Judith L. Bader

Neurofibromatosis and childhood leukemia

Twelve new cases of childhood leukemia and neurofibromatosis were ascertained and evaluated in conjunction with 17 previously well-documented cases. The ratio of ALL: nonlymphocytic leukemia was 9:20, markedly different from the 4:1 ratio in children without NF. Rarer subtypes predominated: 8 CML and 8 AMML. The peculiar distribution of leukemia by cell type and the number of cases observed in the United States indicate that the risk of childhood leukemia in NF is increased. Two possible variants were noted: NF with “transient leukemia,” and multiple skin xanthomas with nonlymphocytic leukemia.

Neurofibromatosis and Cancer

Cancer is among the most serious complications of the autosomal dominant genetic disorder neurofibromatosis (NF). This review will address 13 key questions relevant to the study of NF and cancer. Before beginning, however, certain basic issues must be clarified. First, this paper will consider only peripheral NF, not central NF (bilateral hereditary acoustic neuroma). Second, the definition of cancer is operational. Optic glioma, meningioma, and other low-grade neural tumors that act like and are treated like cancer are herein considered malignant tumors, even though by strict pathologic appearance and nomenclature they may not be malignant. Neurofibromas, including plexiform neurofibromas, are not considered cancers in this discussion. Third, because there is as yet no biomarker, the diagnosis of NF is made on clinical grounds and may not always be straightforward. Young children may not yet have developed a sufficient number of NF stigmata and certain adults may have an equivocal number or array of stigmata when the diagnosis of cancer is made. In these individuals, linking N F to cancer cannot be done with certainty.

Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation.

A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network.

The effect of systemic therapy on local-regional control in locally advanced breast cancer

One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical parital response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower local-regional failure rate compared to IIIB inflammatory patients, with the 5-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer (p = .02), and local-regional failure as any component of first failure 12% versus 36% (p = .01), respectively. When local-regional failure was analyzed by repeat biopsy, 5/31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2/53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy (p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not however, significantly affect either relapse-free or overall survival.

Radiologic and nuclear events: contingency planning for hematologists/oncologists

Untoward events involving radioactive material, either accidental or intentional, are potentially devastating. Hematologists and oncologists are uniquely suited to help manage radiation victims, as myelosuppression is a frequent complication of radiation exposure. In the aftermath of a large event, such as a nuclear detonation, there may be a national call for surge capacity that involves hematologists/oncologists across the country in the disaster response. In preparation, the National Marrow Donor Program and American Society for Blood and Marrow Transplantation have established the Radiation Injury Treatment Network (RITN), a voluntary consortium of transplant centers, donor centers, and umbilical cord blood banks. RITN is partnered with the Office of the Assistant Secretary for Preparedness and Response in the United States Department of Health and Human Services to develop treatment guidelines, educate healthcare professionals, coordinate situation response, and provide comprehensive evaluation and care for radiation injury victims. We outline the current plans for event response and describe scenarios, including catastrophic events that would require extensive support from hematologists/oncologists across the country. In addition, we highlight important reference resources and discuss current efforts to develop medical countermeasures against radiation toxicity. Practitioners and institutions across the country are encouraged to become involved and participate in the planning.

First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation.

OBJECTIVE Hematopoietic syndrome (HS) is a clinical diagnosis assigned to people who present with ≥ 1 new-onset cytopenias in the setting of acute radiation exposure. The World Health Organization convened a panel of experts to evaluate the evidence and develop recommendations for medical countermeasures for the management of HS in a hypothetical scenario involving the hospitalization of 100 to 200 individuals exposed to radiation. The objective of this consultancy was to develop recommendations for treatment of the HS based upon the quality of evidence. METHODS English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to panel members before the meeting and updated during the meeting. Published case series and case reports of individuals with HS, published randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. In cases in which data were limited or incomplete, a narrative review of the observations was made. No randomized controlled trials of medical countermeasures have been completed for individuals with radiation-associated HS. The use of GRADE analysis of countermeasures for injury to hematopoietic tissue was restricted by the lack of comparator groups in humans. Reliance on data generated in nonirradiated humans and experimental animals was necessary. RESULTS Based upon GRADE analysis and narrative review, a strong recommendation was made for the administration of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor and a weak recommendation was made for the use of erythropoiesis-stimulating agents or hematopoietic stem cell transplantation. CONCLUSIONS Assessment of therapeutic interventions for HS in humans exposed to nontherapeutic radiation is difficult because of the limits of the evidence.

Literature Review and Global Consensus on Management of Acute Radiation Syndrome Affecting Nonhematopoietic Organ Systems

OBJECTIVES The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature. METHODS English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation system. In cases in which data were limited or incomplete, a narrative review of the observations was made. RESULTS No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made for the administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/or shock. A strong recommendation is made against the use of systemic steroids in the absence of a specific indication. A weak recommendation is made for the use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and for selective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients. CONCLUSIONS High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future.

Allocation of scarce resources after a nuclear detonation: setting the context

The purpose of this article is to set the context for this special issue of Disaster Medicine and Public Health Preparedness on the allocation of scarce resources in an improvised nuclear device incident. A nuclear detonation occurs when a sufficient amount of fissile material is brought suddenly together to reach critical mass and cause an explosion. Although the chance of a nuclear detonation is thought to be small, the consequences are potentially catastrophic, so planning for an effective medical response is necessary, albeit complex. A substantial nuclear detonation will result in physical effects and a great number of casualties that will require an organized medical response to save lives. With this type of incident, the demand for resources to treat casualties will far exceed what is available. To meet the goal of providing medical care (including symptomatic/palliative care) with fairness as the underlying ethical principle, planning for allocation of scarce resources among all involved sectors needs to be integrated and practiced. With thoughtful and realistic planning, the medical response in the chaotic environment may be made more effective and efficient for both victims and medical responders.

Stem Cells, Multiorgan Failure in Radiation Emergency Medical Preparedness: A U.S./European Consultation Workshop

The concern of the public regarding terrorist actions involving nuclear emergencies resulted in the reopening of the discussion regarding the best ways to cope with the inevitable health impairments. Medical experts from the US and from Europe considered it of importance to harmonize at an international level the diagnostic and therapeutic approaches regarding the radiation‐induced health impairments. The present contribution is the result of the first U.S./European Consultation Workshop addressing approaches to radiation emergency preparedness and assistance, which was held recently at Ulm University, Ulm, Germany. Discussions dealt with the assessment of the extent of damage after total body exposure and, in particular, the quantity and quality of the damage to the hematopoietic stem cell pool. Secondly, the pathogenesis of the multiorgan failure was considered because of the organ‐to‐organ interactions. Thirdly, approaches were considered to harmonize the “triage‐methods” used on an international level using the “Response Category” approach as developed for the European Communities. These discussions lead to the conclusion that there is a strong need for continuing education of physicians, nurses, and support personnel to address the issues posed by the management of patients suffering from radiation syndromes. Finally, the discussions expressed the need for more international cooperation in research and development of more refined methods to treat patients with any type of radiation syndromes. Stem Cells 2009;27:1205–1211

Radiation event medical management (REMM): website guidance for health care providers.

Planning for andexercising the medical response to potential chemical, biological, radiological, nuclear, andexplosive (CBRNE) terrorist events are new responsibilities for most health care providers. Among potential CBRNE events, radiological and/or nuclear (rad/nuc) events are thought to have received the least attention from health care providers andplanners. To assist clinicians, the U.S. Department of Health andHuman Services (HHS) has created a new, innovative tool kit, the Radiation Event Medical Management (REMM) web portal (http://remm.nlm.gov). Goals of REMM include providing (1) algorithm-style, evidence-based, guidance about clinical diagnosis andtreatment during mass casualty rad/nuc events; (2) just-in-time, peer-reviewed, usable information supported by sufficient background material andcontext to make complex diagnosis andmanagement issues understandable to those without formal radiation medicine expertise; (3) a zip-file of complete web portal files downloadable in advance so the site would be available offline without an Internet connection; (4) a concise collection of the printable, key documents that can be taken into the field during an event; (5) a framework for medical teams andindividuals to initiate rad/nuc planning andtraining; and(6) an extensive bibliography of key, peer-reviewed, andofficial guidance documents relevant to rad/nuc responses. Since its launch, REMM has been well received by individual responders andteams across the country andinternationally. It has been accessed extensively, particularly during training exercises. Regular content updates andaddition of new features are ongoing. The article reviews the development of REMM andsome of its key content areas, features, andplans for future development.