bluuebunny/crossref_metadata_2025 huggingface dataset:
Concentration of dynamic stresses in an elastic space with twoperiodic array of elliptical cracks
Authors: Zhbadynskyi Igor
Published: February 2020

Normal incidence of the plane time-harmonic longitudinal wave on double-periodic array of coplanar elliptical cracks, which are located in 3D infinite elastic space is considered. Corresponding symmetric wave scattering problem is reduced to a boundary integral equation for the displacement jump across the crack surfaces in a unit cell by means of periodic Green’s function, which is presented in the form of Fourier integrals. A regularization technique for this Green’s function involving special lattice sums in closed forms is adopted, which allows its effective calculation in a wide range of wave numbers. The boundary integral equation is correctly solved by using the mapping method. The frequency dependencies of mode-I stress intensity factor in the vicinity of the crack front points for periodic distances in the system of elliptical cracks are revealed.
Thermoelasticity if isotropic solids containing non-deformable thread-like inclusions
Authors: Pasternak Jaroslav , Sulym Heorhiy , Ilchuk Nataliia
Published: February 2020

The paper derives integral equations of heat conduction and thermoelasticity of isotropic solids with non-deformable perfectly thermally conducting thread-like inclusions. It is observed that, in spite of the order of singularity, the integral equations obtained are hypersingular due to the symmetry of the kernels. Non-integral terms of these equations are derived. A boundary element method scheme for numerical solution of formulated problems is proposed. A numerical example is provided.
Implementasi Kebijakan Disiplin Pegawai Negeri Sipil Di Balai Latihan Kerja Mandiri Provinsi Jawa Barat
Authors: Anggara Sahya , Nur Mohamad Ichsana , Daroni Ahmad
Published: February 2020

The purpose of this study was to determine the policy implementation of Government Regulation Number 53 of 2010 concerning Discipline of Civil Servants at the Independent Training Center of West Java Province. The method in this reseach used is descriptive qualitative method. In this study, researchers examined the implementation of policy, the researchers used the theory of policy implementation model Edward III in Widodo (2017) about four factors that play an important role in achieving successful implementation, namely communication, resources, disposition, and bureaucratic structure. Data were obtained through observation, interviews, documentation, and library studies and using data analysis techniques according to Miles and Huberman. The results of the study, the Implementation of Government Regulation Number 53 of 2010 concerning Discipline of Civil Servants at the West Java Provincial Independent Training Center has not run optimally. First, communication has gone well because of the distribution of the regulations to the staff. Second, the resources are not optimal because the number of human resources in the West Java Province Independent Training Center is still lacking and the preparedness needs to be improved. Third, the disposition has been well seen from the willingness of the Employees to attend the morning rally, obey working hours, and carry out tasks responsibly. Fourth, the bureaucratic structure has been effective because the West Java Provincial Training Center already has Standard Operating Procedures and clear fragmentation procedures
Implementasi Kebijakan Pengelolaan Parkir Kota Bandung
Authors: Hidayat Asep , Munandar Aris , Armidiana Armidiana
Published: February 2020

The Parking Tax Revenue, from 2013 to 2016, experienced ups and downs and less significant increase, especially in 2015, it run into a very significant decrease from the target. This study aims to analyze the implementation of parking management policy in buildings and parking lots in Bandung. The Research uses a qualitative approach, with descriptive research type. Data collection techniques used are in-depth interviews and literature study. The determination of informants in this study was carried out using the purposive technique. To analyze the data, this research uses  qualitative data analysis, namely by searching and systematically compiling data obtained from interviews, field notes, and other materials. The results of this study indicate that the implementation of Peraturan Wali Kota No. 1005 of 2014 regarding Parking Lease Prices and Technical Guidelines for Parking Management in Buildings and Parking Grounds in Bandung City has not been running optimally, because it has been seen from several factors that influence it.
Kualitas Pelayanan Publik Di Balai Pelayanan, Penempatan, Dan Perlindungan Tenaga Kerja Indonesia Wilayah Bandung
Authors: Abdilah Wawan Setiawan , Miharja Sakrim , Lestari Yeni Dewiyanti
Published: February 2020

This study aims to analyze the quality of public services at the Bandung Service Center, Placement and Protection of Indonesian Workes (BP3TKI) Bandung. This research method uses  qualitative methods with descriptive approach. Data collection techniques used were in-depth interviews and documentation studies. Informants in this study were Head Of Correctional and Program Institution Section, Head of Placement Preparation Section, service staff and TKI. In addition, the steps in data analysis according to Miles and Huberman consist of three stages, namely: data reduction, data presentation and conclusion/ verification. The results of this study were obtained from the results of interviews that: (1) The quality of public service at the Indonesian Workforce Service, Placement and Protection Center (BP3TKI) Bandung has implemented five dimensions namely: Tangible, Reliability, Responsiviness, Assurance, Emphaty along with indicators. However, from some indicators there are still those that have not gone according to the wishes of Indonesian infrastructure, there are still officers who are capable and expert in operating the tools  available at BP3TKI Bandung, and the officers’ inability to process service to TKI. (2) barriers that existin the implementation of public service at the Indonesian Workforce Service, Placement and Protection Center (BP3TKI) in Bandung is that there is no place for medical examinations for Indonesian migrant workers, and banks to pay for insurance so that migrant workers must leave the office, and for facilities and infrastructure that are still not maximal to support the service process.
The relationship of the prolonged PR interval with the long-term survival in patients with heart failure undergoing cardiac resynchronization therapy
Authors: Soldatova A. M. , Kuznetsov V. A. , Gizatulina T. P. , Malishevsky L. M. , Dyachkov S. M.
Published: February 2020

Aim. To assess the relationship between the prolonged PR interval (≥200 ms) and the long-term survival of patients undergoing cardiac resynchronization therapy (CRT).

Material and methods. A total of 85 patients (mean age — 55,1Ѓ}9,9 years; men — 81,2%) with NYHA class II-IV heart failure (HF) were examined. The mean follow-up was 34,0Ѓ}21,2 months. Patients with PR<200 ms (n=52) made up group I, with PR≥200 ms (n=33) — group II. Then the patients were divided into subgroups depending on the QRS duration: ≥150 ms (n=33 in group I and n=14 in group II, respectively) <150 ms (n=19 in group I and n=19 in group II, respectively).

Results. In patients of group II, a history of myocardial infarction (MI) was more often registered (p=0,005), left ventricular ejection fraction (LVEF) was lower (p=0,032). In a multivariate analysis, MI (OR 3,217; CI 95% 1,188-8,712; p=0,022) and LVEF value (OR 0,869; CI 95% 0,780-0,968; p=0,011) had a significant relationship with the PR interval prolongation (≥200 ms). The survival of patients of group I was 59,6%, group II — 18,2% (Log-rank test p<0,001). According to Cox regression model, the initial left ventricle end-systolic volume (OR 1,012; 95% CI 1,006-1,017; p<0,001), inferior wall MI (OR 1,690; 95% CI 1,131-2,527; p=0,011) and PR interval ≥200 ms (OR 2,179; 95% CI 1,213–3,915; p=0,009) were associated with long-term mortality. In patients with PR≥200 ms, survival rate was low, regardless of the QRS duration (21,4% in patients with QRS≥150 ms, 15,8% in patients with QRS<150 ms; Log-rank test p=0,698) In patients with PR<200 ms, the survival rate of patients with QRS≥150 ms was 72,7%, and for patients with QRS<150 ms — 36,8% (Log-rank test p=0,031).

Conclusion. In HF patients, PR interval prolongation (≥200 ms) is associated with long-term mortality increase. The highest survival rates were observed in patients with PR<200 ms and QRS≥150 ms. In patients with QRS≥150 ms, the presence of PR≥200 ms should be considered as an additional criterion for CRT.
Complicated upper extremity deep vein thrombosis (Paget-Schroetter disease): a case report
Authors: Syromyatnikova L. I. , Aliev E. Kh. , Lapin O. M. , Mekhryakov S. A.
Published: February 2020

We report the case of the development of pulmonary embolism in a patient with Paget-Schroetter disease.
Ventricular-arterial coupling parameters and its prognostic value in patients with decompensated heart failure
Authors: Kobalava Z. D. , Lukina O. I. , Meray I. , Villevalde S. V.
Published: February 2020

Aim. To assess ventricular-arterial coupling (VAC) parameters and their prognostic value in patients with decompensated heart failure (HF).

Material and methods. VAC parameters were evaluated upon admission using two-dimensional echocardiography in 355 patients hospitalized with decompensated HF. VAC was expressed as the ratio between arterial elastance (Ea) and end-systolic LV elastance (Ees). The optimal VAC range was considered 0,6-1,2. Parameters of left ventricular (LV) efficacy were calculated using the appropriate formulas. Differences were considered significant at p<0,05.

Results. The median values of Ea, Ees and VAC were 2,2 (1,7;2,9) mmHg/ml, 1,8 (1,0;3,0) mmHg/ml and 1,32 (0,75;2,21) respectively. In 63% of patients, VAC disorders were detected: 55% of patients had VAC >1,2 (predominantly patients with HF with reduced ejection fraction (HFrEF)-79%), 8% of patients had VAC <0,6 (all patients with HF with preserved ejection fraction (HFpEF)). Normal VAC was observed in 78%, 42%, and 1% of patients with HFpEF, HF with mid-range EF and HFrEF, respectively. There was significant correlation between Ea/Ees ratio and levels of NTproBNP (R=0,35), hematocrit (R=-0,29), hemoglobin (R=-0,26), pulmonary artery systolic pressure (PAPs) (R=0,18), dimensions of left atrium (R=0,32) and right ventricle (RV) (R=0,32). After 6 months, rehospitalization with decompensated HF was recorded in 72 (20,3%) patients, 42 (11,8%) patients died. Ea decrease <2,2 mmHg/ml and PAPs increase >45 mmHg increased the risk of rehospitalization with decompensated HF and all-cause mortality 2,5 and 3,7 times, respectively.

Conclusion. Impaired VAC was diagnosed in 63% of patients with decompensated HF. However, the increased risk of all-cause mortality and rehospitalization with decompensated HF over the 6 months was associated with Ea decrease <2,2 mmHg/ml and PAPs increase >45 mmHg.
Treatment of Androgen-Independent Prostate Cancer
Authors: Bubley Glenn J. , Balk Steven P.
Published: February 2020

Androgen-ablative therapy for metastatic prostate cancer is effective for 60%-80% of men, but its effects are always finite and the majority of men develop androgen-independent disease within two years. Although current therapies for androgen-independent disease have not been shown to impact on survival, recent clinical and laboratory insights offer hope for effective therapy. For instance, recent data indicate that androgen-independent disease may still be dependent on hormonal stimulation, suggesting that hormonally based therapies may provide continued benefit. Chemotherapy, especially with estramustine and etoposide, seems to be an effective combination for a majority of patients. Treatment with suramin had been hampered by its side effects, but new dosing schedules are effectively circumventing toxicity. Radioisotopes such as strontium 89 have been shown to provide effective palliation for a majority of androgen-independent patients. Overall, these and other emerging efforts may be the foundation for therapies that offer hope for a significant survival benefit.
Treatment of Meningeal Malignancy
Authors: Berg Stacey L. , Poplack David G.
Published: February 2020

Meningeal metastasis from cancer has become an increasingly frequent problem as the treatment of systemic disease improves. Leukemia, lymphoma and solid tumors may all metastasize to the meninges, where the blood-brain barrier may provide a sanctuary from cytotoxic concentrations of chemotherapeutic agents. Because meningeal disease may be clinically silent or may present with unusual signs and symptoms, it is important to maintain a high index of suspicion for this problem. Diagnosis is usually made by cerebrospinal fluid cytologic testing, magnetic resonance imaging, or both. Treatment options include radiation therapy, systemic chemotherapy and intrathecal chemotherapy. Systemic therapy usually requires administration of either very high drug doses or prolonged infusions in order to overcome the poor penetration of most anticancer agents into the central nervous system. Thus, systemic toxicity is often a major drawback to this approach. Intrathecal chemotherapy results in delivery of anticancer agents directly into the cerebrospinal fluid, usually with minimal systemic toxicity. Intrathecal chemotherapy may be administered by lumbar puncture or by use of an Ommaya reservoir with the tip in the ventricle. Studies are under way to evaluate new agents for both systemic and intrathecal administration. Further research is required to overcome this difficult clinical challenge.
Thyroid Abnormalities after Therapy for Hodgkin's Disease in Childhood
Authors: Bhatia Smita , Ramsay Norma K.C. , Bantle John P. , Mertens Ann , Robison Leslie L.
Published: February 2020

Background. Involvement of the thyroid gland is an important morbidity of therapy for Hodgkin's disease, which should be well recognized by caretakers of these patients. However, the roles of age at the time of therapy for Hodgkin's disease, chemotherapy, treatment with reduced dose of radiation and lymphangiography in causing thyroid abnormalities have not been defined.

Materials and Methods. Eighty-nine pediatric and young adult patients (less than 21 years old at diagnosis) with Hodgkin's disease who were treated with either radiation alone (57 patients), radiation and chemotherapy (20 patients), or chemotherapy alone (12 patients) at the University of Minnesota between 1971 and 1986 were periodically evaluated.

Results. The median age at diagnosis was 14 years, and the median duration of follow up was 11 years. Of 89 patients evaluable for thyroid abnormalities, 51 patients developed biochemical hypothyroidism. The median time to development of hypothyroidism was six years. The estimated actuarial risk of developing hypothyroidism was 60% at 11 years. Radiation to the thyroid region was associated with an elevated risk of development of hypothyroidism (relative risk = 9.9), with patients receiving mantle irradiation alone developing hypothyroidism earlier (median time 2.5 years) than patients receiving combined modality treatment (median time 6 years; p = 0.001). Dose of radiation was the chief correlate for the development of hypothyroidism (relative risk increasing by 1.02/Gy; p < 0.001). Age, gender, chemotherapy and prior lymphangiography were not shown to be significant risk factors for the development of hypothyroidism. Four patients were diagnosed with thyroid nodules, (diagnosed 7.6 to 14.3 years after treatment of Hodgkin's disease), with histology showing multinodular goiter (2), single colloid nodule (1) and papillary carcinoma (1). Transient hyperthyroidism developed in two patients 8 and 13 months after treatment for Hodgkin's disease.

Conclusions. There is a high risk for development of thyroid disease after patients have received radiation therapy for Hodgkin's disease, reinforcing the need for continued clinical and biochemical evaluation of such patients.
Locally Advanced Breast Cancer
Authors: Valero Vicente , Buzdar Aman U. , Hortobagyi Gabriel N.
Published: February 2020

Locally advanced breast cancer encompasses a heterogeneous collection of breast neoplasms and constitutes approximately 10%-20% of the newly diagnosed breast cancers. These cancers may have widely different clinical and biological characteristics. Patients with these tumors may be classified as stage IIB, III or IV breast cancer according to the American Joint Committee for Cancer Staging and End Results Reporting (TNM classification). Multidisciplinary therapy has become the treatment of choice for these patients. Primary or neoadjuvant chemotherapy followed by locoregional therapy, either surgery and/or radiotherapy, and postoperative systemic chemotherapy is now an accepted strategy. More than 70% of patients achieve an objective response (including pathological complete remission in 10%-25% of cases), and many patients experience downstaging through primary chemotherapy. Breast conservation is possible in 10%-40% of patients with locally advanced breast cancer; almost all patients initially are rendered disease-free, and long-term local control is achieved in over 70% of these patients. Primary chemotherapy is the initial choice of treatment for patients with locally advanced tumors, but it is unclear what the optimal sequence of subsequent therapies should be, whether one or two local treatment modalities are necessary, and whether any or different postoperative chemotherapy is needed. The efficacy of primary chemotherapy was demonstrated in several large prospective studies in patients with locally advanced breast cancer. The natural history of this disease was changed dramatically by the introduction of these combined modality therapies. Five-year disease-free survival rates of 35%-70% are commonly reported, and about 25%-40% of patients will survive beyond 10 years without recurrence. In summary, multidisciplinary therapy that includes primary chemotherapy provides appropriate local control and the possibility of breast conservation therapy; it increases surgical resectability and survival rates in patients with locally advanced breast cancer. The role of new innovative therapeutic strategies such as high-dose chemotherapy, with hematopoietic stem cell rescue, new cytotoxic agents and higher dose-intensity therapy is currently under evaluation in patients with locally advanced breast cancer.
Methotrexate: An Effective Agent for Treating Cancer and Building Careers. The Polyglutamate Era
Authors: Schilsky Richard L.
Published: February 2020

This paper chronicles developments in the laboratory of Dr. Bruce Chabner during the period 1978-1981. Initial work demonstrated that methotrexate is taken up by human breast cancer cells by a high-affinity, carrier-mediated, energy-dependent transport system similar to that described in murine leukemia cells. Conversion of methotrexate to a high molecular weight polyglutamate metabolite was also demonstrated to occur in human breast cancer cells. Polyglutamates became the predominant form of intracellular drug, both free in the cytosol and bound to dihydrofolate reductase, during a 24 h exposure to clinically achievable methotrexate concentrations. Intracellular retention of polyglutamates led to prolonged suppression of thymidine synthesis and loss of cell viability after removal of extracellular drug. This work identified methotrexate polyglutamates as biologically active enzyme inhibitors in human tumor cells and launched a series of investigations on the interaction of these derivatives with folate-requiring enzymes.
Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase
Authors: Jolivet Jacques , Dayan Alain , Beauchemin Myriam , Chahla Dounia , Mamo Aline , Bertrand Richard
Published: February 2020

5-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

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

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

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

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

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

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

Invasive 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

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

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

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

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

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

Substantial 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

Recent 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.
Tumor Markers in Ovarian Malignancies
Authors: Eagle Karen , Ledermann Jonathan A.
Published: February 2020

Epithelial ovarian cancer is the most common ovarian malignancy. CA125, the glycoprotein defined by the antibody OC 125, is the most important clinical marker for the diagnosis, treatment and follow-up of epithelial ovarian cancer. However, like most tumor markers, it is neither wholly specific nor sensitive for the disease. We discuss how CA125 in combination with other tests can be used in the differential diagnosis of pelvic masses and as part of the investigations for cancer screening. CA125 is an important indicator of response to treatment, guiding therapeutic decisions and identifying those patients whose response to chemotherapy and survival is short. CA125 has recently been shown to correlate well with response and can be used to define relapse. Thus, it can be used as a surrogate endpoint in the assessment of new therapeutic modalities as well as in reducing the need for tumor imaging. At the moment, the other tumor markers for non-germ-cell neoplasms of the ovary are clinically less important than CA125, but their role alone or in association with CA125 is the subject of intense study as the search for ideal tumor markers to identify early disease, prognosis, and relapse continues.
Positron Emission Tomography: Current Role for Diagnosis and Therapy Monitoring in Oncology
Authors: Strauss Ludwig G.
Published: February 2020

High-resolution cross-sectional imaging improved dramatically the diagnosis and therapy management of oncological patients, although several questions remained open, primarily concerning the exact initial staging, the differential diagnosis of recurrent tumors, and therapy management. Positron emission tomography (PET) is a quantitative, functional imaging modality from the field of nuclear medicine which has the potential to yield physiological information. The diagnosis of tumors with PET is based on the increased regional glucose metabolism. Furthermore, PET can serve as a valuable tool for monitoring therapeutic effects.

The most common tracer used for oncological studies is F-18-deoxyglucose (FDG), a glucose analog. FDG-PET has been evaluated in different tumor types such as colorectal cancer, malignant lymphomas, melanomas, soft-tissue sarcomas, and lung tumors for both the diagnosis of primary tumors and recurrent lesions. The sensitivity of PET-FDG studies exceeds 85%, dependent on tumor type, size, and location. The diagnosis of viable tumor tissue following chemotherapy is another application of PET. A limitation of FDG-PET studies is false positive results, e.g., due to inflammation. This problem may be overcome by the use of multitracer studies and/or labeled amino acids.

Different procedures can be used to evaluate therapeutic effects. FDG follow-up studies are used to assess early effects and to predict long-term response. Pharmacokinetic studies of labeled therapeutic agents such as F-18-fluorouracil or C-11-ethanol provide exclusively quantitative data about transport and elimination of a drug. PET with labeled cytostatic drugs permits a prognosis prior to onset of chemotherapy. This procedure is recommended for monochemotherapy. In patients receiving polychemotherapy, the evaluation of different resistance mechanisms is needed and new approaches using suitable substrates, e.g., for the P-glycoprotein, are being developed or are already in use for scientific purposes.
Clinical Use of Irinotecan:Current Status and Future Considerations
Authors: Saltz Leonard B.
Published: February 2020

Irinotecan (CPT-11, Camptosar), a semisynthetic, water-soluble derivative of the plant alkaloid camptothecin, is a drug which has undergone extensive clinical investigation worldwide. It is, at this time, commercially available in the United States for the treatment of fluorouracil-refractory colorectal cancer. In this review, I will discuss the current approved clinical use, discuss the issues of toxicity and its management, and consider some of the ongoing clinical investigations which are exploring possible future uses for this agent.