Costs of care for lung and colon cancer patients receiving chemotherapy following FDA policy changes.

PURPOSE: Use of erythropoiesis-stimulating agents (ESAs) in US cancer care declined amidst post-marketing evidence of adverse effects and the Food and Drug Administration's (FDA) addition of a "black-box" warning to product labeling in March 2007. Because reduced ESA use may have led to more transfusions or increased anemia-related health care needs, we measured the policy's impact on health care costs of lung and colon cancer patients receiving chemotherapy. METHODS: In a retrospective cohort study of 13,630 lung and 3,198 colon cancer patients in the Department of Veterans Affairs (VA) between 2002 and 2008, we calculated anemia treatment (ESA and transfusion), cancer- and non-cancer-related, and total health care costs for the chemotherapy episode of care. We used multivariable regression to examine health care costs and utilization between patients whose chemotherapy was administered before (PRE) or after (POST) March 1, 2007. RESULTS: ESA costs declined and transfusion costs were similar, resulting in lower overall POST-period anemia treatment costs (lung, $526 lower, P < 0.01; colon, $504 lower, P < 0.01). Other cancer-related health care costs increased, resulting in markedly higher POST-period total health care costs (lung, $4,706 higher, P < 0.01; colon, $11,414 higher, P < 0.01). CONCLUSIONS: Although chemotherapy episode anemia treatment costs declined after the black-box warning, the savings were offset by increases in other cancer-related costs. Those increases were mainly in outpatient services and pharmacy, suggesting that likely drivers include adoption of new high-cost diagnostic approaches and therapeutic modalities. Additional research is needed to determine the effects of anemia management changes on patient outcomes and to more fully understand cost-benefit relationships in cancer treatment.

Trends in anemia management in lung and colon cancer patients in the US Department of Veterans Affairs, 2002-2008.

PURPOSE: In 2007, growing concerns about adverse impacts of erythropoiesis-stimulating agents (ESAs) in cancer patients led to an FDA-mandated black box warning on product labeling, publication of revised clinical guidelines, and a Medicare coverage decision limiting ESA coverage. We examined ESA therapy in lung and colon cancer patients receiving chemotherapy in the VA from 2002 to 2008 to ascertain trends in and predictors of ESA use. METHODS: A retrospective study employed national VA databases to "observe" treatment for a 12-month period following diagnosis. Multivariable logistic regression analyses evaluated changes in ESA use following the FDA-mandated black box warning in March 2007 and examined trends in ESA administration between 2002 and 2008. RESULTS: Among 17,014 lung and 4,225 colon cancer patients, those treated after the March 2007 FDA decision had 65% (lung OR 0.35, CI(95%) 0.30-0.42) and 53% (colon OR 0.47, CI(95%) 0.36-0.63) reduced odds of ESA treatment compared to those treated before. Declines in predicted probabilities of ESA use began in 2006. The magnitude of the declines differed across age groups among colon patients (p = 0.01) and levels of hemoglobin among lung cancer patients (p = 0.04). CONCLUSIONS: Use of ESA treatment for anemia in VA cancer care declined markedly after 2005, well before the 2007 changes in product labeling and clinical guidelines. This suggests that earlier dissemination of research results had marked impacts on practice patterns with these agents.

A phase 1 trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m2 and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma.

In this phase 1 study, we tested increasing doses of total marrow irradiation (TMI) in addition to standard intravenous melphalan at 200 mg/m2 (Mel200) in the conditioning regimen prior to autologous stem cell transplant (ASCT) for multiple myeloma (NCT02043847). Twelve patients aged 18-75 with relapsed myeloma were enrolled in the study and received Mel200 and TMI 3 Gy (n = 3), 6 Gy (n = 3), or 9 Gy (n = 6) prior to transplant. There were no grade 4 extra-hematologic toxicities and a maximum tolerated dose was not reached. Median time to neutrophil and platelet engraftment was 11 and 13 d, respectively. At day 90, 73% of patients were in CR or VGPR. Median progression free survival (PFS) was 449 d and median overall survival (OS) was 966 d. We conclude that TMI at a dose of 9 Gy can be safely combined with Mel200 in therapeutic regimens for autologous transplant. Initial clinical results will prompt a phase 2 study.

Low incidence of neutropenic events in patients with lymphoma receiving first-cycle pegfilgrastim with chemotherapy: results from a prospective community-based study.

BACKGROUND: Most alterations to chemotherapy dose and schedule are because of neutropenic events, which mainly occur in the first chemotherapy cycle. This prospective, community-based study evaluated the effectiveness of pegfilgrastim in patients with lymphoma who were also receiving chemotherapy. PATIENTS AND METHODS: Patients aged > or = 18 years with cancer other than leukemia or myelodysplastic syndromes were eligible, including patients with major comorbidities who were generally not eligible for most clinical trials. Key exclusions were weekly chemotherapy and concurrent radiation therapy. Patients received pegfilgrastim 6 mg approximately 24 hours after chemotherapy in each cycle (up to 8 cycles). Endpoints included neutropenic complications and serious adverse events. RESULTS: This open-label single-arm study enrolled 2249 patients at 319 sites. Of these 2249 patients, 325 patients with non-Hodgkin lymphoma (NHL) and 46 patients with Hodgkin disease were included in the primary analysis set. The median age was 65 years for patients with NHL and 41 years for patients with Hodgkin disease, and 31% and 26% had major comorbidities, respectively. Few patients experienced neutropenic complications, including grade 4 febrile neutropenia (patients with Hodgkin disease: 0 [95% confidence interval (CI), 0-8%]; patients with NHL: 13% [95% CI, 10%-17%]); febrile neutropenia-related hospitalization (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 10% [95% CI, 7%-14%]), neutropenia-related dose reduction (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]), and neutropenia-related dose delay (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]). Serious adverse events were consistent with those observed in patients receiving myelosuppressive chemotherapy. CONCLUSION: Patients with lymphoma receiving myelosuppressive chemotherapy supported by pegfilgrastim experienced few neutropenic complications or neutropenia-related alterations in chemotherapy dose and schedule.

MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review.

Glioblastoma (GBM), also known as grade IV astrocytoma, is the most aggressive primary intracranial tumor of the adult brain. MicroRNAs (miRNAs), a class of small non-coding RNA species, have critical functions across various biological processes. A great deal of progress has been made recently in dissecting miRNA pathways associated with the pathogenesis of GBM. miRNA expression signatures called gene signatures also characterize and contribute to the phenotypic diversity of GBM subclasses through their ability to regulate developmental growth and differentiation. miRNA molecules have been identified as diagnostic and prognostic biomarkers for patient stratification and may also serve as therapeutic targets and agents. This review summarizes: (i) the current understanding of the roles of miRNAs in the pathogenesis of GBM, (ii) the potential use of miRNAs in GBM diagnosis and glioma grading, (iii) further prospects of developing miRNAs as novel biomarkers and therapeutic targets for GBM, and (iv) important practical considerations when considering miRNA therapy for GBM patients.

ß-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q).

Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/ß-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether ß-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here, we report that genetic deletion of a single allele of ß-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the preleukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of ß-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of ß-catenin by indomethacin or ß-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; ß-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of ß-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro Overall, our data support the idea that ß-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q). Cancer Res; 77(15); 4116-26. ©2017 AACR.

A validated, transitional and translational porcine model of hepatocellular carcinoma.

Difficult questions are confronting clinicians attempting to improve hepatocellular carcinoma (HCC) outcomes. A large animal model with genetic, anatomical, and physiological similarities to humans is required to transition from mouse models to human clinical trials to address unmet clinical needs. To validate our previously reported inducible porcine cancer model (Oncopig) as a transitional HCC model, Oncopig hepatocyte cultures were transformed using Cre recombinase. The resulting porcine HCC cells (pHCC) expressed oncogenic TP53R167H and KRASG12D, and displayed nuclear pleomorphisms with pale to granular cytoplasm arranged in expanded plates similar to human HCC histopathology. Human HCC transcriptional hallmarks were detected in pHCC cells using RNA-seq, including TERT reactivation, apoptosis evasion, angiogenesis activation, and Wnt signaling activation. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics, including thick trabeculae formation, pseudoacini patterning, and sheets of well-vascularized stroma. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner (HCC nuclear grade assessment system) grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model's utility for improving detection, treatment, and biomarker discovery relevant to human HCC.

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform.

Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model-the Oncopig Cancer Model (OCM)-as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D , the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice.

Rapid and Sensitive Detection of Breast Cancer Cells in Patient Blood with Nuclease-Activated Probe Technology.

A challenge for circulating tumor cell (CTC)-based diagnostics is the development of simple and inexpensive methods that reliably detect the diverse cells that make up CTCs. CTC-derived nucleases are one category of proteins that could be exploited to meet this challenge. Advantages of nucleases as CTC biomarkers include: (1) their elevated expression in many cancer cells, including cells implicated in metastasis that have undergone epithelial-to-mesenchymal transition; and (2) their enzymatic activity, which can be exploited for signal amplification in detection methods. Here, we describe a diagnostic assay based on quenched fluorescent nucleic acid probes that detect breast cancer CTCs via their nuclease activity. This assay exhibited robust performance in distinguishing breast cancer patients from healthy controls, and it is rapid, inexpensive, and easy to implement in most clinical labs. Given its broad applicability, this technology has the potential to have a substantive impact on the diagnosis and treatment of many cancers.

Activity of combination chemotherapy, docetaxel and epirubicin as neoadjuvant therapy for women with breast cancer.

BACKGROUND: This study assesses the efficacy of epirubicin and docetaxel as neoadjuvant therapy for women with breast cancer. PATIENTS AND METHODS: This is a single institution, single arm, phase II study of epirubicin given at 75 mg/m(2) and docetaxel at 75 mg/m(2) every three weeks for four cycles prior to surgical excision in women with large breast cancers. Pegfilgrastim was routinely administered as primary prophylaxis against febrile neutropenia. RESULTS: Out of the 18 patients enrolled on the study, 12 (66.7%) had a clinical response and 13 (72.2%) had a pathologic response, with a pathologic complete response of 5.6%. Pre-menopausal women and patients with estrogen receptor positive tumors had a higher response rate. One patient died due to sepsis and febrile neutropenia. CONCLUSION: Combination chemotherapy with epirubicin and docetaxel is highly active against breast cancer. With close monitoring for toxicity, this combination can be safely administered with mild side-effects.

The timing of chemotherapy-induced neutropenia and its clinical and economic impact.

Chemotherapy-induced neutropenia (CIN) and its complications exact a substantial toll on patients with cancer. Febrile neutropenia (FN), a sign of life-threatening infections, is associated with lengthy hospitalizations, early mortality, and high medical costs. In addition, neutropenia is the primary cause of dose reductions and dose delays, limiting the delivery of the chemotherapy at full dose and on schedule and thus compromising long-term survival in patients with potentially curable malignancies. Many recent studies in several major tumor types have documented that the greatest risk of neutropenia and its complications is in the first cycle of chemotherapy, with more than 50% of the first episodes of neutropenia and FN occurring in the first cycle. In addition to their other negative effects, these first-cycle events are also associated with early termination of the chemotherapy. The disproportionately high risk of neutropenia in the first cycle has important implications for managing CIN, as well as for the development and use of guidelines for supportive care. It highlights the importance of determining which patients are at high risk for neutropenia and its complications before the chemotherapy is initiated and implementing interventions, such as prophylactic growth factor support in the first and subsequent cycles, to reduce that risk.

First-Cycle CSF use in breast cancer and NHL: guidelines and recommendations.

Grade 3 and 4 neutropenia as well as febrile neutropenia have been demonstrated to occur in all tumor types and are clearly associated with major morbidity and significant mortality; this is particularly true when myelosuppressive regimens are used with curative intent as is the case in most breast cancer and non-Hodgkin's lymphoma regimens. Myeloid colony-stimulating factors (CSFs) substantially decrease the risk of severe and febrile neutropenia. Although the white cell growth factors might not be cost-effective at lower risks of febrile neutropenia, they clearly benefit other outcomes such as the incidence of severe neutropenia and febrile neutropenia, hospitalization, and mortality. Updated guidelines from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the European Organisation for Research and Treatment of Cancer now recommend primary prophylaxis or first-cycle use of white cell growth factors with regimens where the occurrence of febrile neutropenia is approximately 20% (as well as when other risk factors are present). This article briefly describes the rationale for the development of several of the guideline changes as well as highlights some of the ongoing issues related to the use of CSFs.

Marginal zone B-cell lymphoma of the uterus: a case report and review of the literature.

We report here a case of a 52-year-old female in whom immunohistological studies of the uterus established a diagnosis of extranodal marginal zone B-cell lymphoma. Malignant lymphoma arising from mucosa-associated lymphoid tissue (MALT) of uterus is extremely rare. Accurate histologic interpretation of uterine lymphoma is essential, as treatment options and prognosis vary based on the histological grade of such lymphomas. Patients with primary uterine lymphoma generally have intermediate or high-grade lymphoma and poorer prognosis.

Protein kinase C blockade inhibits differentiation of myeloid blasts into dendritic cells by calcium ionophore A23187.

Direct differentiation of myeloid leukemia blasts into antigen-presenting dendritic cells (DCs) for use as cellular vaccines is unique in that identification of tumor-specific antigens may not be necessary because the antigens should already be endogenously expressed. We hypothesized that signaling through protein kinase C (PKC) is required for differentiation of HL-60 promyeloblasts into DCs upon stimulation with calcium ionophore A23187. To demonstrate the inhibitory effect of PKC blockade, we pretreated HL-60 myeloid blasts with the protein kinase inhibitor bisindolylmaleimide I (Bis-1) for 24 hours and then treated the cells with calcium ionophore A23187 for an additional 24 hours. Controls consisted of HL-60 blasts treated with A23187, Bis-1 alone, or media. We noted that blasts cultured in media, Bis-1, or Bis-1 then A23187 did not develop the morphologic and phenotypic DC characteristics, up-regulate Rel B, or activate allogeneic T-cells. Our findings suggested that PKC blockade inhibits morphologic, phenotypic, and functional differentiation of HL-60 promyeloblasts into antigen-presenting DCs. Our findings supported the role of PKC as an obligatory pathway for calcium ionophore A23187-induced differentiation of HL-60 myeloblasts into antigen-presenting DCs.

Symptomatic Massive Splenomegaly in Persistent Polyclonal B-cell Lymphocytosis Requiring Splenectomy.

INTRODUCTION: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare lymphoproliferative hematological disease characterized by binucleated lymphocytes, CD 19+ CD 5-lymphocytosis, and elevated levels of serum immunoglobulin M (IgM). It can rarely be associated with splenomegaly, though the disease usually remains indolent. CASE PRESENTATION: We present a case of PPBL in a young man with massive splenomegaly that mimicked isolated splenic lymphoma requiring splenectomy for persistent pain, symptoms, and diagnosis. DISCUSSION: Determining the etiology of splenomegaly in these patients is often confounding due to a lack of a tissue diagnosis and the limited morphological and immuno-histochemical features of PPBL, therefore, the presentation remains highly concerning for lymphoma. CONCLUSION: The presentation, surgical treatment, tissue and peripheral blood molecular analysis, and flow cytometry integral to managing these patients and to prevent an assumptive and misleading diagnosis are reviewed.

New directions in the management of chemotherapy-induced neutropenia: Risk models, special populations, and quality of life.

New directions in managing chemotherapy-induced neutropenia include the development and validation of patient-based predictive risk models to guide the use of prophylactic colony-stimulating factors (CSFs) and an emerging recognition of the possible impact of chemotherapy-induced neutropenia on patient quality of life. Predictive risk models are being developed to identify patients who are at greater risk of neutropenic complications so that prophylactic CSF can be targeted to them in a timely and cost-effective manner. Current practice dictates the use of CSF prophylaxis primarily on the basis of the chemotherapy regimen; the risk-model approach is based on individual patient risk factors, which may be unconditional (before treatment) or conditional (after the first cycle). Within this new paradigm are patients with special circumstances, in whom prophylactic CSF treatment is currently recommended. Clinical evidence suggests that elderly patients are at particular risk for myelosuppression and should be considered for prophylactic CSF treatment starting with the first chemotherapy cycle. Analytical tools to measure the facets of quality of life related to neutropenia are being tested for validity and will be incorporated in future clinical trials. Thus, the future of neutropenia management promises to further refine the cost-effective use of CSF, while improving our understanding of the impact that chemotherapy-induced neutropenia has on quality of life.

Perspectives in the treatment of colorectal cancer.

The availability of new chemotherapy agents in the last several years has had a significant impact on the treatment of colorectal cancer (CRC), but questions about how best to use these agents remain. In this article we review the evidence for maintaining full dose on schedule (FDOS) chemotherapy in CRC. To date, clinical studies have focused on determining which agents or combinations are optimal in advanced disease or the adjuvant setting. Combinations of irinotecan or oxaliplatin with 5-fluorouracil and leucovorin are currently being evaluated in the adjuvant treatment of CRC, and the addition of targeted biologic agents to standard chemotherapy regimens is being evaluated in the treatment of advanced disease. Few studies have investigated dose intensity in the adjuvant setting, and consequently, there is little evidence for a link between FDOS chemotherapy and outcomes. Nonetheless, the benefits of maintaining FDOS chemotherapy, as shown in trials in breast cancer and non-Hodgkin's lymphoma, may also hold true in CRC. Furthermore, several studies in metastatic CRC have found that greater survival can be achieved with dose-intensified chemotherapy. If FDOS chemotherapy is to become accepted in the treatment of CRC, end points other than overall survival may have to be assessed in metastatic disease and the concept will have to be investigated in the adjuvant setting. For now, the role of FDOS chemotherapy in CRC has not been adequately evaluated.

Prognostic significance of additional cytogenetic abnormalities in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha: a Cancer and Leukemia Group B study.

Secondary cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) have been associated with an inferior outcome in reported series of largely chemotherapy-treated patients. To date, no study has specifically focused on the prognostic significance of secondary karyotypic abnormalities, detected at the time of diagnosis, in interferon (IFN)-alpha treated patients. We compared the outcome of 29 newly diagnosed Ph+ CML patients with additional abnormalities to that of 234 sole Ph+ patients, treated on CALGB protocols with IFN-alpha alone or together with IFN-gamma or low-dose cytarabine. Complete and partial cytogenetic responses were achieved in 20 and 19% of sole Ph+ patients, compared to 23 and 18%, respectively, of patients with additional abnormalities (P=1.00). None of 4 patients with 'high-risk' secondary abnormalities [+8, +Ph and i(17)(q10)], for whom follow-up cytogenetic samples were available, achieved a cytogenetic response. With a median follow-up of 11.3 years, the median overall survival (OS) was 6.0 years for sole Ph+ patients compared to 7.5 years for patients with additional abnormalities (P=0.70), with corresponding 8-year OS of 36 and 38%, respectively. On multivariable analysis, only age (P<0.001) and white blood cell count (P=0.02) were associated with outcome. We conclude that, with the possible exception of +8, +Ph and i(17)(q10), additional chromosomal abnormalities at diagnosis are not associated with inferior outcome in Ph+ CML patients treated with IFN-alpha-based therapy.