutations for effects on viability, cell cycle and apoptosis. Signaling molecules in the MAPK, PI3K-AKT and LKB1-AMPK pathways were studied by Western blot. Results Single agent metformin inhibited proliferation in 12 out of 19 cell lines irrespective of the BRAF mutation status, but in one NRASQ61K mutant cell line it powerfully stimulated cell growth. Synergistic anti-proliferative effects of the combination of metformin with vemurafenib were observed in 6 out of 11 BRAFV600E mutants, including highly synergistic effects in two BRAFV600E mutant melanoma cell lines. Antagonistic effects were noted in some cell lines, in particular in BRAFV600E mutant cell lines resistant to single agent vemurafenib. Seven out of 8 BRAF wild type cell lines showed marginally synergistic anti-proliferative effects with the combination, and one cell line had highly antagonistic effects with the combination. The differential effects were not dependent on the sensitivity to each drug alone, effects on cell cycle or signaling pathways. Conclusions The combination of vemurafenib and metformin tended to have stronger anti-proliferative effects on BRAFV600E mutant cell lines. However, determinants of vemurafenib and metformin synergism or antagonism need to be understood with greater detail before any potential clinical utility of this combination.

Purpose. This double-blind, randomized, phase III clinical trial evaluated time to progression (TTP) and overall survival in women with metastatic breast cancer (MBC) who received sialyl-TN (STn) keyhole limpet hemocyanin (KLH) vaccine. Secondary endpoints included vaccine safety and immune response. Experimental design. The study population consisted of 1,028 women with MBC across 126 centers who had previously received chemotherapy and had had either a complete or a partial response or no disease progression. All women received one-time i.v. cyclophosphamide (300 mg/m2) 3 days before s.c. injection of 100 μg STn-KLH plus adjuvant (treatment group) or 100 μg KLH plus adjuvant (control group) at weeks 0, 2, 5, and 9. Subsequently, STn-KLH without adjuvant or KLH without adjuvant was then administered monthly for 4 months, and then quarterly until disease progression, without cyclophosphamide. Results. STn-KLH vaccine was well tolerated; patients had mild to moderate injection-site reactions and reversible flu-like symptoms. Week-12 antibody testing revealed high specific IgG titers and a high rate of IgM-to-IgG seroconversion; the median IgG titers in STn-KLH recipients were 320 (anti-ovine submaxillary mucin) and 20,480 (anti-STn), with no detectable antimucin antibodies in the control group. The TTP was 3.4 months in the treatment group and 3.0 months in the control group. The median survival times were 23.1 months and 22.3 months, respectively. Conclusions. Although STn-KLH was well tolerated in this largest to date metastatic breast cancer vaccine trial, no overall benefit in TTP or survival was observed. Lessons were learned for future vaccine study designs.

Author(s): Atefi, Mohammad; von Euw, Erika; Attar, Narsis; Ng, Charles; Chu, Connie; Guo, Deliang; Nazarian, Ramin; Chmielowski, Bartosz; Glaspy, John A; Comin-Anduix, Begonya; Mischel, Paul S; Lo, Roger S; Ribas, Antoni | Abstract: BackgroundThe sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.Methodology/principal findingsThe sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Conclusions/significancePrimary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.

Background. The clinical staging and management of both primary and metastatic lung lesions depends on accurate imaging techniques. Biochemical imaging with positron emission tomography, (PET), and the glucose analog 2-[18F]-fluoro-2-deoxy-D-glucose, (FDG), complements anatomic imaging with conventional radiologic methods. Methods. A new “whole-body” PET FDG technique that produces two-dimensional, nontomographic and tomographic longitudinal images of the entire body has been developed at UCLA. Sixteen patients with known pulmonary nodules who had undergone thoracic computed tomography (CT) were studied with whole-body PET FDG imaging at the UCLA Medical Center. Results. This PET FDG imaging method identified metabolically active tumor foci in all eight patients with bronchogenic carcinomas, four patients with metastatic lesions to the thorax, and two patients with Hodgkin disease. All diagnoses were confirmed histologically. Additionally, the PET FDG technique detected extrathoracic metastases in 4 of 16 patients. Thoracic CT was not diagnostic of neoplasm in two of the eight patients with bronchogenic carcinomas. In one patient with an ACTH-producing bronchial carcinoid, the lesion ultimately was detected on high-resolution CT but was not metabolically active on PET FDG imaging. Conclusions. This is the first report of whole-body PET FDG imaging in patients with thoracic lesions. PET FDG imaging accurately detected metabolically active tumor (both intrathoracic and extrathoracic) in patients with bronchogenic carcinoma, pulmonary metastatic disease, and Hodgkin lymphoma. Because lung cancer is characteristically a multisystem disease, this whole-body PET FDG technique has significant implications for treatment planning. Cancer 1993; 72:82–90.

Objective This study was done to determine the feasibility and potential utility of whole-body PET using the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (FDG) for the detection of primary malignancies and metastatic lesions. Materials and methods This was a prospective, nonrandomized study of whole-body FDG-PET imaging carried out at a large university teaching hospital in Los Angeles, CA, U.S.A. The study group consisted of all patients referred for PET imaging (87) with a suspected diagnosis of primary or recurrent malignancy and who had eventual histological confirmation of their lesions. Results In the 87 patients, whole-body PET studies were positive (presence of focal FDG uptake relative to surrounding tissues uptake) in 61 of 70 patients (87%) with subsequent biopsy-confirmed primary or recurrent malignant lesions, including carcinomas of breast, lung, ovary, prostate, colon, urinary bladder, and gallbladder origin, as well as malignant melanoma, carcinoid, osteosarcoma, lymphoma, and spinal cord astrocytoma. The PET images revealed no focal hypermetabolism at the known site of tumor in patients with primary prostate carcinoma (two), microscopic ovarian carcinoma (two), breast carcinoma (one), low-grade carcinoid tumors (two), and one patient with recurrent microscopic osteogenic sarcoma. The PET studies detected the primary lesion in 15 of 17 patients with breast carcinoma and in 6 of 6 patients with primary lung carcinoma. Of the 17 patients with benign biopsies, 13 patients had FDG-PET studies without focal areas of uptake. Conclusion Because of the high glycolytic rate of malignant tissue, the whole-body FDG-PET technique has promise in the detection of a wide variety of both primary and metastatic malignancies. The presence of FDG uptake in benign inflammatory conditions may limit the specificity of the technique. The sensitivity for the detection of malignant lesions was 87% and the positive predictive value was 94%. The whole-body FDG-PET method is promising both in determining the nature of a localized lesion and in defining the systemic extent of malignant disease.

Costs of biologic response modifiers, specifically myeloid growth factors, are discussed relative to cost offsets they may produce in the total amount spent on health care in patients with certain disease states. Even though the biologic response modifiers granulocyte colony-stimulating factor (filgrastim) and granulocyte-macrophage colony-stimulating factor (sargramostim or molgramostim) are similar in name, they are chemically and biologically different. These differences result in different clinical applications. Administered after myelosuppressive antineoplastic therapy, filgrastim decreases the risk of infection. The growth factors may also be useful in patients undergoing bone marrow transplantation, in nonneutropenic patients with bacterial infections, and in patients with other disease states. Although the myeloid growth factors are somewhat expensive in terms of acquisition cost, their use is usually associated with a decrease in the risk of medical complications requiring health care expenditures, often for hospitalizations or antimicrobials. The precise cost of acquiring and administering myeloid growth factors depends on three interdependent variables: the factor used, the dosage of the drug, and the duration of therapy. Cost offsets may be more difficult to define, but they would include direct cost offsets, such as reduced episodes of febrile neutropenia and fewer, less-intense days of hospitalization or treatment. Sargramostim and molgramostim have demonstrated efficacy when given after bone marrow transplantation; filgrastim has been shown to lower infection rates by at least 50% after myelosuppressive antineoplastic therapy and in patients with severe chronic neutropenia.(ABSTRACT TRUNCATED AT 250 WORDS)

A 45-year-old female with a long history of HLA-B27-positive ankylosing spondylitis and ulcerative colitis developed cyclic neutropenia. She was hospitalized for high fever during each of three consecutive episodes of absolute neutropenia. On the third hospitalization, granulocyte-colony-stimulating factor (G-CSF), 5 micrograms/kg/day, was given by subcutaneous injection and resulted in an increase of absolute neutrophil count from 0 to 2.2 x 10(9)/liter and an associated decrease of platelet count and hemoglobin as well as severe bone and joint pain predominantly in the middle and lower back and purulent diarrhea. The back pain necessitated discontinuation of the drug. Oral cyclosporine therapy was begun, and although the neutrophil count continued to oscillate, both the peaks and the nadirs were higher than previously, and symptoms of neutropenia subsided. We conclude that cyclosporine can be an effective treatment for cyclic neutropenia associated with autoimmunity since G-CSF may cause exacerbations of autoimmune disorders.