Jeffery Hunter Young, M.D., M.H.S.

• Associate Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0007602/jeffery-young

Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia antibiotics livestock order generic minocycline pills. Pharmacology of cytarabine given as a continuous infusion followed by mitoxantrone with and without amsacrine/etoposide as reinduction chemotherapy for relapsed or refractory pediatric acute myeloid leukemia antibiotics for sinus infection nhs buy generic minocycline. Relationship of 1-b-D-arabinofuranosylcytosine in plasma to 1-b-D-arabinofuranosylcytosine 5-triphosphate levels in leukemic cells during treatment with high-dose 1-b-D-arabinofuranosylcytosine virus notification proven minocycline 50mg. Intracellular retention of cytosine arabinoside triphosphate in blast cells from children with acute myelogenous and lymphoblastic leukemia antibiotics for acne in india buy cheap minocycline online. Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity virus neutralization test buy minocycline online from canada. Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants bacteria without cell wall purchase cheap minocycline. Risk factors for high-dose cytarabine neurotoxicity: an analysis of a Cancer and Leukemia Group B trial with acute myeloid leukemia. Cerebellar toxicity during cytarabine therapy associated with renal insufficiency. High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Comparison of the cellular pharmacokinetics and toxicity of 2,2-difluorodeoxycytidine and 1-beta-Darabinofuranosylcytosine. Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. Gemcitabine in patients with solid tumors and renal impairment: a pharmacokinetic phase I study. Saturation of 2,2-difluorodeoxycytidine 5-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. Altered thymidylate synthetase in 5-fluorodeoxyuridine-resistant Ehrlich ascites carcinoma cells. Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. Improving fluorouracil chemotherapy with novel orally administered fluoropyrimidines. Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes. A pilot study of interferon alfa-2a in combination with 5-fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients. Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients. More evidence for circadian rhythm effects in cancer chemotherapy: the fluoropyrimidine story. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Circadian rhythm varying plasma concentration of 5-fluorouracil during a 5-day continuous venous infusion at a constant rate in cancer patients. Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer. Severe 5-fluorouracil toxicity to dihydropyrimidine dehydrogenase deficiency: a potentially more common pharmacogenetic syndrome. Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5fluorouracil induced toxicity. Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracilbased chemotherapy. Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. A critical evaluation of the mechanism of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast cancer. Pharmacokinetics and pharmacodynamics of long-term continuous-infusion doxorubicin. Comparative pharmacokinetic study of idarubicin and daunomycin in leukemia patients. Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols. Doxorubicin concentrations in plasma and myocardium and their respective roles in cardiotoxicity. Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion doxorubicin in rabbit. Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. A phase I study of idarubicin hydrochloride in patients with acute leukemia: the Idarubicin Study Group of Japan. Pharmacokinetics of doxorubicin and its active metabolite in patients with normal renal function and in patients on hemodialysis. Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study. Adriamycin chemotherapy: efficacy, safety and pharmacologic basis of an intermittent single high-dosage schedule. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Acute doxorubicin toxicity: relationship to pretreatment liver function, response and pharmacokinetics in patients with acute non-lymphocytic leukemia. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. Time- and dose-dependent changes in ejection fraction determined by radionuclide angiography after anthracycline therapy. Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. Cardiac effects of anthracyclines used in the treatment of childhood acute lymphoblastic leukemia: a 10-year experience. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. Impact of scheduling on toxicity and clinical efficacy of doxorubicin: what do we know in the mid-nineties Adriamycin given as a weekly schedule without a loading course: clinically effective with reduced incidence of cardiotoxicity. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration. Doxorubicin cardiotoxicity in children: reduced incidence of cardiac dysfunction associated with continuous-infusion schedules. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. Initial congestive heart failure, six to ten years after doxorubicin chemotherapy for childhood cancer. Functional myocardial impairment in children treated with anthracyclines for cancer. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. Evaluation of anthracycline cardiotoxicity: predictive ability and functional correlation of endomyocardial biopsy. Concentrations of doxorubicin and its metabolites in human autopsy heart and other tissues. Serum troponin T levels and echocardiographic evaluation in children treated with doxorubicin. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Troponin T in the first 24 hours after the administration of chemotherapy and the detection of myocardial damage in children. Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. Subacute cardiotoxicity caused by anthracycline therapy in children: can dexrazoxane prevent this effect Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance. The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. Mitoxantrone is effective in treating childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia. Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies. Cumulative incidence and risk factors of mitoxantrone-induced cardiotoxicity in children: a systematic review. Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics. Sclerotherapy for malignant pleural effusions: a prospective randomized trial of bleomycin vs doxycycline with smallbore catheter drainage. Treatment of multiple superficial tumors of bladder with intravesicular bleomycin. Serum creatinine level during chemotherapy for testicular cancer as a possible predictor of bleomycin-induced pulmonary toxicity. Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary Pulmonary toxicity in patients with advanced-stage germ cell tumors receiving bleomycin with and without granulocyte colony stimulating factor. Subcutaneous infusions of bleomycin: a practical alternative to intravenous infusion. Bleomycin serum pharmacokinetics as determined by a radioimmunoassay and a microbiologic assay in a patient with compromised renal function. The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance. In vitro selection and characterization of a bleomycin-resistant subline of B16 melanoma. Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer. Development of an antibody to actinomycin D and its application for the detection of serum levels by radioimmunoassay. Inhibition of tubulin-microtubule polymerization by drugs of the vinca alkaloid class. The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Vincristine in childhood leukaemia: no pharmacokinetic rationale for dose reduction in adolescents. Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. Comparative pharmacokinetics of vindesine, vincristine, and vinblastine in patients with cancer.

This deficiency may delay the acceptance of an important advance or antibiotic resistance update order minocycline 50mg otc, more commonly antibiotic resistance neisseria gonorrhoeae discount minocycline 50 mg otc, as in small studies with limited power antibiotics used for uti order minocycline in india, may suggest the acceptance or rejection of a concept based when further investigation is really required infection after dc buy minocycline 50mg without a prescription. This section should clearly describe the experimental conditions antibiotics for deep acne buy minocycline online now, including the specifics of patient registration procedures bacteria 1 buy minocycline 50mg overnight delivery, inclusion and exclusion criteria, the target patient population, the details of the treatment regimen and any modifications, the schedule of follow-up evaluations, the definitions of and procedures used to assess major end points (including whether the person making the end point evaluation was "blinded" to the treatment assignment), and, in comparative trials, the nature of the control group and the specific methods used for treatment assignment. Randomization procedures and their timing relative to patient entry on study should be discussed. A brief description of quality control procedures can ensure the reader that the information reported is complete and accurate. Finally, a discussion of the statistical procedures used to analyze the data allows the reader to assess the reliability of the reported results. This description includes identification of analytic procedures used and explanatory material for techniques likely to be unfamiliar to the journal readership. References to articles or books describing all but the simplest and most standard techniques should be provided. The results section presents the outcome of the experiment; clear and detailed exposition is crucial. A complete description of the patients entered on the study, including age, disease characteristics, nature and amount of prior therapy, and other items considered important in determining eligibility or establishing prognosis, should be provided. Toxicity and compliance information should be included, and outcomes for all patients entered should be reported. Confining information to patients deemed evaluable prevents accurate comparisons across studies whose policies regarding evaluability may differ. If the data have been analyzed appropriately, the conclusions are usually self-evident. Potential sources of bias, the need for independent confirmation, and any other warnings should be included in the discussion. Claims of patient benefit should be circumspect and based on the demonstrated difference in outcome between experimental and control groups, whose characteristics have been accurately described. Claims of no benefit should be accompanied by a confidence interval around the observed difference; a calculated probability. Clinical development of anticancer agents-a National Cancer Institute perspective. Phase I studies of chemotherapeutic agents in cancer patients: a review of the designs. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Methods for dose finding studies in cancer clinical trials: a review and results of a Monte Carlo study. Estimating the probability of toxicity at the recommended dose following a phase I clinical trial in cancer. An extension of the continual reassessment methods using a preliminary up-and-down design in a dose finding study in cancer patients, in order to investigate a greater range of doses. Some practical improvements in the continual reassessment method for phase I studies. Early average change in tumor size in a phase 2 trial: efficient endpoint or false promise Rank tests and the one-sample logrank test for comparing observed survival data to a standard population. Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study. Using short-term response information to facilitate adaptive randomization for survival clinical trials. Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia. A two-stage design for choosing among several experimental treatments and a control in clinical trials. Report and recommendations of the Rome workshop concerning poor-prognosis acute lymphoblastic leukemia in children: biologic bases for staging, stratifcation, and treatment. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Computations for group sequential boundaries using the LanDeMets spending function method. Power and sample size determination for noninferiority trials using an exact method. Phase 0 clinical trials: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for protection of human subjects of research. Title 45, Code of Federal Regulations, Part 46: Health and Welfare, Protection of Human Subjects. Title 21, Code of Federal Regulations, Part 50: Food and Drugs, Protection of Human Subjects. Title 21, Code of Federal Regulations, Part 56: Food and Drugs, Institutional Review Boards. Title 45, Code of Federal Regulations, Part 46, Subpart D: Health and welfare, protection of human subjects, additional protections for children involved as subjects in research. American Society of Clinical Oncology Statement on minimum standards and exemplary attributes of clinical trial sites. Role of independent data-monitoring committees in randomized clinical trials sponsored by the National Cancer Institute [see comments]. Eligibility exclusions, losses to follow-up, removal of randomized patients, and uncounted events in cancer clinical trials. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. Subgroup analysis and other (mis)uses of baseline data in clinical trials [see comments]. Comparing survival of responders and nonresponders after treatment: a potential source of confusion in interpreting cancer clinical trials. Responder versus nonresponder comparisons: daunorubicin plus prednisone in treatment of acute nonlymphocytic leukemia [letter]. Practical problems in fitting a proportional hazards model to data with updated measurements of the covariates. Outcome of treatment in childhood acute lymphoblastic leukemia with rearrangements of the 11q23 chromosomal region. Outcome of treatment in children with Philadelphia chromosomepositive acute lymphoblastic leukemia. Intensifcation of mercaptopurine/methotrexate chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. Dangers of using "optimal" cutpoints in the evaluation of prognostic factors [see comments]. The effect of stratified randomization on size and power of statistical tests in clinical trials. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. A meta-analysis of the neuropsychological sequelae of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukemia: overview of 42 trials involving 12,000 randomized children. A comparison of statistical methods for combining event rates from clinical trials. Obtaining data from randomised controlled trials: how much do we need for reliable and informative meta-analyses Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses Methodologic guidelines for systematic reviews of randomized control trials in health care from the Potsdam Consultation on Meta-Analysis. Guidelines for publishing papers on cancer clinical trials: responsibilities of editors and authors. Statistics in medical journals: a survey of current policies and proposals for editors. This was only discovered several months later during a routine review of her medical records. It was determined that the ordering physician had written "cyclophosphamide 4 g/sq m over four days" with the intention that the patient receive a total of 1 gram per square meter over 4 sequential days. However, the order was interpreted as prescribing 4 grams per square meter for each of 4 sequential days. Betsy Lehman died 3 weeks later from the cardiac complications ensuing from this massive overdose. In 1980, the American Society of Anesthesiologists was the first professional group to form a patient safety committee after reviewing a television expose of anesthesia incidents. In the 1990s, the literature on medical errors started to become voluminous, and in 2009, PubMed (the search engine of the National Library of Medicine) listed more than 80,000 publications under the search term "medical error. Most publications describe interventions in the emergency room or during anesthesia, but few have addressed the special challenges involved in the treatment of children with complex disorders. In a prospective study over a year, the total and significant error rate, respectively, per 1,000 orders, was 3. A similar rate was found for residents and fellow trainees at any level: the error rate was 2. Furthermore, certain agents are highly toxic if administered by the wrong route. Caregivers, especially nurses and physicians, must adjust their medication orders not only to the underlying disease but also to the age, weight, and height of the child. Although "standard dosing" provides some measure of safety in adults because it brings familiarity with certain doses, the dosing is different for each child and the dosage schedule often changes during the course of the treatment, because the child may lose weight or develop new organ dysfunctions. In a review of oral chemotherapy for children with acute lymphoblastic leukemia, one or more errors were found with 17 of 172 (9. Eighty-five percent (264) of the 310 reported pediatric chemotherapy errors reached the patient, and 49 (15. Medication errors are defined as errors that occur at any stage in the medication use P. However, an additional 5% are "near misses" that fail to cause injury by chance or because they are intercepted before reaching the patient. Medication errors are frequent and cause substantial resource waste due to the need to discard the wrong medication, the additional work in preparing a new dose, and the necessary reporting and cause analysis. Recognizing and Reporting of Problems Different techniques have been used to assess error rates in the medical setting. In 2002, a conference entitled "Measuring Medication Safety in Hospitals" was held in Tucson, Arizona, and experts in the field (including physicians, pharmacists, and nurses) discussed the pros and cons of each method. The voluntary reporting method is strongly influenced by the culture of the organization and is most helpful in an environment where reporting is not perceived as being followed by a punitive action. In general, this method does not produce quantitative information, because only a small number of events are being reported, but it can furnish very valuable qualitative information about both errors and "near misses. Although often helpful in better understanding complex cases and the outcome and consequences of different pathologies, these conferences are fraught with hindsight bias, focus on diagnostic errors, and are infrequently and rather randomly used in most academic institutions. The chart review method is readily available and commonly used but is often inaccurate due to the lack of precise documentation and hindsight bias. It is also very labor intensive and dependent on consensus and confidence of the reviewers. The observation method measures actual errors during drug administration and dispensing. This method is more accurate and efficient than chart reviews but does require trained observers (nurses, pharmacists, or pharmacy technicians). In this method, deviations in timing of medication delivery, omission of doses, and the actual dosage administered are determined and can later be reviewed and graded by a medication safety committee in regard to significance. The practitioner intervention method involves keeping a formal log of interactions that occur daily between pharmacists and nurses or physicians to clarify an order. This method predominantly captures events at the prescribing stage and is also very useful for detecting "near misses. Nurses keep track of events where the pharmacy delivered the wrong drug, or at the wrong time, or to the wrong patient. Computerized monitoring has become more widely available as information technology has matured. However, coding is done weeks to months after discharge, and is generated for reimbursement and legal goals, and is thus not very reliable for detecting adverse events. Incident Reporting Internal reporting of adverse events is required by health care institutions, both to meet external regulatory requirements and to provide information to leadership to prevent other such events in the future. Each institution defines what should be reported and how it is carried out based on institutional priorities, relevant state law, and guidelines or requirements from regulatory agencies. Although incident reports themselves are not placed in the patient chart, disclosure to the patient should be documented in a progress note that also describes the event. In some, but not all, states, incident reports are considered peer review material and protected from legal discovery. As an organization focuses on patient safety and a nonpunitive reporting environment, the rate of incident reports tends to increase, a sign of success rather than failure. Occurrence Screens Most, if not all, health care organizations utilize dedicated staff members or automated reports to screen for the occurrence of specific events in the hospital, such as transfer to the intensive care unit, death, readmission within 72 hours, and return to the operating room within 48 hours.

Metastases to organs other than lungs or bones are rare in the absence of widespread disease and are associated with pulmonary or osseous P treatment for dogs galis order minocycline on line amex. Evaluation Clinical Evaluation the evaluation of a patient with suspected osteosarcoma begins with a full history antibiotic resistance metagenomics buy minocycline amex, physical examination antimicrobial spray cheap minocycline, laboratory evaluation antibiotics for uti caused by e coli order minocycline 50mg without prescription, and plain radiographs antibiotics for uti making me nauseous buy minocycline overnight delivery. The focus of the clinical history is determining the extent and duration of physical symptoms as well as the associated physical limitations (if any) bacteria gumball purchase minocycline now. Most patients present with pain and swelling of the affected area lasting from 2 to 6 months. Physical examination is generally only remarkable for the presence of a soft tissue mass at the site of the primary tumor. The most important prognostic factor is the presence of metastatic disease most commonly to the lungs,23 which drastically worsens outcome. Radiologic Evaluation Diagnostic imaging plays a major role in the management of children with osteosarcoma. In most cases, it is findings on conventional radiographs that indicate the presence of a malignant bone tumor. The periosteal new bone may be spiculated or laminated and tumors that occur in the diaphyses may have onion-skin periosteal reaction that simulates Ewing sarcoma. Occasionally a classic high-grade intramedullary osteosarcoma is completely sclerotic or lucent. However, the telangiectatic subtype of osteosarcoma typically presents as a cystic, lucent lesion with subtle matrix mineralization and a geographic margin with a wide zone of transition. On radiographs, these tumors appear as lobulated masses that attach to the cortex and are ossified centrally. Occasionally, parosteal osteosarcomas must be differentiated from myositis ossificans, which is ossified in the periphery and usually not attached to the cortex. The imaging findings can help in the selection of the optimal site for biopsy and this course of action will avoid distortion of the imaging findings by postbiopsy changes. A: T2-weighted fat-saturated image shows the tumor (curved arrows) involving and surrounding the femur and focal high signal area (straight arrow). B: Flowsensitive image shows high signal intensity flow in blood vessels (curved areas) to help identify the neurovascular bundle. C: T1-weighted, fat-saturated image showing predominantly enhancing tumor with nonenhancing focus confirming that the high signal area in A is fluid (straight arrow). Additional imaging is performed to detect metastatic disease, the majority of which is in the lungs. The size, number, and margins of the nodules can assist in making this distinction. Sharply marginated lesions larger than 5 mm in diameter, especially when multiple, are likely to be metastases,290 while solitary nodules less than 5 mm with unsharp margins are likely to be benign. Benign lesions are likely to remain unchanged in size, while lesions that increase or decrease in size are more likely to be metastases. However, in those uncertain cases wherein the diagnosis is crucial, nodule resection and biopsy are indicated. A: Axial image reviewed at lung windows shows multiple, small, welldefined peripheral nodules (arrows). B: Axial image reviewed at soft tissue windows shows high attenuation regions (arrows) corresponding to calcification within the lung metastases in a different patient. Thallium-201 has shown value in evaluating tumor response to chemotherapy, but has not gained widespread application. The placement of the biopsy site relative to the location of the tumor and the anatomic structures of the patient is also of critical importance. Generally, if a malignant bone tumor is suspected, an excisional biopsy is rarely, if ever, utilized. This is due to the fact that the tumor is often large at presentation and that neoadjuvant therapy is usually appropriate prior to definitive resection. If the lesion is most likely benign based upon the preoperative history, physical examination, and imaging studies, then at the time of excision a frozen section should be obtained. Primary excision of an expendable bone should only be considered by an experienced musculoskeletal oncologist. Expendable bones may include a rib, clavicle, sternum, ilium, scapular body, and perhaps, distal ulna. Most bone tumors of uncertain biologic potential, where there is a significant suspicion for malignancy, are biopsied via an incisional approach. It is strongly recommended that the biopsy be performed by the surgeon who will perform the definitive resection so that the biopsy tract can be ellipsed within the planned surgical incision. This can be conducted using a local anesthetic, which reduces the cost of the procedure. Accordingly, deep deployment of the needle within the tumor is unnecessary and likely to lead to problems such as deep contamination and bleeding. Again the needle biopsy site must be carefully planned so that it may be excised at the time of definite resection. Core biopsies are minimally invasive, can be performed under local anesthesia, maintain the architecture of the tissue, and can obtain adequate specimen for advanced studies. Since the final diagnosis should not be based on the frozen section, the patient must wait until the results are finalized, which may take several days if special studies are necessary. If the specimen is indeterminate, which can occur in 25% to 33% of cases, even at experienced centers,312 then a delay will most definitely occur. However for suspected bone malignancies, it is usually recommended that they be performed in the operating room. Generally speaking, longitudinal incisions are the rule since transverse incisions potentially contaminate flap planes and can compromise neurovascular structures. During the approach to the tumor, no flaps should be developed to minimize contamination. The area where the tumor is most superficial is preferable unless other factors, such as an overlying vessel or nerve, preclude this option. Furthermore, the preoperative imaging may suggest that a specific area within the tumor may be more diagnostic. A frozen section must be obtained to determine if diagnostic tissue has been retrieved, but not to establish the definitive diagnosis. Careful communication with the pathologist is essential preoperatively to clarify the amount of tissue necessary for special studies and any special processing of the tissue. Formaldehyde fixes the tissue, preventing the application of conventional cytogenetics and some molecular tests. A trephine is usually adequate but if a larger window is required it is imperative that it be round or oval to minimize stress risers. A pituitary rongeur may then be used to retrieve tissue from within the medullary canal. In such cases, a drain must be placed, in line with the incision distally, and sewn in place. While their use provides for a bloodless approach, they must be let down prior to closure to assure adequate hemostasis. If used, the limb should not be exsanguinated to minimize the risk of tumor embolus. Classification and Staging Tumor extent (local and systemic) as well as malignant potential must be taken into account when classifying and staging bone tumors. Surgical approaches are a function of the osteosarcoma subtype, as well as the location and extent of disease at the time of initial diagnosis. The successful management of osteosarcoma has evolved into a multimodality approach. Advances in chemotherapy have significantly improved survival, and surgical extirpation generally occurs after a course of neoadjuvant chemotherapy. It is of paramount importance that resumption of chemotherapy not be delayed postoperatively as a delay beyond 2 to 3 weeks has been associated with an increased risk of death. This, in combination with improved neoadjuvant therapy, has enabled the oncologic surgeon to obtain local control rates equivalent to amputation. However, in severe cases, where limb salvage may compromise the oncologic outcome, amputation is mandated. Because of the complexity of the musculoskeletal system, different reconstructive options are performed depending upon the site of involvement. Generally, bone tumors arise in the distal femur, proximal tibia, proximal humerus, proximal femur, and the diaphyses of long bones. Types of Reconstruction Conceptually, reconstruction involves rebuilding the skeletal and soft tissue defect to enable optimal function for the patient. The main reconstructive options include autogenous bone grafts, structural bone allografts (intercalary or osteoarticular), and metallic endoprosthetics. Allografts and endoprosthetics may be used in conjunction as a composite reconstruction. Which technique is employed remains a function of the location of the tumor, age of the patient, and types of adjuvant therapies employed. Large structural allografts and endoprosthetics should generally be reserved for children older than 8 years. Nonvascularized autografts from the pelvis or other sites may be used in a limited fashion for relatively small defects and work well in children. Vascularized autografts such as the fibula are attractive because, when successful, the graft incorporates and even may remodel itself secondary to the forces exerted across it. The major drawback to allografts is difficulty incorporating with the host bone (nonunion) and fracture. Infections can occur in 10% to 15% of allografts323,325,329,334,335,336 and nonunion at the osteosynthesis site in 10% to 25% of cases. Augmentation of the allograft with a vascularized fibula, while adding its own set of potential complications may facilitate osseous integration of the structural graft thereby preventing the inherent problems associated with allografts. In select cases, a combination of vascularized auto- and allografting techniques may be optimal. Infections are a significant risk with endoprosthetics as well, with rates ranging from 0% to 35%. The durability of any endoprosthesis is subject to a variety of influences but the anticipated event-free 5-year survival for proximal femur reconstructions approaches 90%, while for the distal femur is about 60% and the proximal tibia just over 50%. Improved metallurgy has resulted in a significant reduction in metal fatigue and failure of the implants. Articulating, moving components need revision at a rate in direct relation to the cyclical loading of the prosthesis. Sometimes failure can be catastrophic, as can be seen with late infections, necessitating a delayed amputation. Expandable prosthetics are available with multiple, varying mechanism for expansion. Stress shielding and mechanical loosening are compounded by the continued diametrical growth of the host bone. While revision surgery is possible, the resultant bone stock for refixation can be quite tenuous. Modular components are now available for both pediatric and adult patients making the delay for customization the exception. The use of expandable prosthesis is a contentious topic and is influenced by cultural factors. More biologic reconstructive options, as discussed subsequently, are preferred by some surgeons, in the best interest of their patients, and yet the cosmetic considerations, which can be so heavy influential in some societies, is a counterargument endorsed by others. For metallic prosthesis, newer cementless, porous ingrowth systems have been developed346,363,364 but have not yet replaced cement in most centers. A novel prestress compliant fixation device, with encouraging early results, is also currently available that obviates the need for long intramedullary stems, thereby avoiding stress shielding. Arthrodesis remains an option in limb preservation surgery, but it is utilized with diminishing frequency as endoprostheses and allografts have improved. The advantage to fusion is that once healed the construct is very durable and may endure heavy labor. The procedure may be better tolerated in the upper rather than the lower extremity,380 with perhaps the exception of the ankle in select cases. Reconstruction as a Function of Location For tumors of the shoulder and proximal humerus, limb salvage is generally possible with preservation of the neurovascular structures. One unique reconstructive option for the proximal humerus is the clavicula pro humero whereby the clavicle is disarticulated from the manubrium and rotated on its vascular pedicle and fused to the remaining distal humerus providing a very stable and durable reconstruction. The middle and proximal fibula, rib, clavicle, scapular body, and iliac wing can forgo reconstruction with good functional results. In the pelvis, for iliac wing resections involving the sacroiliac joint and/or posterior column (Zone I), autografts, either non- or vascularized, can be employed to reconnect the supra-acetabular pelvis to the sacrum although reconstruction is not always necessary. External hemipelvectomy (hind quarter amputation) historically was the only surgical option. When no reconstruction is performed, the space between the hip and residual pelvis/sacrum results in significant limb shortening (up to 4 inches) and poor function, albeit better than external hemipelvectomy. An attempt at creating a sling from synthetic material to prevent proximal migration, which is subsequently augmented by scarring, may assist in minimizing limb length inequality. Saddle endoprosthetic, allograft-hip arthroplasty composites, and complete endoprosthetic replacement have all been performed. If internal hemipelvectomy is to be attempted, the goal must be an adequate resection of the tumor, which can prove to be quite difficult. Special Considerations for the Skeletally Immature the skeletally immature patient presents a particular challenge in that the reconstruction must be dynamic in order to accommodate future growth when a physis is sacrificed. Because osteosarcoma generally arises in the child and adolescent, this can become a significant issue. In girls, the growth spurts occur in pre- and early adolescence, while in boys it happens later. Most of the growth in the lower extremity is provided for by the physes about the knee (distal femur approximately 40%, proximal tibia approximately 30%) while the upper femur and lower tibia have modest contributions of about 15% each. Limb lengthening via distraction osteogenesis is also an option,405,406,407 but there remains concern in utilizing this complex technique concurrently with P.

Treatment of Paraspinal Neuroblastoma Because of the anatomic location of paraspinal sympathetic ganglia antimicrobial mouthwash purchase on line minocycline, primary neuroblastomas arising in these structures P antibiotic resistance uptodate order minocycline cheap online. This is a true medical emergency antibiotics for sinus infection in toddlers buy generic minocycline line, and the onset of symptoms can be indolent or acute antibiotics empty stomach best purchase minocycline. Many of these patients are quite young antimicrobial agents 1 order discount minocycline, and so extensive laminectomies or radiation to the spine can result in long-term morbidity bacteria game minocycline 50 mg for sale. Several groups have reported their retrospective experience with the management of intraspinal neuroblastoma. Thus, chemotherapy appears to be both a safe and effective initial modality to manage spinal canal invasion, and it has far less long-term morbidity than surgery or radiation therapy. Treatment of Recurrent Disease Standardized and highly effective salvage approaches are available for low- and intermediate-risk disease patients who have local disease relapse. Patients with high-risk neuroblastoma who have recurrent or refractory disease or develop progressive disease remain a significant clinical challenge, and currently there are no known curative salvage regimens. Nevertheless, there has been a dramatic shift in focus over the past decade, and several highly active agents have been identified in this setting, resulting in prolonged survival for a subset of patients. Recent advances in our understanding of the molecular basis of high-risk neuroblastoma has identified tractable therapeutic targets that will likely result in exceptional antitumor activity when studied in the clinic. This section highlights recent advances in the treatment of recurrent or refractory high-risk neuroblastoma. Novel Conventional Chemotherapeutic Agents the camptothecin analogs topotecan and irinotecan are topoisomerase I antagonists that have proven activity against refractory neuroblastoma. Garaventa436 reported a 64% response rate with higher dose topotecan for 5 days followed by a 48-hour infusion of vincristine and doxorubicin. Irinotecan has been studied intensively in recent years because of the relatively mild hematologic toxicity and potential for abrogation of diarrheal complications by concomitant administration of oral antibiotics. Circumvention of de novo or acquired drug resistance is likely critical to improve response rates in the relapse setting. Targeted Delivery of Radionuclides Generally, neuroblastomas are radiation sensitive, but because the disease is often disseminated, there has been interest in delivering radionuclides targeted to neuroblastoma cells. A completed phase 2 trial at the 18 mCi per kg dose level in 167 neuroblastoma patients demonstrated acceptable toxicity and objective response rates of 45% to 50% in a heavily pretreated patient population. A pilot study for children with newly diagnosed high-risk neuroblastoma will open soon to assess the feasibility of a topotecan-containing induction regimen P. Current preclinical and clinical studies are focused on determining which naturally occurring retinoid or synthetic derivative gives optimal systemic exposure allowing for maximum tumor differentiation (or kill) without excessive toxicity. However, because of relatively poor oral bioavailability of the formulation studied, a very large number of capsules were required to deliver the maximum tolerated dose. Immunotherapy Immunotherapeutic strategies for treating neuroblastoma were originally postulated on the basis of the hypothesis that spontaneous regression might result from a host immune response to neuroblastoma. This approach has been shown to have activity and manageable toxicity in a recent phase 2 study. However, neovascular inhibition strategies are challenging in young children with developing organs and tissues, and this needs to be considered during the preclinical and clinical development of this class of drugs. Kinase Inhibitor Therapies Paradigm shifting advances in cancer require discovering the key oncogenic drivers of the malignant process, understanding the detailed molecular mechanisms, and exploiting this transdisciplinary knowledge therapeutically. This will represent the first therapy for neuroblastoma specifically developed for a mutated oncogenic driver. Although mutations in the neurotrophin receptors have not been seen, there is evidence that aberrant Trk receptor expression contributes to aggressive clinical behavior in neuroblastomas and may be a good therapeutic target. Screens of the neuroblastoma "kinome" for other potential drug targets, especially those in late-stage clinical development for adult malignancies, are ongoing. Chromosome instability is a prevalent finding in pediatric and adult cancers, and functional abnormalities of centrosomes have been strongly associated with aneuploidy in cancer cells. The Aurora A kinase gene is amplified and/or overexpressed in many adult cancers,493,494,495,496,497 and its overexpression results in the transformation of normal cells, thus supporting its role as an oncogene. Preliminary data suggest that the Aurora A kinase gene is overexpressed in neuroblastoma cells,498,499 and that selective small molecule inhibition of this kinase has potential application in this disease. Other Strategies Because epigenetic silencing of genes such as caspase 8, which are critical for inducing programmed cell death, appears to occur frequently in neuroblastomas,500 use of demethylating agents such as decitabine are being explored. Inhibitors of histone deacetylation are being developed for multiple cancers and have demonstrated preclinical activity against neuroblastoma. Moreover, there is an expanding portfolio of potential drugs to be tested in pediatric phase 1 clinical trials, so it is becoming increasingly important to have firm biological rationale and evidence for efficacy in appropriate preclinical models in order to prioritize drug development and guide their use in the patients most likely to benefit. Late Effects A variety of complications of neuroblastoma and its treatment may occur that are not unique to this tumor. Indeed, there is a trend toward observation for patients with localized and biologically favorable tumors, but the consequences of not removing large tumors will have to be followed carefully. Patients in the intermediate-risk category are exposed to surgery as well as moderately intensive chemotherapy. However, recent approaches have been directed toward overall reduction in therapy to avoid treatment-related morbidity for these patients, and this trend will likely continue as we improve our ability to more precisely define patient risk using biological markers. High-risk patients are at the greatest risk of experiencing treatment-related complications. Survivors often have significant long-term health issues that can affect multiple organ systems, and these can be partly anticipated based on the treatment delivered. A number of different second neoplasms have been reported in patients with neuroblastoma following treatment, such as thyroid cancer, pheochromocytoma, brain tumors, acute leukemia, osteosarcoma, breast cancer, and renal cell carcinoma. Continued improvements in risk stratification based on evolving knowledge of neuroblastoma biology should allow the most appropriate intensity of therapy to be selected, minimizing the likelihood of either undertreatment or overtreatment. Longer term improvements in cure rates are likely only to come from a more precise understanding of the biological basis of neuroblastoma. The ability to survey the entire cancer genome, transcriptome, or proteome is in hand, and many investigators are applying these technologies to neuroblastoma. Translation of these findings to the clinic will include further refinement of risk stratification so that treatment can be individually tailored. Perhaps more important, these data will allow for the identification of rational targets for drug development. The major cooperative groups will need to adopt more facile early phase clinical trial designs to efficiently evaluate candidate drugs with a longer term focus on where these agents will fit into the current multimodal high-risk neuroblastoma therapy backbone. Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring. Parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring. German neuroblastoma mass screening study at 12 months of age: statistical aspects and preliminary results. Screening infants for neuroblastoma does not reduce the incidence of poor-prognosis disease. Comparison of the incidences of neuroblastoma for screened and unscreened cohorts. Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study. Increased risk of cancer among siblings of long-term childhood cancer survivors: a report from the childhood cancer survivor study. Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p. Homozygous deletion of the neurofibromatosis-1 gene in the tumor of a patient with neuroblastoma. Abnormal constitutional karyotypes in patients with neuroblastoma: a report of four new cases and review of 47 others in the literature. Identification and high-resolution mapping of a constitutional 11q deletion in an infant with multifocal neuroblastoma. Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature. Unequivocal delineation of clinicogenetic subgroups and development of a new model for improved outcome prediction in neuroblastoma. A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma. Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. Genetic heterogeneity of neuroblastoma studied by comparative genomic hybridization. Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients. Inverse relationship between trk expression and N-myc amplification in human neuroblastomas. Expression of N-myc by neuroblastomas with one or multiple copies of the oncogene. Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma. Analysis of 1;17 translocation breakpoints in neuroblastoma: implications for mapping of neuroblastoma genes. The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma. Deletion of chromosome 1p loci and microsatellite instability in neuroblastomas analyzed with short-tandem repeat polymorphisms. Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastomas: correlation with N-myc amplification. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. Fluorescence in situ hybridization analyses of chromosome band 1p36 in neuroblastoma detect two classes of alterations. Identification and characterization of a 500-kb homozygously deleted region at 1p36. Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. Coordinate deletion of chromosome 3p and 11q in neuroblastoma detected by comparative genomic hybridization. Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus. Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes. Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas. High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Expression profiling and characterization of 4200 genes cloned from primary neuroblastomas: identification of 305 genes differentially expressed between favorable and unfavorable subsets. Meta-mining of neuroblastoma and neuroblast gene expression profiles reveals candidate therapeutic compounds. Role of neurotrophins and their receptors in human neuroblastomas: a primary culture study. Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Cisplatin-induced cytotoxicity is blocked by brain-derived neurotrophic factor activation of TrkB signal transduction path in neuroblastoma. Differential effect of P75 coexpression on TrkA and TrkB response to ligands in neuroblastoma. Expression of the ret proto-oncogene in human neuroblastoma cell lines and its increase during neuronal differentiation induced by retinoic acid. Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. Evidence for the development of p53 mutations after cytotoxic therapy in a neuroblastoma cell line. Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Oncogenic cooperation between H-Twist and N-Myc overrides fail safe programs in cancer cells. Disruption of cooperation between Ras and MycN in human neuroblastoma cells promotes growth arrest. Histopathological prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Neuroblastoma with meningeal involvement causing increased intracranial pressure and coma in two children. Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus.

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