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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.

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. 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. 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. 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.

Polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor (MGDF) may boost the production of platelets in patients undergoing chemotherapy. Chemotherapy can often cause a drop in platelet counts, which can cause hemorrhage. Researchers randomly assigned 53 patients receiving chemotherapy for lung cancer to take either MGDF or placebo. Patients who took MGDF had significantly higher platelet counts throughout their treatment compared to those taking placebo. Platelet counts were restored to normal levels faster in those taking MGDF.

Cancer patients undergoing chemotherapy are subject to a wide variety of adverse side effects from the toxic drugs that are administered to combat their disease. Among these side effects are fever and neutropenia (depletion of white blood cells), a potentially lethal combination. Before the advent of modern methods of caring for chemotherapy patients, fever and neutropenia could result in death in as high as 80 percent of the affected patients. Even now, with optimized intravenous antibiotic therapies, mortality remains at about 10 percent. It has been proposed that certain growth factors, which stimulate the production and transformation of bone marrow cells into immune system effector cells, can reduce chemotherapy-related neutropenia in cancer patients. To test this hypothesis, 211 patients with small-cell lung cancer (199 of whom yielded complete data) were given either placebo or granulocyte colony-stimulating factor (G-CSF; a white blood cell differentiation-promoting growth factor) on days 4 through 17 of a 21-day chemotherapy cycle. The incidence of fever was 77 percent in the placebo group, but only 40 percent in the G-CSF group. Neutropenia lasted six days in the placebo group compared with one day in the group treated with G-CSF. Other indices of white blood cell depletion were reduced in the drug-treated group by about 50 percent. Twenty percent of the patients receiving G-CSF complained of mild-to-moderate bone pain during treatment. It is concluded that G-CSF is a relatively well-tolerated drug that reduces some of the deleterious side effects of cancer chemotherapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) remodel tumor microenvironment and promote cancer metastasis. Among the MMP family proteases, the proteolytic activity of the pro-tumorigenic and pro-metastatic membrane-type 1 (MT1)-MMP constitutes a promising and targetable biomarker of aggressive cancer tumors. In this study, we systematically developed and characterized several highly sensitive and specific biosensors based on fluorescence resonant energy transfer (FRET), for visualizing MT1-MMP activity in live cells. The sensitivity of the AHLR-MT1-MMP biosensor was the highest and five times that of a reported version. Hence, the AHLR biosensor was employed to quantitatively profile the MT1-MMP activity in multiple breast cancer cell lines, and to visualize the spatiotemporal MT1-MMP activity simultaneously with the underlying collagen matrix at the single cell level. We detected a significantly higher level of MT1-MMP activity in invasive cancer cells than those in benign or non-invasive cells. Our results further show that the high MT1-MMP activity was stimulated by the adhesion of invasive cancer cells onto the extracellular matrix, which is precisely correlated with the cell’s ability to degrade the collagen matrix. Thus, we systematically optimized a FRET-based biosensor, which provides a powerful tool to detect the pro-invasive MT1-MMP activity at single cell levels. This readout can be applied to profile the invasiveness of single cells from clinical samples, and to serve as an indicator for screening anti-cancer inhibitors. [ABSTRACT FROM AUTHOR]

Objective. The last decade has witnessed the great impact of 5-hydroxytryptamine-3 receptor (5-HT3) antagonists in revolutionizing the management of platinum-based chemotherapy-induced acute nausea and vomiting (CINV). However, despite the availability of a variety of 5-HT3 antagonists, little data is published to support superiority of one drug over another, leaving the choice of serotonin receptor antagonist largely empirical. The National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines for management of chemotherapy-associated nausea and vomiting clearly endorse the use of serotonin receptor antagonist; however, no single agent is preferred over the rest. Methods. Data for patients (n =159) receiving platinum-based chemotherapy regimens were retrospectively collected. Patients getting 5-HT3 antagonists without steroids or those with known history of brain metastasis, gastroparesis, and intestinal obstruction were not eligible for the study. Patient characteristics including age, gender, primary diagnosis, history of heavy alcohol intake, chemotherapy regimen administered, number of cycles, and Eastern Cooperative Oncology Group performance status at the start of therapy were noted. Primary outcome was the complete control of platinum-induced acute nausea and vomiting. Secondary outcome measures included control of ≥grade 1 nausea or vomiting, comparison of two doses of dexamethasone, and antiemetic efficacy among various platinum drugs. National Cancer Institute Common Toxicity Criteria version 2.0 was used to assess toxicity. Results. A total of 126 patients received 369 cycles of platinum-based therapy. Dolasetron (n = 57), granisetron (n = 81), and ondansetron (n = 131) achieved complete control of vomiting in 89.8, 95.5, and 92.3% (p = 0.67) of cycles, respectively. Respectively, complete nausea control was observed in 68.1, 75.3 and, 69.4% (p = 0.50). [ABSTRACT FROM AUTHOR]

Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with Zubrod performance status 0-2. Docetaxel 65 mg/m2 and carboplatin (AUC of 6) were given IV in a 21-day cycle to 68 patients. Response probability was 25 percent (95%CI: 15-38). The major toxicity observed was neutropenia, with 36 patients (61 percent) experiencing Grade 3 or worse. Median progression-free survival was 3.8 months (95%CI, 3.1-4.8) Median overall survival was 7.4 months (95%CI, 6.2-8.9). The results of this study suggest this regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status. [ABSTRACT FROM AUTHOR]

The impact of first- and subsequent-cycle growth factor use in the community setting has not been studied extensively. We conducted this large, prospective, noncomparative study to assess neutropenia and related complications in patients receiving myelotoxic chemotherapy with pegfilgrastim support in community practices. Patients ≥18 years old with cancers other than leukemia or myelodysplastic syndrome, including those with major comorbidities, were eligible. Pegfilgrastim (6 mg) was to be administered ∼24 hours after chemotherapy in all cycles (minimum, four cycles). A total of 2,112 patients was included in the analyses. The most common tumor types were breast cancer (46%), non-Hodgkin's lymphoma (15%), and non-small cell lung cancer (13%). Chemotherapies administered most often were a platinum plus a taxane (18%), and anthracycline plus an alkylating agent (18%), and a taxane plus an anthracycline plus an alkylating agent (16%). The percentage of patients with neutropenia-related hospitalization was 2.9% in cycle 1 and 5.6% across all cycles. Chemotherapy dose reductions and delays were attributed to neutropenia in 1.8% and 0.9% of patients, respectively, in cycle 2 and 2.9% and 2.1% of patients, respectively, across all cycles. Febrile neutropenia (absolute neutrophil count <1.0 x 109/l with temperature ≥38.2°C) occurred in 3.6% of patients in cycle 1 and in 6.3% of patients across all cycles. The most frequently reported serious adverse events were febrile neutropenia (3.4%), neutropenia (2.6%), and dehydration (2.6%). Bone pain (0.1%) was the only related serious adverse event reported in more than one patient. Data from this community-based study suggest that patients undergoing chemotherapy benefit from pegfilgrastim support beginning in the first cycle of chemotherapy. [ABSTRACT FROM AUTHOR]

The article describes the rationale for the development of several guideline changes updated from the American Society of Clinical Oncology, the National Comprehensive Cancer Network and the European Organization for Research and Treatment of Cancer and highlights some of the ongoing issues related to the use of colony-stimulating factors.

The article discusses the study on chemotherapy-induced neutropenia and its complications on patients with cancer. Several studies on major tumor types show that the greatest risk of neutropenia and its complications is in the first cycle of chemotherapy, with over 50 percent of the first episodes of neutropenia and febrile neutropenia occurring in the first cycle. In addition to their other negative effects, the first cycle events are also related to the early end of the chemotherapy.

Focuses on the potential role of filgrastim or recombinant methionyl human granulocyte colony-stimulating factor, in the reduction of mucositis. Analysis of oral mucositis using the unadjusted chi-square test; Reduction in the incidence of chemotherapy-related oral mucositis across multiple cycles of treatment in patients treated with filgrastim.