Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.     

High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival.

PURPOSE: In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event originates from the CD34(+)CD38(-) stem cell compartment. Survival of these cells after chemotherapy may lead to minimal residual disease (MRD) and subsequently to relapse. Therefore, the prognostic impact of stem cell frequency in CD34-positive AML was investigated. EXPERIMENTAL DESIGN: First, the leukemogenic potential of unpurified CD34(+)CD38(-) cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34(+)CD38(-) compartment at diagnosis correlates with MRD frequency after chemotherapy and clinical outcome in 92 AML patients. RESULTS: In vivo data showed that engraftment of AML blasts in nonobese diabetic/severe combined immunodeficient mice directly correlated with stem cell frequency of the graft. In patients, a high percentage of CD34(+)CD38(-) stem cells at diagnosis significantly correlated with a high MRD frequency, especially after the third course of chemotherapy. Also, it directly correlated with poor survival. In contrast, total CD34(+) percentage showed no such correlations. CONCLUSIONS: Both in vivo data, as well as the correlation studies, show that AML stem cell frequency at diagnosis offers a new prognostic factor. From our data, it is tempting to hypothesize that a large CD34(+)CD38(-) population at diagnosis reflects a higher percentage of chemotherapy-resistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ultimately, future therapies should be directed toward malignant stem cells.     

Parent and physician perspectives on quality of care at the end of life in children with cancer.

PURPOSE: To ascertain parents' and physicians' assessments of quality of end-of-life care for children with cancer and to determine factors associated with high-quality care as perceived by parents and physicians. METHODS: A survey was conducted between 1997 and 2001 of 144 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital (Boston, MA) or Children's Hospitals and Clinics of St Paul and Minneapolis, MN, between 1990 and 1999 (65% of those located and eligible) and 52 pediatric oncologists. RESULTS: In multivariable models, higher parent ratings of physician care were associated with physicians giving clear information about what to expect in the end-of-life period (odds ratio [OR] = 19.90, P = .02), communicating with care and sensitivity (OR = 7.67, P < .01), communicating directly with the child when appropriate (OR = 11.18, P < .01), and preparing the parent for circumstances surrounding the child's death (OR = 4.84, P = .03). Parent reports of the child's pain and suffering were not significant correlates of parental ratings of care (P = .93 and .35, respectively). Oncologists' ratings of care were inversely associated with the parent's report of the child's experience of pain (OR = 0.15, P = .01) and more than 10 hospital days in the last month of life (OR = 0.24, P < .01). Parent-rated communication factors were not correlates of oncologist-rated care. No association was found between parent and physician care ratings (P = .88). CONCLUSION: For parents of children who die of cancer, doctor-patient communication is the principal determinant of high-quality physician care. In contrast, physicians' care ratings depend on biomedical rather than relational aspects of care.     

Predictors of a positive baseline bone scan in breast cancer

The aim of this retrospective study was to determine the predictors of a positive bone scan in female patients with breast carcinoma. The participants were 126 females with newly diagnosed breast carcinoma and a baseline bone scan. Patients who had started treatment before their bone scan were excluded. Bone scans were assessed as ‘no metastases’ or ‘definite skeletal metastases’ without knowledge of the patient's predictor variables. Those with ‘possible metastases’ were correlated with other available imaging and clinical information, and recategorized as ‘no metastases’ or ‘definite skeletal metastases’. Results were compared with predictor variables. Significant predictors were increasing age, a higher histopathological grading and positive progesterone receptor status following a forward-stepwise logistic regression analysis. Axillary nodal status, tumour size and oestrogen receptor status did not correlate with a positive bone scan. Not every patient needs a staging bone scan. This study is important because it predicts the need for baseline scintigraphy for specific patients in whom skeletal metastases are more likely to be present or to develop. The findings are particularly valuable in times of worldwide resource scarcity and evolving surgical practice.     

Inhibition of cell cycle and induction of apoptosis by 2‐oxoheksyl isothiocyanate and alyssin in cell lines carrying various inherited BRCA1 mutations

An important aspect of the chemopreventive activity of isothiocyanates (ITC) is their ability to induce cell growth inhibition and apoptosis. In this study, the effect of two sulforaphane analogues, 2‐oxoheksyl isothiocyanate and alyssin, on lymphoblastoid cells, derived from people carrying four different germ‐line mutations in BRCA1 gene, was tested and compared to the effect on wild type cells. The mutations studied were: C61G; 3819del5; 4153delA, and 5382INSC. Changes in cell viability and density after 2‐oxoheksyl isothiocyanate and alyssin treatment were evaluated, as well as cell cycle progression, mitochondrial membrane potential changes, and phosphatidylserine externalization. Both isothiocyanates were shown to reduce cell viability and density in all cell lines tested, as well as the change in cell cycle phase's distribution. The response of cells to two ITC tested was various, as well as mutation type‐modulated. We found that change of cellular maintenance by chemopreventive agents can be modulated by single allele BRCA1 mutation. Drug Dev. Res. 65:84–92, 2005. © 2005 Wiley‐Liss, Inc.     

International consensus statement on attention-deficit/hyperactivity disorder (ADHD) and disruptive behaviour disorders (DBDs): clinical implications and treatment practice suggestions.

Researchers and clinicians worldwide share concerns that many youngsters with attention-deficit/hyperactivity disorder (ADHD) and/or disruptive behaviour disorders (DBDs) do not receive appropriate treatment despite availability of effective therapies. At the request of Johnson and Johnson (sponsor), 11 international experts in child and adolescent psychiatry were selected by Professor Stan Kutcher (chair) to address these concerns. This paper describes the experts' consensus conclusions, including treatment practice suggestions for physicians involved in the early treatment of youngsters with ADHD (or hyperkinetic disorder, in countries preferring this classification) and/or DBDs internationally: suggested first-line treatment for ADHD without comorbidity is psychostimulant medication aided by psychosocial intervention. For ADHD with comorbid conduct disorder (CD), psychosocial intervention combined with pharmacotherapy is suggested. For primary CD, suggested first-line treatment is psychosocial intervention, with pharmacotherapy considered as an 'add-on' when aggression/impulsivity is marked and persistent. Pharmacotherapy requires careful titration; full-day coverage is the suggested goal. Regular long-term follow-up is recommended.     

Vascular cerebral thrombosis during pregnancy and post-partum

Pregnancy and puerperium are associated with a number of cerebrovascular conditions that may result in stroke. Those include cerebral venous thrombosis and cerebral arteries occlusions. Comparing stroke rates during pregnancy with those of non-pregnant women showed only a marginal excess risk during pregnancy and puerperium. Strokes due to cerebral venous thrombosis represent 10-20 per 100 000 deliveries in western countries. The cause of intracranial venous thrombosis is usually unknown. However, better understanding of abnormalities in coagulation leading to intravascular clotting in the early puerperium is resulting in better understanding of this disease. Nevertheless, an etiological work up should be performed, particularly when the thrombosis occurs during pregnancy. Its clinical manifestations often include focal neurological signs, seizures and headache. Alterations in consciousness occur as intracranial pressure increases. Arterial occlusions account for about 60% to 80% of cerebral ischemic lesions. A probable cause of ischemic stroke is diagnosed on the basis of clinical, biological and radiological data. Eclampsia is the main cause of nonhemorrhagic stroke. A search for rare causes of stroke linked to pregnancy such as post-partum cardiomyopathy, paradoxical embolism, choriocarcinoma, cardiac and hematological disorders may be appropriate.     

CYP1A2 and NAT2 genotype/phenotype relations and urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a human dietary intervention study.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking, and is subsequently metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). Respective genes encoding for these enzymes, display polymorphic distribution in the human population and are thus believed to cause interindividual differences in cancer risk susceptibility. The present study investigated the influence of dietary exposure and CYP1A2 and NAT2 genotypes and phenotypes on differential urinary PhIP excretion levels in 71 human volunteers after consumption of either a high (7.4 ng/g) or low (1.7 ng/g) dose of PhIP. Urinary PhIP excretion levels were found to reflect recent dietary exposure levels, with average levels of 174% (high dose group) and 127% (low dose group), as compared to pre-feed levels. Urinary caffeine metabolite ratios were significantly different between the two NAT2 genotypes, whereas for CYP1A2, the apparent difference in metabolic ratios between the genotypes was statistically non-significant. Significant correlations were firstly found between the CYP1A2-164A-->C (CYP1A2*1F) polymorphism and differential urinary PhIP excretion levels. Although the found correlations are driven primarily by a small number of subjects possessing the homozygous variant constellation, the strong influence of this genotype indicates that the CYP1A2*1F polymorphism could play an important role in human cancer risk susceptibility.