Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells

Clinical studies of patients with chronic myeloid leukemia revealed that a common pattern of response is a dramatic fall in the circulating population of blast cells, with a minimal or delayed decrease in marrow blasts, suggesting a protective environment. These observations suggest that a greater understanding of the interaction of stromal cells with leukemic cells is essential. Here, we present an in vivo system for monitoring relative tumor accumulation in leukemic mice and residual disease in leukemic mice treated with a tyrosine kinase inhibitor and an in vitro system for identifying integral factors involved in stromal-mediated cytoprotection. Using the in vivo model, we observed high tumor burden/residual disease in tissues characterized as significant sources of hematopoiesis-promoting stroma, with bone marrow stroma most frequently showing the highest accumulation of leukemia in untreated and nilotinib-treated mice as well as partial protection of leukemic cells from the inhibitory effects of nilotinib. These studies, which showed a pattern of leukemia distribution consistent with what is observed in imatinib- and nilotinib-treated chronic myeloid leukemia patients, were followed by a more in-depth analysis of stroma-leukemia cell interactions that lead to protection of leukemia cells from nilotinib-induced cytotoxicity. For the latter, we used the human BCR-ABL-positive cell line, KU812F, and the human bone marrow stroma cell line, HS-5, to more closely approximate the bone marrow-associated cytoprotection observed in drug-treated leukemia patients. This in vitro system helped to elucidate stromal-secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells.     

Autonomic tone in medical intensive care patients receiving mechanical ventilation and during a CPAP weaning trial

Mechanical ventilator support and the resumption of spontaneous ventilation or weaning create significant alterations in alveolar and intrathoracic pressure that influence thoracic blood volume and flow. Compensatory autonomic tone alterations occur to ensure adequate tissue oxygen delivery, but autonomic responses may produce cardiovascular dysfunction with subsequent weaning failure. The authors describe autonomic responses of critically ill patients (n = 43) during a 24-hr period of mechanical ventilatory support and during the 24 hr that included their initial spontaneous breathing trial using continuous positive airway pressure. Nearly two thirds of these patients demonstrated abnormal autonomic function and this dysfunction was more severe in those patients who were unable to sustain spontaneous ventilation (n = 15). With further systematic study, autonomic responses may be useful in the identification of patients who are likely to develop cardiac dysfunction with the resumption of spontaneous breathing.     

Spinocerebellar ataxia type 8 in Scotland: frequency, neurological, neuropsychological and neuropsychiatric findings

Objectives –  The objectives of this study were to: (i) establish whether the spinocerebellar ataxia type 8 (SCA 8) expansion is associated with ataxia in Scotland; (ii) test the hypothesis that SCA 8 is associated with neuropsychological impairment; and (iii) review neuroradiological findings in SCA 8.
Methods –  The methods included: (i) measurement of SCA 8 expansion frequencies in ataxic patients and healthy controls; (ii) comprehensive neuropsychological assessment of patients with SCA 8 and matched controls, neuropsychiatric interview; and (iii) comparison of patient and matched control magnetic resonance imaging (MRI) scans.
Results –  (i) 10/694 (1.4%) unrelated individuals with ataxia had combined CTA/CTG repeat expansions >100 compared to 1/1190 (0.08%) healthy controls ( P  < 0.0005); (ii) neuropsychological assessment revealed a dysexecutive syndrome among SCA 8 patients, not readily explained by motor or mood disturbance; neuropsychiatric symptoms occurred commonly; (iii) cerebellar atrophy was the only salient MRI abnormality in the patient group.
Conclusions –  The SCA 8 expansion is associated with ataxia in Scotland. The disorder is associated with a dysexecutive syndrome.     

Treatment of advanced-stage Kienböck's disease with proximal row carpectomy: an average 15-year follow-up

PURPOSE: The purpose of this study was to evaluate the long-term clinical results of a proximal row carpectomy with an average 15-year follow-up for the primary treatment of advanced-stage (Lichtman IIIA and IIIB) Kienb?ck's disease. This study is a follow-up to a paper by the senior author in a similar cohort of patients where the clinical results of a proximal row carpectomy were evaluated for the treatment of advanced-stage Kienb?ck's disease at an average 3-year follow-up. METHODS: Seventeen patients with a minimum of 10 years of follow-up were identified who met criteria for inclusion. Thirteen of these patients were located and agreed to participate. Patients were seen, examined, and queried regarding their wrists. Range of motion, grip strength, and subjective patient satisfaction were all obtained and quantified using a clinical outcomes scale. RESULTS: Twelve of 13 patients demonstrated excellent or good results based on the clinical outcomes scale used (5 excellent, 7 good, 1 fair, and none poor). Total arc of motion averaged 73% of the uninvolved side. Grip strength averaged 92% of the uninvolved side. Compared with preoperative values, range of motion improved an average of 16% and grip strength improved an average of 129%, an overall average improvement of 12 degrees and 18 kg, respectively. At the most recent follow-up, all patients remained employed. Seven patients held manual labor positions, 2 were nurses, and 4 were employed in sedentary vocations. All patients demonstrated some degree of degenerative changes, usually localized to the radiocapitate articulation in the lunate fossa. Clinical results did not correlate with radiographic degeneration. CONCLUSIONS: This study demonstrates proximal row carpectomy to be a reliable motion-preserving procedure with good clinical results maintained out to an average of 15 years postoperatively.     

The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells

BACKGROUND: Clonal cytogenetic abnormalities (CCA) were detected in Philadelphia chromosome (Ph)-negative cells in some patients with chronic myeloid leukemia (CML) who attained a cytogenetic response to imatinib mesylate. In some patients, CCA/Ph-negative status was associated with myelodysplasia or acute myeloid leukemia. The objective of the current study was to determine the prognostic impact of CCA/Ph-negative cells. METHODS: The authors compared the pretherapeutic risk factors (Kruskall-Wallis test), exposure to cytotoxic drugs (chi-square test), and overall and progression-free survival (Kaplan-Meyer and logistic regression analysis, respectively) of 515 patients with mostly chronic-phase CML who were treated with imatinib mesylate after failure of interferon-alpha according to whether they attained a major cytogenetic response (MCR) (n = 324 patients), an MCR with CCA/Ph-negative status (n = 30 patients), or no MCR (n = 161 patients). RESULTS: CCA/Ph-negative status most frequently involved chromosomes Y, 8, and 7. No significant differences in pretherapeutic risk factors were detected between patients who attained an MCR with and without CCA/Ph-negative cells, except that exposure to alkylating agents was more frequent in patients with CCA/Ph-negative cells, and overall and progression-free survival were identical. With a median follow-up of 51 months, only 2 patients developed myelodysplastic syndromes (MDS). CONCLUSIONS: The overall prognosis for patients who had CML with CCA/Ph-negative status was good and was driven by the CML response to imatinib mesylate. Isolated CCA/Ph-negative cells in the absence of morphologic evidence of MDS do not justify a change in therapy.