bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase
Authors: Jolivet Jacques , Dayan Alain , Beauchemin Myriam , Chahla Dounia , Mamo Aline , Bertrand Richard 
Published: February 2020

Abstract5-FormylH4folate is administered clinically under the name Leucovorin™ in association with the antineoplastic agent 5-fluorouracil (5-FU) to enhance the cytotoxic effects of 5-FU. The combination has been shown to be superior to 5-FU alone in the treatment of patients with metastatic colorectal carcinoma. Methenyltetrahydrofolate synthetase (MTHFS) catalyzes the transformation of 5-formyltetrahydrofolate to methenylH4folate, which is the obligatory initial metabolic step prior to the intracellular conversion of 5-formylH4folate to other reduced folates and the increase in intracellular folate pools required for 5-FU potentiation. In the following paper, we will summarize results of biochemical and molecular studies of human MTHFS.
P-Glycoprotein, Multidrug Resistance and Protein Kinase C
Authors: Fine Robert L. , Chambers Timothy C. , Sachs Clifford W. 
Published: February 2020

Abstract
The multidrug resistant (MDR) phenotype is a well-studied subject that has been recognized as a determinant underlying specific types of drug resistance in human cancer. Although it is clear that the P-glycoprotein plays a major role in MDR, it is not clear whether post-translational modifications such as phosphorylation have any major impact on its modulation.
The laboratory of Dr. Bruce Chabner was one of the first to describe increased expression and activity of protein kinase C (PKC) associated with the MDR phenotype. Since that time, a similar correlation has been observed in many other MDR cell lines. Most of these studies have been performed with doxorubicin-selected cells that have acquired MDR and have shown increased PKC activity, mainly for PKC-α isoenzyme. Intrinsic MDR in human renal cell carcinoma lines has been shown to correlate directly with PKC activity, but further studies with intrinsic MDR cell lines are needed before any conclusions can be drawn.
More recent evidence suggests that there is a complex biochemical process by which PKC isoenzymes differentially phosphorylate specific serine residues in the linker region of P-glycoprotein which may lead to alterations in P-glycoprotein ATPase and drug-binding functions. To further complicate matters, PKC plays an important role in anti-apoptotic pathways, which can confound the dissection and elucidation of drug-resistance mechanisms. However, these areas are still under active investigation and not fully answered. Further studies are needed to specifically answer the question of whether PKC directly modulates basal and/or drug-stimulated P-glycoprotein function.
This manuscript reviews the majority of the literature on PKC and MDR, as well as offers caveats for interpretation of these studies to answer the above questions.
Clinical Reversal of Multidrug Resistance
Authors: Bates Susan E. , Wilson Wyndham H. , Fojo Antonio T. , Alvarez Manuel , Zhan Zhirong , Regis Joanna , Robey Rob , Hose Curtis , Monks Anne , Kang Yoon Koo , Chabner Bruce 
Published: February 2020

Abstract
Reversal of drug resistance offers the hope of increasing the efficacy of conventional chemotherapy. We tested dexverapamil as a P-glycoprotein antagonist in combination with EPOCH chemotherapy in refractory non-Hodgkin's lymphoma. In a cross-over design, dexverapamil was added to EPOCH after disease stabilization or progression occurred. Objective responses were observed in 10 of 41 assessable patients. Biopsies for mdr-1 were obtained before EPOCH treatment and at the time of cross-over to dexverapamil. Levels of mdr-1 were low before EPOCH, but increased fourfold or more in 42% of patients in whom serial samples were obtained. Pharmacokinetic analysis revealed median peak concentrations of dexverapamil and its metabolite, nor-dexverapamil, of 1.66 μmol/l and 1.58 μmol/l, respectively. Since both are comparable antagonists, a median peak total reversing concentration of 3.24 μmol/l was achieved. Pharmacokinetic analysis of doxorubicin and etoposide levels confirmed a delay in the clearance of doxorubicin ranging from 5% to 24%; no change in the pharmacokinetics of etoposide was observed. This study provides sufficient rationale for testing dexverapamil in a randomized clinical trial.
Treatment of Aplastic Anemia
Authors: Speck B. , Nissen C. , Tichelli A. , Gratwohl A. 
Published: February 2020

Abstract
There is general agreement that in children and adolescents with an HLA-identical or syngeneic sibling, bone-marrow transplantation (BMT) should be performed without delay. More controversial are young-to-middle-aged adults with an HLA-identical sibling. Because of comparable survival rates, some centers advocate BMT; others advocate immunosuppression as primary treatment. BMT cures severe aplastic anemia (SAA), but has a higher early mortality. Immunosuppression usually induces hemopoietic improvement and has hardly any early mortality. However, there are late problems. After immunosuppression, there may be relapse and clonal hematopoietic disease. After BMT, there may be late graft failure, severe or even fatal chronic graft-versus-host-disease (GVHD). Both procedures are followed by a slight increase in second malignancies. Retrospective studies show no significant differences in long-term survival between the two treatment modalities. In patients over the age of 40, immunosuppression is favored by most centers because in this age group there is a very high transplant-related mortality with BMT. Androgens and hematopoietic growth factors have hardly any role in therapy of SAA. Splenectomy helps some patients with severe thrombocytopenia and problems with supportive care, but does not improve the overall prognosis. BMT with unrelated donors has usually been performed in late stages of the disease with disappointing results.
The Problem of Thrombocytopenia after Hematopoietic Stem Cell Transplantation
Authors: Nash Richard A. , Gooley Ted , Davis Chris , Appelbaum Frederick R. 
Published: February 2020

Abstract
Thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of bleeding and utilization of significant resources. This review presents an analysis of risk factors associated with delayed platelet engraftment. The retrospective analysis included 1,468 recipients of autologous or allogeneic transplants treated between January 1, 1990 and July 1, 1995. Risk factors associated with delayed platelet engraftment after autologous HSCT included use of marrow rather than peripheral blood as the source of stem cells, being transplanted for acute myeloid leukemia rather than other diseases, positive patient serology for cytomegalovirus and the presence of infection post-transplant before engraftment. Risk factors associated with delayed platelet engraftment after allogeneic marrow transplantation included unrelated as opposed to related donor transplants, being transplanted for diseases other than chronic myelogenous leukemia, increased age, onset of acute graft-versus-host disease (GVHD), male gender, the administration of methotrexate for GVHD prophylaxis and the presence of infection before engraftment. Delayed platelet recovery is associated with decreased survival after both autologous and allogeneic transplants. Management of delayed platelet recovery by transfusion of blood products requires significant medical resources and is of some risk to the patients. Further development of new strategies may safely reduce the need for blood products. These include peripheral blood stem cell transplants (allogeneic and autologous), new algorithms for administering routine platelet transfusions and investigative biological agents for stimulating megakaryocytopoiesis. Further studies may elucidate the cause of increased platelet consumption associated with infection and GVHD.
Chemotherapy for Childhood Medulloblastoma and Primitive Neuroectodermal Tumors
Authors: Packer Roger J. , Finlay Jonathan L. 
Published: February 2020

Abstract
Medulloblastoma is the most common form of childhood brain tumor, and management has evolved over the past two decades. Chemotherapy is now an integral part of the treatment of the majority, if not all, patients with this disease. Medulloblastoma is a chemosensitive tumor, and recurrent disease will often respond to a variety of different chemotherapeutic agents. The use of higher-dose chemotherapy supplemented with aggressive hematological support may improve outcome for patients with recurrent disease. The results of prospective randomized trials and large, single, institutional trials in children with newly diagnosed disease suggest that chemotherapy, when given during and after radiotherapy, improves outcome. This is especially true for children with more extensive disease at the time of diagnosis. Event-free survival rates as high as 85% have been reported in children with newly diagnosed medulloblastomas treated with radiation and adjuvant chemotherapy consisting of CCNU, vincristine, and cisplatinum. At the present time, there is no clear evidence that preradiation chemotherapy improves survival for children with medulloblastoma. In fact, two prospective trials suggest that treatment with pre-irradiation chemotherapy may result in poorer overall outcome than treatment with similar doses of radiation therapy or radiation therapy supplemented by postradiation chemotherapy. There is preliminary evidence that chemotherapy may allow for a reduction in the dose of craniospinal irradiation therapy required to control disease, especially for children with nondisseminated disease at the time of diagnosis. Treatment for infants with medulloblastoma and other primitive neuroectodermal tumors remains suboptimal. Some infants and young children will experience long-term disease control after treatment with chemotherapy alone or chemotherapy followed by radiation when the child is older. High-dose chemotherapy supplemented by autologous bone marrow rescue or peripheral stem cell rescue has been utilized in young infants with promising results. The need for postchemotherapy radiation therapy and the volume of radiotherapy required to control disease remain under study.
Recent Developments in Acute Myelogenous Leukemia Therapy
Authors: King Mary E. , Rowe Jacob M. 
Published: February 2020

Abstract
Recent progress has been made in several areas in the treatment of acute myelogenous leukemia (AML): prognostic factors, allogeneic bone marrow transplantation, and new and targeted therapies. Delineation and clarification of prognostic factors have led to improved risk determination, with research moving from cytogenetics to an examination of molecular markers. Trends in the area of allogeneic bone marrow transplantation include broad adoption of reduced-intensity conditioning despite the lack of prospective comparative studies. Although the preponderance of data has established this as a feasible option, a true understanding of how much of an advantage it conveys needs to be established in prospective studies. The use of alternative donors is another advance, and recent data are promising, but survival is poor if transplantation is performed when disease is active, especially during refractory relapse or refractory disease. When haploidentical matched donors are used, survival rates appear similar to those reported with matched unrelated-donor transplants. Analysis of the data for allogeneic transplantation shows that HLA-identical sibling transplants to patients in the first complete remission (CR1) provide the highest probability of long-term survival, compared with HLA-identical sibling transplants to patients in later remissions. Similarly, unrelated-donor transplants to high-risk patients in CR1 lead to a greater degree of success than unrelated-donor transplants to patients in CR2 or later remission. Cord blood has also been established as a suitable source for hematopoietic transplantation in AML. A third area of recent progress involves new and targeted therapies. Multiple new agents with tremendous potential are in development and clinical trials. Therapy can even be tailored to several specific genetic subtypes of AML.
Role of Macrophages in Host Defense Against Aspergillosis and Strategies for Immune Augmentation
Authors: Segal Brahm H. 
Published: February 2020

AbstractInvasive aspergillosis is a major cause of morbidity and mortality in highly immunocompromised patients with cancer. Alveolar macrophages ingest inhaled conidia (spores). Through pathogen recognition receptors that ligate fungal cell wall motifs, macrophages are able to coordinate the inflammatory response to Aspergillus species. Macrophages and dendritic cells play an important role in regulating the balance between the proinflammatory and anti-inflammatory cytokine responses that are required for recruitment and activation of neutrophils, and in augmenting or attenuating cellular immunity. Macrophages are therefore a target for immune augmentation strategies that include administration of cytokines, colony-stimulating factors, and pathogen recognition receptor ligands.
Proposal for a New Staging Scheme for Intraocular and Extraocular Retinoblastoma Based on an Analysis of 103 Globes
Authors: Pratt Charles B. , Fontanesi James , Lu Xiaolong , Parham David M. , Elfervig Jon , Meyer David 
Published: February 2020

Abstract
Management of retinoblastoma is highly individualized and depends heavily on grouping or staging. In view of evolving methods of imaging and treating retinoblastoma, we have developed and evaluated a revised staging scheme. We analyzed the survival data of 73 patients treated at St. Jude Children's Research Hospital to compare the ability of the Reese-Ellsworth grouping system, the original St. Jude, and the modified St. Jude staging schemes to predict progression-free survival. None of the staging schemes significantly correlated with progression-free survival. This modified staging scheme provides an instrument for assessing the natural history of retinoblastoma based on ophthalmologic, other clinical, and imaging findings. Because it can identify patients at higher risk, the modified St. Jude scheme may be useful in selecting appropriate therapy regimens for children with retinoblastoma.
High-Dose Chemotherapy in Adult Solid Tumors and Lymphoproliferative Disorders: The Need for Randomized Trials
Authors: Droz Jean-Pierre , Culine Stéphane , Biron Pierre , Kramar Andrew 
Published: February 2020

Abstract
The demonstration of a dose-effect relationship in a wide spectrum of malignancies including solid tumors and lymphoproliferative disorders, along with the development of new techniques of hematopoietic stem cell support, have given rise to a growing interest for high-dose chemotherapy in recent years. Results in more than 3,000 patients included in nonrandomized trials have been reported in the literature. However, only nine randomized trials addressing the issue of the impact of high-dose chemotherapy on survival have been published: three in non-Hodgkin's lymphoma, one in multiple myeloma, two in metastatic breast cancer, one in germ-cell tumors, one in melanoma, and one in small-cell lung cancer. Firm, reliable conclusions can only be drawn from studies conducted in the salvage treatment of non-Hodgkin's lymphoma and in the first-line treatment of multiple myeloma: high-dose chemotherapy used in a consolidation setting after conventional chemotherapy leads to a survival advantage in chemosensitive patients. Promising but not firmly conclusive results were reported in metastatic breast cancer. The results of the sixteen ongoing randomized trials as well as studies addressing the issue of cost-effectiveness will be critical in establishing definite conclusions on the role of high-dose chemotherapy. With the exception of multiple myeloma and relapsed non-Hodgkin's lymphoma, there is no evidence for treating patients with high-dose chemotherapy outside randomized clinical trials.
Applications of Therapeutic Apheresis in Patients with Malignant Disease
Authors: Pineda Alvaro A. , Vamvakas Eleftherios C. 
Published: February 2020

Abstract
Therapeutic apheresis (TA) provides the means for the removal of blood components that are abnormal or that circulate in excessive amounts and have a defined pathogenetic role, or are thought to have one. Multiple disease processes have been treated with TA at one time or another, but scientific assessment of the therapeutic effects of the procedure has lagged behind application of the technology. This led the American Medical Association and the American Society for Apheresis to publish position papers on the proper applications of TA. In the field of oncology, therapeutic plasma exchange (TPE) and related procedures may be the treatment of choice for some conditions (e.g., TPE for thrombotic thrombocytopenic purpura, therapeutic leukapheresis for extreme leukocytosis in acute myelogenous leukemia, etc.), or may represent a promising therapeutic modality whose efficacy needs to be established by randomized controlled trials in the future (e.g., photopheresis for the treatment of cutaneous graft-versus-host disease). Some applications should be considered strictly investigational, and should be offered to patients only if they are part of an approved research protocol (e.g., extracorporeal immunoadsorption with staphylococcal protein A for non-hematologic cancer). Routine use of TA should be restricted to conditions where the benefit has been established by controlled studies or the best available evidence.
Central Nervous System Involvement and the Role of Prophylactic Cranial Irradiation in Small Cell Lung Cancer
Authors: Alexopoulos C.G. , Vaslamatzis M. , Patila E. , Taranto L. 
Published: February 2020

Abstract
This paper studies the frequency and manifestations of central nervous system (CNS) involvement and assesses the role of prophylactic cranial irradiation in small cell lung cancer (SCLC). All patients with confirmed diagnosis, admitted to our department within the last 15 years, were included. Patients were staged as having limited or extensive disease. Irradiation (40 Gy/20f) was offered to all complete responders immediately after polychemotherapy. There were 200 patients (176 men and 24 women, median age 58), 68 with limited and 132 with extensive disease. Twenty (10%) presented with CNS involvement, 14 (7%) developed it during chemotherapy and 47 (23.5%) during follow-up. In total, 81 (40.5%) developed CNS involvement, and in 57 (28.5%) it was the main manifestation. There was no relation to disease extent or type of response to therapy. The most frequent site of metastases was brain (33%), followed by leptomeninges (6%), spinal cord (1.5%), and pituitary (1.5%).
Of 79 complete responders, 51 (65%) received prophylactic cranial irradiation (PCI) and 28 (35%) did not. Frequency of CNS involvement was not significantly different (49% and 39%, respectively). Actuarial probabilities of developing CNS involvement were also not different. Nevertheless, 91% of complete responders without PCI relapsed only to CNS involvement, versus 48% with prophylactic irradiation. Cranioprophylaxis administration was followed by an improvement in overall survival, which was highly significant in limited disease. The actuarial survival of complete responders at two and four years was 46% and 26% with cranioprophylaxis versus 18% and 9% without, respectively.
CNS involvement in SCLC not only is a frequent complication, but also its frequency increases with lengthening survival. The necessity of routine use of brain CT scan during staging and follow-up is questioned in view of the present data. Administration of cranioprophylaxis did not reduce the frequency of CNS involvement in our series apparently because while it significantly delays CNS involvement, it does not abolish it. Nevertheless, survival of complete responders was prolonged with cranioprophylaxis and very significantly so in limited disease. This last finding, although clear cut, must await confirmation from randomized trials.
Management of Tracheal Neoplasms
Authors: Meyers Bryan F. , Mathisen Douglas J. 
Published: February 2020

Abstract
Primary tracheal tumors are rare neoplasms which often present with indolent and nonspecific symptoms. Despite a tendency for late presentation, more than half of patients with benign and malignant neoplasms will be candidates for curative resection upon diagnosis. This review describes the diagnostic and staging evaluation of tracheal neoplasms. Curative surgical procedures including laryngotracheal resection, tracheal resection, and carinal resection are discussed. Palliative therapies such as external beam radiation, endolumenal brachytherapy, bronchoscopic laser resection, and endoprosthetic stenting are reviewed.
New Advances in Interferon Therapy of Cancer
Authors: Wadler Scott , Schwartz Edward L. 
Published: February 2020

AbstractSubstantial increases in both the understanding of the cellular mechanisms of actions of interferon (IFN) and in its clinical use in cancer have occurred in recent years. The efficacy of interferon for the treatment of select malignancies has been established, and IFN-α and IFN-β have been approved by the Food and Drug Administration for multiple clinical indications. IFN-α increased median survival and relapse-free survival in patients with locally advanced melanoma when used as adjuvant therapy and had modest activity against advanced disease. In other tumors where studies indicated that IFN lacked direct therapeutic activity, clinical trials suggested that it increased the antitumor activity of cytotoxic chemotherapeutic agents when used in combination therapy. IFN has substantial activity in chronic myelogenous leukemia, increasing survival in patients in early chronic phase when compared with conventional chemotherapy, and has some activity in non-Hodgkin's lymphoma in combination with cytotoxic agents. Recent molecular and pharmacologic studies defining cellular receptor activation, signal transduction pathways, and biochemical modulating activities of interferon have yet to be fully incorporated into clinical development. Further preclinical advances along with the expanding identification of potentially clinically sensitive tumors make it likely that the use of IFN in cancer chemotherapy will continue to grow.
Vaccine Trials for the Clinician: Prospects for Viral and Non-Viral Vectors
Authors: Goedegebuure Peter S. , Eberlein Timothy J. 
Published: February 2020

AbstractRecent progress in tumor genetics, tumor biology, and tumor immunology has renewed interest in the development of tumor vaccines. Unlike the previous generation of vaccines that consisted of the patient's own tumor cells in some form, the new vaccines contain defined peptides or genes with a known function. In order to induce a potent and long-lasting cell-mediated antitumor response, viral as well as nonviral vectors have been explored as vehicles for gene delivery. Both types of vectors have shown encouraging results in animal models. However, because of the many possible vectors that have been designed, it may be too early to say which type of vector is most efficient in the human. Clearly, viral vectors have a higher transduction efficiency than most nonviral delivery systems. A drawback is that viral vectors may be toxic or immunogenic. Current research focuses on enhancing the targeting and specificity of both viral and nonviral vectors and control of transgene expression levels. Clinical studies using a variety of both viral and nonviral vectors have begun, and the results are forthcoming.