Nasopharyngeal carcinoma in the pediatric age group: the northern Israel (Rambam) medical center experience, 1989-2004

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for less than 1% of all malignancies. Radiation therapy has been the mainstay of treatment of many years, but to improve survival, the use of chemotherapy has been advocated. This is a retrospective analysis of 13 patients less than 20 years of age treated for NPC the Rambam Medical Center during 1989 to 2004. Eight boys and five girls with a median age of 14.5 years (range 10-19) were included. Median follow up (including patients who died) was 6.15 years (range 1-15 years). Duration of symptoms was 1 to 24 months (median 5 months). Of the 13 patients, one patient had stage I, 6 had stage III, 5 had stage IV-A, and 1 had stage IV-B disease. Ten patients (77%) had undifferentiated carcinoma (WHO type III) and three patients (23%) had nonkeratinizing carcinoma (WHO type II). Most of the children received two or three courses of neoadjuvant multiagent chemotherapy consisting of cisplatin and 5-FU, followed by radiotherapy with doses in excess of 60 Gy. One child received concomitant chemoradiation. Ten of the 13 patients (77%) are alive without disease 6 years after diagnosis (range 1-15 years). One patient developed local and distant metastases 1 year after diagnosis and is currently receiving combined radiochemotherapy. Two patients died. Overall survival was 84%; event-free survival was 77%. Nine patients (69%) developed moderate to severe long-term complications. Pediatric NPC is curable by combined radiation and chemotherapy, with doses of radiation in excess of 60 Gy. Long-term follow-up is important for early detection of second malignancies as well as for radiation-induced endocrinologic deficiencies and other normal tissue complications.     

Changes in astigmatism after congenital cataract surgery and foldable intraocular lens implantation

PURPOSE: To evaluate the changes in astigmatism after cataract extraction and implantation of a foldable intraocular lens (IOL) in children. Only eyes with astigmatism of 3.0 D or more were included in the study. METHODS: The charts of children who had undergone surgery for nontraumatic cataract using a foldable IOL were retrospectively reviewed. In 13 eyes with astigmatism of 3.0 D or more, the refraction was tested and recorded at 1 week, 3 months, and 5 months postoperatively. A paired t test was used to compare the variables. RESULTS: Mean astigmatism 1 week postoperatively was 4.7 +/- 1.9 D (range, 3.0-10.0 D). Thereafter, the astigmatic component of the refractive error underwent a spontaneous steady decline, reaching a mean value of 0.9 +/- 0.9 D (range, 0-2.25 D) 5 months after surgery. The difference between the mean values at 1 week and 5 months was statistically significant (P < .0001). CONCLUSION: Children who underwent congenital cataract surgery and IOL implantation showed a significant spontaneous reduction in astigmatism postoperatively.     

Role of disengagement failure and attentional gradient in unilateral spatial neglect - a longitudinal study

Purpose: To assess the importance of 'disengagement failure' and 'attentional gradient' in unilateral spatial neglect (USN) and in recovery from neglect.

Method: Eight right-hemisphere-damaged stroke patients performed the standardized Behavioural-Inattention-Test battery for visual neglect, line-bisection tests, and two computerized reaction-time (RT) tasks: a variant of Posner's 'Spatial-Cueing' paradigm (with special emphasis on the magnitude of leftward disengagement time) and a signal-detection task (marking the spatial gradient of attention by the distribution of RTs to target stimuli in different spatial locations). The correlation between the different measures was assessed at two points in time, before and after a period of rehabilitation treatment.

Results: A recovery pattern could be identified in both RT paradigms. However, the correlation between standard measures of neglect and performance on both, spatial-cueing and signal-detection tasks, was weak.

Conclusion: Neither difficulty disengaging attention from an ipsilesional stimulus nor changes in the attentional gradient can fully explain the processes underlying USN and its recovery. A large interpersonal variance exists among USN patients in the expression of disengagement and other spatial-attention deficits. Hence, individual patients should be tested by measuring different factors known to play a role in USN. This information is crucial for assigning the appropriate treatment for each patient in accord with the specific deficit revealed.     

Time course and predictors of median nerve conduction after carpal tunnel release

PURPOSE: To identify predictors of outcome and of electrophysiologic recovery in patients with carpal tunnel syndrome (CTS) treated by endoscopic carpal tunnel release using a nerve conduction testing system (NC-Stat; NEUROMetrix, Inc, Waltham, MA). METHODS: Validity of the automated nerve conduction testing system was shown by comparing presurgical distal motor latencies (DMLs) against a reference obtained by referral to an electromyography laboratory. The DML was evaluated in 48 patients with CTS. Measurements were obtained within 1 hour of surgery and at 2 weeks, 6 weeks, 3 months, and 6 months after carpal tunnel release. Presurgical and postsurgical DMLs were then compared and correlated with variables and possible predictors of outcome including age, body mass index, gender, and presurgical DMLs. RESULTS: The automated nerve conduction testing system DMLs matched those of reference electromyography/nerve conduction study values with high correlation. Sensitivity of the automated nerve conduction testing system when compared with a standardized CTS case definition was 89%, with a specificity of 95%. A significant correlation was found between the DML before release and the DML 1 hour after release. Moreover, maximal postsurgical DML improvement was highly dependent on the presurgical DML, with no improvement shown for the <4-ms group, mild improvement for the 4-to-6-ms group, and maximal improvement in the >6-ms group. Among the clinical variables of age, gender, and body mass index only age was mildly predictive of postrelease DML changes at 6 months. No other correlations between clinical variables and postsurgical DMLs were significant. In addition the predictive value of age was lost when combined with the presurgical DML in a multivariate analysis. CONCLUSIONS: Postsurgical changes in the median nerve DML were highly dependent on the prerelease latency. The sensitivity and specificity of a nerve conduction monitoring system in detecting and aiding in the diagnosis of CTS is useful in the long-term management of patients with CTS and can aid in determining the level of improvement in median nerve function after endoscopic carpal tunnel release.     

CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m(null) mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.     

Sil overexpression in lung cancer characterizes tumors with increased mitotic activity

Sil (SCL interrupting locus) was cloned from the most common chromosomal rearrangement in T-cell acute lymphoblastic leukemia. It is an immediate early gene whose expression is associated with cell proliferation. Sil protein levels are tightly regulated during the cell cycle, reaching peak levels in mitosis and disappearing on transition to G1. A recent study found Sil to be one of 17 genes whose overexpression in primary adenocarcinomas predicts metastatic spread. We hypothesized that Sil might have a role in carcinogenesis. To address this question, we utilized several approaches. Using a multitumor tissue array, we found that Sil protein expression was increased mostly in lung cancer, but also at lower levels, in a subset of other tumors. Microarray gene expression analysis and immunohistochemistry of lung cancer samples verified these observations. Sil gene expression in lung cancer correlated with the expression of several kinetochore check-point genes and with the histopathologic mitotic index. These observations suggest that overexpression of the Sil gene characterizes tumors with increased mitotic activity.     

Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients

Acquired resistance towards apoptosis is the hallmark of most if not all types of cancer. We have previously identified and characterized ARTS, a broadly expressed protein localized to mitochondria. ARTS was initially shown to mediate TGF-beta induced apoptosis. Recently, we have found that high levels of ARTS induce apoptosis without additional pro-apoptotic stimuli. Further, ARTS promotes apoptosis in response to a wide variety of pro-apoptotic stimuli. Here, we report that the expression of ARTS is lost in all lymphoblasts of more than 70% of childhood acute lymphoblastic leukemia (ALL) patients. The loss of ARTS is specific, as the related non-apoptotic protein H5, bearing 83% identity to ARTS, is unaffected. During remission, ARTS expression is detected again in almost all patients. Two leukemic cell lines, ALL-1 and HL-60 lacking ARTS, were resistant to apoptotic induction by ara-C. Transfection of ARTS into these cells restored their ability to undergo apoptosis in response to this chemotherapeutic agent. We found that methylation process contributes to the loss of ARTS expression. We conclude that the loss of ARTS may provide a selective advantage for cells to escape apoptosis thereby contributing to their transformation to malignant lymphoblasts. We therefore propose that ARTS can function as a tumor suppressor protein in childhood ALL.     

Adverse events due to discontinuations in drug use and dose changes in patients transferred between acute and long-term care facilities

BACKGROUND: Care transitions are commonplace for ill older adults, but no studies to our knowledge have examined the occurrence of iatrogenic harm from medication changes during patient transfer. OBJECTIVES: To identify medication changes during transfer between hospital and nursing home and adverse drug events (ADEs) caused by these changes. METHODS: Participants were residents of 4 nursing homes in the New York City metropolitan area admitted to 2 academic hospitals. Nursing home and hospital medical records were reviewed to identify changes in medication regimens between sites. Medications were matched and compared regarding dosage, route, and frequency of administration. Two physician investigators used structured implicit review to identify ADEs attributable to transfer-related medication changes. RESULTS: During a total of 122 admissions, the mean numbers of medications altered during transfer from nursing home to hospital and hospital to nursing home were 3.1 and 1.4, respectively (P<.001 for comparison). Most changes in drug use were discontinuations, followed by dose changes and class substitutions. Of 71 bidirectional transfers that were reviewed by 2 physician investigators, ADEs attributable to medication changes occurred during 14 (20%). The overall risk of ADE per drug alteration (n = 320) was 4.4% (95% confidence interval, 2.5%-7.4%). Although most medication changes (8/14) implicated in causing ADEs occurred in the hospital, most ADEs (12/14) occurred in the nursing home after nursing home readmission. CONCLUSIONS: Medication changes are common during transfer between hospital and nursing home and are a cause of ADEs. Research is needed on interinstitutional patient care and systems interventions designed to prevent ADEs.