Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine.

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

The pain resource nurse training program: a unique approach to pain management.

Adequate pain management is a 24 hr a day responsibility for health-care professionals working with cancer patients. Because nurses spend more time with patients in pain than any other member of the health-care team, they play a central role in pain assessment and pain management. The City of Hope National Medical Center, a clinical cancer center, developed a pain management course for staff nurses entitled "The Pain Resource Nurse (PRN) Training Program." The purpose of this innovative course was to prepare staff nurses to assume an active role in pain management. Twenty-six registered nurses participated in the 40-hr didactic and clinical course. The curriculum included information on pain assessment, pharmacology, nondrug interventions, and cultural, ethical, and psychosocial issues related to pain. After completion of the course, program staff have remained available to the PRNs to provide current information on pain management, and to assist with role implementation and guidance on interfacing with staff. This paper reports on the development, implementation, and 3-mo evaluation of this unique program.

New from nursing research: the basic knowledge assessment tool (BKAT) for critical care nursing.

The BKAT is a valid and reliable test of basic knowledge in critical care nursing. Validity was established through a panel of nine experts in critical care nursing practice and education. Reliability was established at the alpha coefficient of 0.86 for the total test during the pilot study on a sample of 100 nurses working in CCUs . The BKAT , which is a 90-item test, has been used on both a supervised and an unsupervised basis. Findings from the pilot study included a statistically significant difference in basic knowledge between new graduates and nurses with 6 months to more than 5 years of experience in critical care nursing, and that the length of critical care experience is the best predictor of basic knowledge. No statistically significant differences were found in basic knowledge in the following groups of nurses: (1) ICU, SICU , and coronary care unit nurses, (2) those working in university or teaching hospitals, community hospitals, and government hospitals, and (3) nurses with an associate degree, diploma, or baccalaureate degree. The BKAT -2, a revision of the BKAT , indicates that the basic knowledge assessment tool can be updated as new technologies and new knowledge become part of the body of nursing knowledge related to safe practice in critical care nursing.

Community-based educational programs for cancer nursing.

A United Way grant allowed the Department of Nursing Research and Education to make available its expertise in cancer nursing and establish itself as a resource for oncology. Community educational needs were assessed by a questionnaire sent to outside agencies prior to designing an oncology educational program. In a 9-month period, 57 classes at 21 different facilities representing 417 hours of instruction were provided. Nurses attending the classes totaled 1,175. Results showed an increase in scores from pre-test to post-test, indicating that participants demonstrated increased knowledge as a result of class participation. This funding provided the catalyst to prepare a large number of community hospital nurses in the complex care of oncology patients.

Heterogeneity of erythropoietin-dependent erythrocytosis: case report in a child and synopsis of primary erythrocytosis syndromes.

To investigate the pathogenesis of polycythaemia in a child with isolated, primary erythrocytosis, we measured serum erythropoietin activity and in vitro erythroid progenitor cell responsiveness to erythropoietin. Unstimulated erythropoietin activity was markedly elevated (1.8 IU/ml), and isovolaemic phlebotomy induced a four-fold increment above this level. In contrast to findings in our index case with this syndrome, normal erythroid colony growth patterns were present in patient marrow cultures. The primary mechanism of polycythaemia in this individual is similar to that reported in the index case: an inappropriately elevated regulatory set point for erythropoietin production. Since an additional defect of progenitor cell hypersensitivity to erythropoietin is not always present, we conclude that abnormalities at single or multiple sites of the erythropoietic regulatory axis may occur in primary erythropoietin-dependent erythrocytosis.

Erythropoietin-dependent primary pure erythrocytosis.

We investigated the pathogenesis of isolated erythrocytosis of 14 yr duration in a 28-yr-old man. The increase in red cell mass was attributed to increased erythropoietin production. An extensive search for recognized causes of secondary erythrocytosis was unrevealing. Family members were found to be hematologically normal. After reduction of the circulating red cell mass by 20%, erythropoietin activity nearly quadrupled, thus suggesting a normal erythropoietin response to phlebotomy. When bone marrow cells of the patient were cultured in plasma clots in the absence of added erythropoietin, endogenous erythroid colony formation was observed, a pattern previously believed to be specific for polycythemia vera bone marrow cells. Our observations suggest that the erythrocytosis in this individual is best explained by an abnormal "servoregulatory" mechanism of erythropoietin production. In addition, this is the first instance in which the rule that endogenous erythroid colony formation is correlated with the diagnosis of polycythemia vera has not held.