Tissue stem cells: definition,plasticity, heterogeneity,self-organization and models--a conceptual approach

The classical definition of adult tissue stem cells (TSC) is fundamentally based on a functional perspective. A TSC is an undifferentiated cell, capable of proliferation, self-renewal, production of a large number of differentiated functional progeny, regenerating tissue after injury and a flexibility in the use of these options. Here, we discuss the necessity for amending this definition in the light of recent insight into stem cell biology regarding stem cell heterogeneity, lineage plasticity, clonal fluctuation and cell-environment interactions. We conclude that the definition needs amendments. A decade ago the flexibility criterion has attracted little attention but recent findings have indicated its importance. Flexibility and reversibility of tissue and lineage specification (tissue plasticity) and of properties within a tissue (within-tissue plasticity) have major implications with regard to concepts of stem cell function. We advocate to give up the view of TSC as being entities with a preprogrammed development and to replace it by a concept that makes the capabilities for flexible and regulated tissue self-organization based on cell-cell and cell-environment interactions the new paradigm. This concept would permit to incorporate the context-dependent lineage plasticity, within-lineage plasticity and generation of stem cell heterogeneity as a result of a dynamically regulated process. Such concepts need a rigorous examination by formal modeling including simulation studies. We provide some general ideas on how to proceed with such theories and illustrate this with worked models for tissue stem cells of the hematopoietic system and the intestinal epithelium.     

Safety and efficacy of quinupristin/dalfopristin for treatment of invasive Gram-positive infections in pediatric patients

BACKGROUND: Antibiotic-resistant Gram-positive pathogens are an increasingly common cause of serious pediatric infections. Although quinupristin/dalfopristin demonstrates favorable activity against resistant Gram-positive pathogens (including many vancomycin-resistant and methicillin-resistant staphylococci), published experience in the pediatric patient population is limited. METHODS: We retrospectively analyzed data from the global quinupristin/dalfopristin Emergency-Use Program, which enrolled patients with serious Gram-positive infections who had no further therapy options because of resistance to, failure on or intolerance to standard antibiotic treatments. Our subset included safety and efficacy data from pediatric patients (age <18 years). There were no restrictions on underlying diseases, severity of illness or prior/concomitant antimicrobial use. RESULTS: Between May 1995 and October 1999, 127 pediatric patients with 131 infections were enrolled. Microbiologic confirmation of etiology was available in 124 patients. All patients had 1 or more concomitant conditions, including malignancy and solid organ or bone marrow transplantation. The most frequent causative pathogens were vancomycin-resistant (80%), spp. (7%), methicillin-resistant (6%) and (4%). All but 21 patients received intravenous quinupristin/dalfopristin 7.5 mg/kg every 8 h. The favorable clinical response rate of quinupristin/dalfopristin was 86 of 124 (69%); the favorable microbiologic response rate was 97 of 124 (78%). Eleven patients (8%) had nonvenous adverse events classified as possibly or probably related to quinupristin/dalfopristin. CONCLUSIONS: Quinupristin/dalfopristin demonstrated favorable response rates and was reasonably well-tolerated in pediatric patients with serious Gram-positive infections unable to receive alternative therapy. In our opinion quinupristin/dalfopristin is a therapeutic option for the management of such infections.     

Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity

OBJECTIVE: We sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery. METHODS: Between November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5-35 mm), and the median tumor volume was 1.4 cm(3) (range, 0.1-15.9 cm(3)). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10-18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12-102.6 mo). RESULTS: The actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9-99.9%) and 93.6% (95% CI, 88.3-99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2-98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85-97.6%) and 89.4% (95% CI, 82-96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed. CONCLUSION: Proton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.     

Dose-volume prediction of radiation-related complications after proton beam radiosurgery for cerebral arteriovenous malformations

OBJECT: The use of radiosurgery for the treatment of cerebral arteriovenous malformations (AVMs) and other lesions demands an accurate understanding of the risk of radiation-related complications. Some commonly used formulas for predicting risk are based on extrapolation from small numbers of animal experiments, pilot human treatment series, and theoretical radiobiological considerations. The authors studied the incidence of complications after AVM radiosurgery in relation to dose, volume, and other factors in a large patient series. METHODS: A retrospective review was conducted in 1329 patients with AVM treated by Dr. Raymond Kjellberg at the Harvard Cyclotron Laboratory (HCL) between 1965 and 1993. Dose and volume were obtained from HCL records, and information about patient follow up was derived from concurrent clinical records, questionnaires, and contact with referring physicians. Multivariate logistic regression with bootstrapped confidence intervals was used. Follow up was available in 1250 patients (94%); the median follow-up duration was 6.5 years. The median radiation dose was 10.5 Gy and the median treatment volume was 33.7 cm(3). Twenty-three percent of treated lesions were smaller than 10 cm(3). Fifty-one permanent radiation-related deficits occurred (4.1%). Of 1043 patients treated with a dose predicted by the Kjellberg isoeffective centile curve to have a less than 1% complication risk, 1.8% suffered radiation-related complications. Actual complication rates were 4.7% for 128 patients treated at Kjellberg risk centile doses of 1 to 1.8%, and 34% for 61 patients treated at risk centile doses of 2 to 2.5%. The fitted logistic model showed that complication risk was related to treatment dose and volume, thalamic or brainstem location, and patient age. CONCLUSIONS: The Kjellberg isoeffective risk centile curve significantly underpredicted actual risks of permanent complications after proton beam radiosurgery for AVMs. Actual risks were best predicted using a model that accounted for treatment dose and volume, lesion location, and patient age.     

A syringe adapter to facilitate aspiration at amniocentesis

BACKGROUND: Syringes were developed for injection, not aspiration. We describe an adapter that attaches to a standard syringe and aspirates by advancement rather than withdrawal. TECHNIQUE: The adapter consists of a syringe barrel extension and an attachable finger grip. The adapter attached to a standard syringe allows aspiration by advancement rather than withdrawal, with the same hand motion used as with injection. EXPERIENCE: In a comparison of timed in vitro fluid aspiration by 10 practitioners, mean times for aspiration of 15 mL were 32.4 seconds (range 24-45) with standard technique and 25.3 seconds (range 24-30) with the adapted syringe (P < .003, paired t test). Thirteen of 14 physicians who used the adapted syringe in vivo reported that much less effort was required, and one physician reported that a little less effort was required. Overall, eight practitioners reported that the adapted syringe made amniocentesis much easier and six found no difference between the two devices. CONCLUSION: This adapter converts a standard syringe to one permitting aspiration by advancement rather than withdrawal. Practitioner feedback was positive with regard to ease of use, degree of effort, and overall satisfaction.     

Stereotactic Irradiation: potential new treatment method for brain metastases resulting from ovarian cancer

Stereotactic irradiation (radiosurgery) is a method of precisely focusing well-defined beams of radiation at small intracranial targets. The technique has been applied to the treatment of brain lesions that are benign (e.g., arteriovenous malformations, meningiomas, pituitary adenomas) and malignant (e.g., gliomas, metastases). This paper introduces preliminary data suggesting the possible value of radiosurgery in the management of ovarian cancer metastatic to the brain. Among 32 women with ovarian cancer metastatic to the brain treated with whole brain irradiation, nine (29%) experienced a complete radiographic response, compared with two of the five patients (40%) treated with radiosurgery. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received whole brain irradiation without radiosurgical boost. Stereotactic irradiation may be of clinical benefit to select patients with brain metastases resulting from ovarian cancer. A prospective randomized trial has been implemented by the Radiation Therapy Oncology Group (RTOG 95-08) to determine whether such observations are reproducible on a national scale.     

Intraventricular haemorrhage in the preterm infant without hyaline membrane disease

The clinicopathological associations of 33 singleton infants who died with intraventricular haemorrhage (IVH) without hyaline membrane disease (HMD) ('IVH only') were compared with those of 39 infants who died with IVH+HMD over the same gestation range in order to determine what factors other than those related to HMD may contribute to the pathogenesis of IVH. The incidence of 'IVH only' was inversely related to gestational age in the Hammersmith birth population, whereas the incidence of IVH+HMD rose to a peak at 28-29 weeks' gestation. Infants with 'IVH only' lived longer on average than those with IVH+HMD despite a lower birthweight and shorter gestation. Infants who died in the first 12 hours from 'IVH only' had suffered severe birth asphyxia but in those who died later the main symptom was recurrent apnoea. Fewer infants with asphyxia but in those who died later the main symptom was.recurrent apnoea. Fewer infants with 'IVH only' were given alkali therapy or were connected to the ventilator as compared to those with IVH+HMD, but there were no differences in alkali therapy in those who lived for 12 hours or more. In the 'IVH only' group there was a high incidence of haemorrhage from other sites and of bacterial infections. It is suggested that, in the absence of HMD, extreme immaturity is the main factor determining the occurrence of IVH. Birth asphyxia, apnoeic attacks, haemorrhage, and infections may play subsidiary roles, possibly through development of metabolic acidosis.     

Clinical evaluation of a new digitizing device for improved film mammography

RATIONALE AND OBJECTIVES: The study was designed to evaluate a new digitizing device, the iView (Maxxvision, LLC, Gainesville, FL), which aims to replace the magnifying glass in mammography with real-time film digitization, display, and processing. MATERIALS AND METHODS: A receiver operating characteristic (ROC) experiment was performed with 5 certified mammographers and 114 mammograms that were read with and without the iView. A satisfaction survey was also conducted on the system's features and usefulness. RESULTS: Data analysis suggested that (1) Cancer sensitivity could improve with the use of the iView system. ROC area differences showed improvements from 2% to 24% although these were not always statistically significant. At a false positive rate of 0.2, the true positive rate increased up to 60% depending on the set of cases and the observer's experience. (2) Specificity could also be improved. At a true positive rate of 0.9, the false positive rate decreased by as much as 55%. (3) Most observers felt more confident in their decisions when using the iView, although the prototype's ergonomic problems did not allow full utilization of its capabilities. CONCLUSION: Our pilot clinical study showed that the iView has the potential to improve mammogram interpretation. In addition, the system could broaden the applicability of electronic information and provide wider access to digital technology through a relatively simple and cost-effective approach. Observers recommended several improvements in the ergonomics and default display of the system that are currently implemented by the company. A larger clinical study of the improved system is necessary to clearly demonstrate its clinical value for mammography.