A ribosome-related signature in peripheral blood CLL B cells is linked to reduced survival following treatment.

We have used polysome profiling coupled to microarray analysis to examine the translatome of a panel of peripheral blood (PB) B cells isolated from 34 chronic lymphocytic leukaemia (CLL) patients. We have identified a 'ribosome-related' signature in CLL patients with mRNAs encoding for ribosomal proteins and factors that modify ribosomal RNA, e.g. DKC1 (which encodes dyskerin, a pseudouridine synthase), showing reduced polysomal association and decreased expression of the corresponding proteins. Our data suggest a general impact of dyskerin dysregulation on the translational apparatus in CLL and importantly patients with low dyskerin levels have a significantly shorter period of overall survival following treatment. Thus, translational dysregulation of dyskerin could constitute a mechanism by which the CLL PB B cells acquire an aggressive phenotype and thus have a major role in oncogenesis.

Distribución relativa de genotipos de virus papiloma humano en muestras de carcinoma escamoso de laringe / Relative distribution of human papilloma virus in laryngeal squamous cell carcinoma

Introducción: La relación entre virus papiloma humano (VPH) y cáncer escamoso de la vía aéreo-digestiva superior está claramente establecida en la literatura. Objetivo: El objetivo del presente trabajo es conocer la frecuencia de identificación de ADN de VPH y la distribución relativa de genotipos en muestras de carcinoma escamoso de laringe. Material y método: Se extrajo ADN desde muestras fijadas en formalina e incluidas en parafina, de biopsias de carcinoma escamoso de laringe de pacientes operados en el Servicio de Otorrinolaringología del Hospital San Juan de Dios. La detección de ADN viral se realizó mediante PCR con partidores de consenso MY09/11, y la genotipificación se realizó mediante endonucleasas de restricción Rsal. La calidad de la muestra se controló mediante amplificación de beta-globina. Resultados: Se incluyeron 90 casos. En 24 de ellos (27 por ciento) se identificó la presencia de ADN de VPH. Los genotipos más frecuentes fueron VPH18 (7/24), VPH16 (5/24), VPH54 (2/ 24). En 3 casos no se logró identificar el genotipo. No se detectaron infecciones múltiples. Conclusiones: La presencia de genotipos de VPH de alto riesgo oncogénico sugieren que el virus papiloma humano tendría un rol en la etiopatogenia de un subgrupo de pacientes portadores de carcinoma escamoso de laringe.

Introduction: Human papillomaviruses (HPV) have been detected in benign and neoplastic laryngeal lesions, with variable frequency (20-60 percent). These viral agents are proposed as an adjuvant or cofactor in head and neck carcinogenesis because of their oncogenic properties. Aim: The aim of this study was to identify HPV in laryngeal carcinoma samples and to describe their genotype distribution. Material and method: Tumor samples from patients with newly diagnosed laryngeal carcinomas were collected, fixed in formalin and paraffin-embedded. HPV genome was identified by use of polymerase chain reaction (PCR) using primers complementary to the conserved region L1 (MY09-11). Genotyping was accomplished by restriction fragment length polymorphism. Results: 24 of the 90 samples were positive for HPVDNA (27 percent), all of the samples were positive for human 3-globin. The genotypes identified were HPV 16(5 cases), HPV 18 (7 cases), and HPV 39, 45, 51, 58, 59, 61, and 66 (1 case each). Conclusions: High-risk HPV genotypes were identified, suggesting a role of human papilloma virus in the etiology of a subgroup of laryngeal squamous cell carcinomas.

Clinical management of women at increased risk for breast cancer.

A large number of women in the population are at risk for the development of breast cancer. Methods now exist to accurately assess risk and to provide quantitative estimates of the chance of a woman developing breast cancer in her lifetime. Histologic assessment of premalignant breast pathology aids in the evaluation of risk. The availability of primary chemoprevention clinical trials reduces the number of indications for prophylactic mastectomy. Women at risk for breast cancer and women who have had a malignant lesion at another anatomic site have an increased risk for new cancers at multiple sites. We propose screening strategies based on epidemiologic information about the risks of these diseases and on the predictive value of the available screening tests. The merits and inadequacies of specific management strategies are considered. We review the risks and benefits of estrogen replacement therapy for women at increased risk for breast cancer and consider the ethical implications of both risk assessment and the various interventions.

Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon alfa-2b in patients with advanced cancer.

PURPOSE: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. PATIENTS AND METHODS: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 x 10(6) U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. RESULTS: The maximum-tolerated dose of rIFN-a was 10 x 10(6) U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Css; range, 0.77 +/- 0.35 mumol/L to 1.85 +/- 0.48 mumol/L), elimination half-life (t1/2; mean, 9.7 +/- 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 mumol/L x hours), total-body clearance (CI; range, 1,172 to 3,236 mL/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 mumol/L) was greater than that before rIFN-a administration (1.02 mumol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. CONCLUSION: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

Efficacy of chlorhexidine gluconate use in the prevention of perirectal infections in patients with acute leukemia.

The frequency of rectal infections is increased in patients with acute leukemia. Complications associated with rectal lesions may be severe enough to cause life-threatening septicemia. Clinical research evaluating the effects of preventive perirectal skin care is scarce. This study's purpose was to determine whether using chlorhexidine gluconate (CHG) in a prophylactic perirectal skin-care regimen decreases perirectal infections and whether it produces more skin irritation than a nonmedicated skin cleanser. The sample consisted of 40 patients, 16 of whom were randomized to use chlorhexidine and 24 of whom were randomized to use nonmedicated skin cleanser. Chi-square and t-tests were used to analyze the incidence of skin breakdown and rectal infections; the correlation between the two factors; a positive history of rectal infections, fissures, or hemorrhoids; presence of hemorrhoids; severity of diarrhea; and duration and severity of granulocytopenia. A positive relationship was found between the severity of granulocytopenia and the incidence of rectal infections (p = 0.02). No significant difference was seen in the occurrence of perirectal infections (p = 0.35) or skin breakdown (p = 0.18) between the two groups. The data suggest that CHG does not offer increased protection against perirectal infections in patients undergoing intensive chemotherapy, nor is it more irritating than a nonmedicated skin cleanser. Further studies are needed to examine the efficacy of hygienic measures such as using skin disinfectants to prevent infections in patients who are immunocompromised.

Assessment and management of gouty arthritis.

Gout is a metabolic disorder of purine metabolism that leads to elevated serum concentrations of uric acid. When this happens, urate crystals may precipitate and accumulate in the joints and bursae. Gout is characterized by recurrent, painful attacks of arthritis, which is the major clinical complication of the disease. Early diagnosis and treatment of gout are important to prevent complications, and with early, sustained therapy, most patients can live without functional disability. If gout becomes chronic, individuals may experience severe limitations of activity. This article discusses the clinical manifestations, diagnosis and treatment of acute and chronic gout.

Occult primary malignancies.

Occult primary malignancies (OPMs) are the eighth most common cancer in the United States. Generally, the prognosis is poor, with survival usually lasting two to four months from the time of diagnosis. The primary tumor will never be found in more than half of the patients, even after an exhaustive diagnostic workup and eventual autopsy. The majority of these tumors are metastatic at the time of diagnosis; therefore, therapy is palliative. Nursing implications include providing symptom management, psychological support, and patient education.

Assessment and management of hypothyroidism.

Hypothyroidism is a hypoactive metabolic state associated with a deficiency in thyroid hormone metabolism. This condition affects many bodily systems, including the nervous system, circulatory system, muscular system, the heart and energy-producing system, and the endocrine glands. The goal of treatment for this hypometabolic state is replacement of thyroid hormones. Health care practitioners need to be aware of early signs and symptoms, and subsequent treatment and monitoring of patients with hypothyroidism.

Myelodysplastic syndromes.

A cure for MDS has yet to be found. The aim of therapy is to attempt to restore normal hematopoiesis and prevent evolution to acute leukemia. The major trend is supportive care. Blood counts and bone marrow aspirations are taken to evaluate the disease, and transfusions of blood products and antibiotics are given when necessary. A new encouraging modality of therapy is the use of hematopoietic growth factors to reverse cytopenias. As there is no curative treatment for MDS, the patient is likely to be offered investigational drugs either singly or in combination. Future trends in the treatment of MDS will be combinations of agents including biological agents with retinoic acid or vitamin D, low-dose Ara-C, the interferons, and colony-stimulating factors.

Ifosfamide and mesna: marginally active in patients with advanced carcinoma of the pancreas.

Ifosfamide, an analogue of cyclophosphamide, has therapeutic activity against a wide variety of human malignancies. In a phase II trial in carcinoma of the pancreas, we treated 31 patients who had not received prior chemotherapy with a median ifosfamide dose of 2 g/m2/d (range, 1.5 to 2 g/m2/d) administered intravenously (IV) over one hour for five consecutive days every 3 weeks. 2-mercaptoethane sulphonate (mesna), an acrolein antagonist with known uroendothelial protective properties, was administered IV at a dose of 400 mg/m2 over 15 minutes before the daily dose of ifosfamide and repeated every four hours for two additional doses. Among 30 evaluable patients, one patient achieved a complete remission (26+ months) and another patient had a partial remission (4 months). The median duration of survival of all patients from the start of ifosfamide therapy was only 3 months (range, 1 to 26+ months). Treatments were generally well tolerated. The most common toxic effects included granulocytopenia, nausea and vomiting, malaise, anorexia, and mild hematuria. Mesna offers an adequate protection against uroendothelial injury caused by ifosfamide. Despite the previously reported response rate of greater than 20% at the same or lower doses of ifosfamide in other studies, our data suggest that ifosfamide is only marginally active against cancer of the pancreas and appears to be of minimal value in the treatment of patients with this tumor.