A qualitative analysis of an advanced practice nurse-directed transitional care model intervention.

PURPOSE: The purpose of this study was to describe barriers and facilitators to implementing a transitional care intervention for cognitively impaired older adults and their caregivers lead by advanced practice nurses (APNs). DESIGN AND METHODS: APNs implemented an evidence-based protocol to optimize transitions from hospital to home. An exploratory, qualitative directed content analysis examined 15 narrative case summaries written by APNs and fieldnotes from biweekly case conferences. RESULTS: Three central themes emerged: patients and caregivers having the necessary information and knowledge, care coordination, and the caregiver experience. An additional category was also identified, APNs going above and beyond. IMPLICATIONS: APNs implemented individualized approaches and provided care that exceeds the type of care typically staffed and reimbursed in the American health care system by applying a Transitional Care Model, advanced clinical judgment, and doing whatever was necessary to prevent negative outcomes. Reimbursement reform as well as more formalized support systems and resources are necessary for APNs to consistently provide such care to patients and their caregivers during this vulnerable time of transition.

Mechanism-based competitive inhibitors of glyoxalase I: intracellular delivery, in vitro antitumor activities, and stabilities in human serum and mouse serum.

S-(N-Aryl-N-hydroxycarbamoyl)glutathione derivatives (GSC(O)N(OH)C6H4X, where GS = glutathionyl and X = H (1), Cl (2), Br (3)) have been proposed as possible anticancer agents, because of their ability to strongly inhibit the methylglyoxal-detoxifying enzyme glyoxalase I. In order to test this hypothesis, the in vitro antitumor activities of these compounds and their [glycyl,glutamyl] diethyl ester prodrug forms (1(Et)2-3(Et)2) have been examined. All three diethyl esters inhibit the growth of L1210 murine leukemia and B16 melanotic melanoma in culture, with GI50 values in the micromolar concentration range. Cell permeability studies with L1210 cells indicate that growth inhibition is associated with rapid diffusion of the diethyl esters into the cells, followed by enzymatic hydrolysis of the ethyl ester functions to give the inhibitory diacids. In contrast, the corresponding diacids neither readily diffuse into nor significantly inhibit the growth of these cells. Consistent with the hypothesis that cell growth inhibition is due to competitive inhibition of glyoxalase I, preincubation of L1210 cells with 2(Et)2 increases the sensitivity of these cells to the inhibitory effects of exogenous methylglyoxal. Compound 2(Et)2 is much less toxic to nonproliferating murine splenic lymphocytes, possibly reflecting reduced sensitivity to methylglyoxal and/or reduced chemical stability of the diacid inside these cells. Finally, a plasma esterase-deficient murine model has been identified that should allow in vivo testing of the diethyl esters.

Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice.

PURPOSE: The efficacy of 13-cis-retinoic acid (13-CRA) given as a single agent or in combination with tamoxifen (TAM) was determined in athymic nude mice bearing advanced s.c. MCF-7 human breast cancers. METHODS: 13-CRA alone was given by gavage at doses ranging from 26.4 to 200 mg/kg. TAM alone was given by gavage at doses of 7.5, 15, 30, or 60 mg/kg. For combination studies, each dose of TAM was followed 4 h later by 13-CRA at doses of 25, 50, 100, or 200 mg/kg. All treatments began on day 12 and were continued for 3 weeks. RESULTS: The median time to two doublings recorded for the control and for 13-CRA and TAM given as single agents at the highest dose were 22.2, 29.2, and 54.7 days, respectively. In combination, 100 and 200 mg/kg 13-CRA with 7.5 mg/kg TAM resulted in a delay in tumor growth at least as high as that achieved with highest-dose TAM alone, but the effect was not synergistic. Pharmacokinetic analysis of 13-CRA was performed in plasma, liver, and tumor from mice bearing 0.5- to 2.0 g carcinomas following a single dose of 100 mg/kg 13-CRA. Results showed that 13-CRA was metabolized differently in various tissues, but concentrations of 13-CRA detected in tumor were in the range reported to be active in vitro. all-trans-Retinoic acid (ATRA) concentrations were about 5% of the 13-CRA concentrations detected in plasma, 68% of those found in liver, and 20% of those found in tumor. 4-oxo-CRA represented between 2% and 10% of 13-CRA concentrations detected in plasma and liver but was not detected in tumor. Furthermore there was no difference in peak plasma 13-CRA concentrations found in the same tissues at 30 min after a single dose or after the eighth dose of 100 mg/kg 13-CRA or 13-CRA and TAM. Mean 13-CRA concentrations detected in liver and tumor were 50-90% and 16-30% of plasma peak concentrations, respectively. No difference in 4-oxo-CRA concentration was observed between the treatment groups. CONCLUSIONS: These data suggest that 13-CRA is not effective against established human breast tumor xenografts despite the stability of the pharmacokinetics of 13-CRA and the generation of ATRA as a metabolite. The addition of 13-CRA to TAM did not improve the efficacy of TAM against these estrogen-receptor-positive xenografts.

Medical management of eosinophilic granuloma of the cervical spine.

We report a case of eosinophilic granuloma involving the vertebral bodies of the cervical spine in a 33-month-old girl. This lesion was diagnosed by needle biopsy and treated with prednisone and vinblastine therapy along with immobilization in a Minerva brace. The child has done well over a 9-month follow-up and has shown MRI evidence of resolution of the lesion, reestablishment of structural integrity within the cervical spine and potential reconstitution of the involved vertebral bodies.

The use of counterflow centrifugal elutriation for the depletion of T cells from unrelated donor bone marrow.

Transplantation of marrow from unrelated donors is associated with an increased incidence and severity of graft-versus-host disease (GVHD). In an attempt to minimize GVHD without compromising engraftment, unrelated donor marrow was depleted of lymphocytes by counterflow centrifugal elutriation (CCE), and a fixed dose of 0.5 x 10(6) CD3+ T cells/kg, as measured in real time by flow cytometry, was added back to the graft. Patients received cyclosporine (CYA) and corticosteroids for GVHD prophylaxis and to facilitate engraftment. In the first cohort (study I), 7 patients received busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (CY) and one patient received CY (200 mg/kg) + 1260 cGy fractionated TBI. Of 6 who were evaluable for both engraftment and rejection, 4 rejected their graft. The study was terminated, and the protocol was modified (study II) by the addition of antithymocyte globulin (ATG) to the pre-BMT and post-BMT therapy. Twelve patients received CY + TBI as above plus ATG given pre-BMT and post-BMT. Ten of twelve who received ATG engrafted. Twelve patients from studies I and II were evaluable for acute GVHD. Two developed grade I acute GVHD. Two patients developed grade II acute GVHD, 2 patients developed grade III GVHD, and 1 patient developed grade IV acute GVHD. Two of three cases of acute GVHD (> grade II) occurred later than day 100 after BMT concomitant with reduction of immunosuppressive therapy. The rate of engraftment was significantly higher in study II (p = .054). In numbers of CD34+ cells infused, numbers of CFU-GM infused, and numbers of nucleated cells did not correlate with engraftment. We conclude that (a) in contrast to the results seen in recipients of marrow from HLA-matched sibling donors, the depletion of unrelated donor marrow of all but 0.5 x 10(6) CD34+ cells/kg together with CYA + corticosteroids was not sufficient to facilitate engraftment. The use of a more immunosuppressive regimen containing TBI and ATG appeared to improve engraftment. (b) The reduction of the graft T cell dose to 0.5 x 10(6) CD34+ cells/kg resulted in a higher incidence of acute GVHD than that seen in recipients of marrow from genotypically identical donors whose marrow was similarly processed.

Delayed resection in the management of non-orbital rhabdomyosarcoma of the head and neck in childhood.

This retrospective study was undertaken to evaluate the effect of delayed resection on outcome of head and neck rms in a single institution which has experience in cranial base surgery. Since 1988, patients with primary non-orbital rms of the head and neck following treatment at the Children's Hospital of Pittsburgh, were evaluated by the Department of Otolaryngology, Eye and Ear Hospital at the University of Pittsburgh Medical Center either at the time of presentation or when response to chemotherapy and/or radiation therapy was thought to have been optimized for the possibility of definitive surgery. Medical records of patients who did or did not have delayed surgery were reviewed and compared with respect to demographics, tumor stage, response to therapy, survival, and cosmetic results. Of 16 children diagnosed with non-orbital head and neck rms from 1988-1994 and treated with chemotherapy according to IRS II-IV, 3 had group I or II disease following extensive surgery at diagnosis. Thirteen had group III or IV disease. Of these, 6 patients had delayed resection and 7 did not. Delayed resection was undertaken 3-12 months (median, 4 months) from diagnosis in 4 children who had a partial response (PR) and 2 children who had stable disease (SD) with chemotherapy and/or radiation. Delayed resection converted all children to complete responses (CR), including one child with clinical SD and one with PR who were found to have no viable tumor at surgery. The overall percentages of CRs for patients with group III or IV disease (documented any time post-diagnosis) were at least as good for patients who had undergone delayed surgery as for those who had not (100% vs. 71%, p = .465). Median survivals for patients with advanced disease were 3 1/2 years and 2 years, respectively (p = .2801). Cosmetic and functional problems attributable to surgery were not severe but included facial asymmetry (n = 4), trismus (n = 1), cranial nerve deficits (n = 1), and abnormal dentition (n = 1). In locally extensive head and neck rms, cranial base surgery should be considered after initial cytoreductive therapy, since it may contribute to achievement of CR and to survival with acceptable morbidity.

Transient 7q- in association with megaloblastic anemia due to dietary folate and vitamin B12 deficiency.

PURPOSE: We describe a case of acquired megaloblastic anemia in a 7 1/2 year-old white boy whose bone marrow showed unusual morphology and a nonrandom del(7q). METHODS AND RESULTS: This patient was found to have megaloblastic anemia due to acquired folic acid and vitamin B12 deficiencies. Bone marrow examination exhibited unusual morphology, including intranuclear inclusions. Cytogenetic analysis revealed a nonrandom del(7q), a clonal abnormality usually associated with the myelodysplastic syndrome (MDS) or secondary acute myelogenous leukemia (AML). Specific treatment with both folic acid and vitamin B12 corrected the clinical as well as the marrow morphologic and cytogenetic abnormalities. CONCLUSIONS: Megaloblastic anemia causes abnormalities in DNA synthesis and repair that may result in unusual marrow findings, both morphologic and cytogenetic. Such findings must be interpreted with caution in view of total reversibility with specific vitamin therapy.

An abnormal clone with monosomy 7 and trisomy 21 in the bone marrow of a child with congenital agranulocytosis (Kostmann disease) treated with granulocyte colony-stimulating factor. Evolution towards myelodysplastic syndrome and acute basophilic leukemia.

Cytogenetic analysis of bone marrow cells revealed an abnormal clone with monosomy 7 and trisomy 21 in a 12-year-old child with Kostmann disease (KD). The patient presented with anemia, thrombocytopenia, and splenomegaly after 5 years of treatment with granulocyte colony-stimulating factor (G-CSF). The bone marrow morphology was consistent with the diagnosis of myelodysplastic syndrome (MDS). Administration of G-CSF was discontinued at this point. Bone marrow studies 2 and 5 months later showed persistence of both myelodysplasia and the abnormal clone with monosomy 7 and trisomy 21. Monosomy 7 was also confirmed by fluorescence in situ hybridization (FISH). After 2 months of follow-up, the patient presented with acute basophilic leukemia, a very rare variant of acute myeloid leukemia (AML), expressing the same bone marrow chromosome abnormalities as observed earlier. This is a rare case of KD with prolonged survival and a cytogenetically abnormal clone evolving to MDS and acute basophilic leukemia. The significance of monosomy 7 and trisomy 21 in KD treated with G-CSF is discussed.

Progressive varicella presenting with pain and minimal skin involvement in children with acute lymphoblastic leukemia.

PURPOSE: Here we report the experience at the Children's Hospital of Pittsburgh (CHP) with varicella zoster virus (VZV) in children with acute lymphoblastic leukemia (ALL). This record review was prompted by a patient with ALL who died suddenly of varicella hepatitis within 24 hours of presentation with a single skin lesion. METHODS: We reviewed the medical records of children diagnosed with ALL at the CHP from January 1984 through December 1993, who subsequently developed VZV infection. RESULTS: Of 294 patients aged 0 to 15 years, 41 (14%) were identified as having had 42 episodes of VZV infection. Twenty patients (49%) had received prophylaxis with varicella zoster immunoglobulin (VZIG), and all 39 patients in whom the diagnosis was made premortem were treated with acyclovir. Twenty-nine of the 42 cases (70%) had disease limited to the skin. Thirteen cases (30%) had extracutaneous involvement, and five of these episodes (12% of all cases) ended in death. Risk factors for progressive varicella included age greater than 6 years and intensive immunosuppressive therapy at the time of exposure. Six of eight patients with progressive varicella, including two who died, had received VZIG. The clinical presentation in 10 of 13 patients with progressive disease and in four of five patients who died was dominated by severe abdominal and/or back pain. In seven cases, these symptoms preceded the development of skin lesions by several days, and in six patients were associated with extensive involvement of the spleen by varicella, as demonstrated histopathologically by the presence of Howell-Jolly bodies on peripheral-blood smear or radiographically. No patient with uncomplicated varicella was reported to have had premonitory pain. CONCLUSION: Recognition of these prodromes and suspicion of varicella even in the absence of skin lesions and even in children with a history of prior disease or VZIG administration should prompt early diagnostic and therapeutic measures.

FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation.

Steroid-resistant graft-versus-host disease (GVHD) is an often lethal complication of bone marrow transplantation (BMT). FK506 (tacrolimus) is a new potent immunosuppressant which has been shown to be superior to conventional immunosuppression in the prevention and treatment of graft rejection in recipients of solid organ transplants. To determine whether FK506 is effective in the treatment of steroid-resistant acute GVHD, 6 children with biopsy-proven severe GVHD were studied. FK506 was administered as intravenous or oral therapy and the dose was adjusted to achieve serum levels between 0.5 and 1.0 microgram/ml by ELISA. Steroid doses were tapered based on clinical grading in each organ. Within 1-2 days, improvement occurred in skin and gut in all patients, and in liver in 3 patients. Toxicity attributable to FK506 was similar to that described in solid organ transplant patients and included neurotoxicity, nephrotoxicity and gastrointestinal effects. While FK506 is effective in the treatment of steroid-resistant acute GVHD, toxicity may limit its use. Further studies evaluating FK506 as GVHD prophylaxis and treatment of less advanced GVHD are needed.

Herpes simplex dissemination following glucocorticoids for upper airway obstruction in an adolescent girl.

A previously healthy adolescent female suddenly developed a severe febrile pharyngitis and impending upper airway obstruction. Her Monospot test was positive, and her throat culture grew group A beta-hemolytic streptococcus. After treatment with antibiotics and glucocorticoids, she developed a fulminant course dominated by disseminated intravascular coagulation and hepatic necrosis. At autopsy, herpes simplex virus type-1 was cultured from lung, liver, and spleen tissue. We believe this is the first report of disseminated herpes simplex infection after steroid use for upper airway obstruction.

Catecholamine metabolites in ganglioneuroma.

With rare exception, ganglioneuroma (GN) is a benign lesion which presents as a localized mass without metastatic potential and which is chemotherapy resistant. Thus, its distinction from neuroblastoma (NB) may be important. The diagnosis of GN implies the absence of neuroblastic elements. Incomplete resection prevents complete microscopic examination and raises the possibility that focal NB was not sampled. In an attempt to determine what features other than histology distinguish these two entities, we reviewed the charts of 25 patients with GN with regard to patient age and sex, tumor location and size, and urine catecholamine metabolite levels. One patient with GN (5%) and gross total resection had elevated quantitative vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels (2.4 x upper limit of normal for age), and two others had positive spot analyses for VMA. An additional patient with a large mass, multiple biopsies of which documented GN, also had greatly elevated (approximately 5 x normal) VMA and HVA levels. However, a subsequent attempt at resection disclosed several gross foci of NB. Even excluding this patient, there was a trend for elevated values in GN patients to correlate with tumor size (P = .07 and .14 for VMA and HVA, respectively). The incidence of elevated values appears to increase as a function of tumor size, and small tumors are not likely to result in positive urinary measurements. We conclude that while elevations of VMA and HVA are consistent with a well-documented diagnosis of GN, extreme elevations (> 3 x nl) should prompt careful serial evaluation for occult NB.

Toxicity following concurrent intrathecal and moderate-dose intravenous methotrexate.

To evaluate factors predisposing children with non-Hodgkin's lymphoma to toxicity from moderate dose methotrexate (MTX) (300 mg/m2 per 4 hours), we reviewed the medical records of 15 patients treated at our institution according to two similar protocols. Five patients experienced hyperemesis and/or severe mucositis. In two of these patients, pharmacokinetic analysis demonstrated delayed terminal excretion of methotrexate with a half-life of 3-3.5 days, compared to a previously reported t1/2 of 8-15 hours in subjects with normal clearance. All affected patients were large (body surface area 1.6-1.9 m2), and MTX toxicity was seen only during courses where intravenous MTX was given concurrently with intrathecal MTX. Four patients also received simultaneous prophylactic doses of oral trimethoprim-sulfamethoxazole (trimethoprim 5 mg/kg per day). We recommend that, in protocol design, consideration be given to avoiding concurrent use of intravenous and intrathecal MTX, and possibly trimethoprim-sulfamethoxazole. Where high doses of MTX are given based on large body surface area, urine alkalinization may be indicated.

Spontaneous remission of infantile acute nonlymphocytic leukemia for 11 years in a child with normal karyotype.

BACKGROUND: Leukemia or a leukemia-like picture in phenotypically normal infants with a normal marrow karyotype who undergo spontaneous remission is extremely unusual. RESULTS: A 6-week-old, phenotypically normal boy first was seen in 1979 with hepatosplenomegaly, a 36 x 10(9)/l leukocyte count, a leukoerythroblastic picture, and increased blasts in the bone marrow aspirate. Because no other known causes of leukemoid reaction could be demonstrated, the picture was consistent at that time with acute nonlymphocytic leukemia (ANLL), French-American-British (FAB) M1; however, because of the age of the child, the low blast count, normal cytogenetics, and questions about this diagnosis, treatment was withheld. Hematologic laboratory values normalized by the time he was 1 year of age. Eleven years later, he presented a similar picture that rapidly progressed to overt leukemia (FAB M1). A normal marrow karyotype was consistent throughout the 11 years of follow-up. Treatment of ANLL was initiated, resulting in marrow remission. This was followed by allogeneic bone marrow transplantation. He had a relapse again and was retreated, achieving a second marrow remission, and had a second allogeneic bone marrow transplantation. However, the patient died of venoocclusive disease of the liver after the second transplant. CONCLUSION: The diagnosis and prognosis of infants with an abnormal hematologic picture similar to ANLL but who are phenotypically and karyotypically normal are not as straightforward as in the older child or adult. Treatment should be withheld in this setting until the leukemic process is overt.