Smoothing Splines on Unit Ball Domains with Application to Corneal Topography.

Optical coherence tomography (OCT) is a non-invasive imaging technique used to study and understand internal structures of biological tissues such as the anterior chamber of the human eye. An interesting problem is the reconstruction of the shape of the biological tissue from OCT images, that is not only a good fit of the data but also respects the smoothness properties observed in the images. A similar problem arises in Magnetic Resonance Imaging (MRI). We cast the problem as a penalized weighted least squares regression with a penalty on the magnitude of the second derivative (Laplacian) of the surface. We present a novel algorithm to construct the Kimeldorf-Wahba solution for unit ball domains. Our method unifies the ad-hoc approaches currently in the literature. Application of the theory to data from an anterior segment optical coherence tomographer is presented. A detailed comparison of the reconstructed surface using different approaches is presented.

Epidermal growth factor receptor-directed therapy in esophageal cancer.

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US. The long-term survival of patients with this cancer remains poor; only 25% of patients undergoing surgical excision are alive after 5 years. Multimodal programs that incorporate radiotherapy, chemotherapy and surgery for localized tumors may result in a modest survival advantage. However, significant strides in this disease can result from the inclusion of targeted therapies. The epidermal growth factor receptor (EGFR) family represents one such target and is receiving increasing attention due to the advent of specific inhibitors. Studies conducted by us and others have shown that the overexpression of EGFR family signaling intermediates is common in Barrett's esophagus and EAC. In the latter case, EGFR expression may have prognostic significance. EGFR inhibitors, including oral tyrosine kinase inhibitors and monoclonal antibodies, result in a synergistic antitumor effect with chemotherapeutic agents or with radiotherapy. Therefore, several ongoing studies include EGFR-directed therapy either alone or in combination with chemoradiotherapy for this disease. Our study of gefitinib, oxaliplatin and radiotherapy suggested that gefitinib can be safely incorporated into an oxaliplatin-based chemoradiation program for esophageal cancer, although the clinical activity of this combination is modest. Herein, we review the current literature on this subject.

Management of locoregional stage esophageal cancer: a single center experience.

Therapeutic options for locoregional esophageal cancer (EC) include primary surgery, neoadjuvant or definitive chemoradiation and systemic chemotherapy. The role of surgery in these multimodal strategies has recently been debated and definitive chemoradiation is being offered as an alternative to surgery at many centers. We examined our results with multimodal therapy and surgery in this patient population. We conducted a retrospective analysis of 172 patients with locoregional (AJCC stages I-III) EC treated at RPCI between February 14, 1990 and September 20, 2002. Median age was 65 years (range, 36-95); there were 136 male patients. There were 100 regional (stages IIB-III), 69 local (stages I-IIA) and three in situ cases. Initial therapy was either combined modality (n = 122) or single modality (surgery) (n = 50). There was 0%, 30-day, postoperative mortality. Median survival for all patients was 25.3 months and was better for local stage with surgery alone (75 months) than with neoadjuvant (35.7 months) or definitive chemoradiation (19.1 months, P < 0.001). Survival for patients with regional disease treated with surgery alone, neoadjuvant or definitive chemoradiation was 21.5, 24.4 and 11.8 months, respectively (P = not significant). The associations of prognostic factors with overall survival were evaluated using Cox proportional hazards regression analysis and 2-sided Wald's chi-square test. On multivariate analysis, carefully selected patients treated with surgery alone had better outcomes compared with those treated with definitive chemoradiation (P < 0.001). Patients with locoregional esophageal cancer who are eligible for surgical resection either alone or as a part of multimodal therapy may have better outcomes than those treated with non-surgical approaches.

Audit of operating theatre time utilization in neurosurgery.

Utilization of operating theatre time is an important issue in neurosurgery, in a National Health Service Hospital. NHS Trusts are under ever increasing pressure to meet specified 'targets' in relation to admissions and operations. We performed a retrospective audit on the utilization of neurosurgical operating theatres at Royal Preston Hospital, analysed the times required for various common neurosurgical operations, and broke them down into clinical (operating and anaesthetic) and non-clinical times. We have also looked at the adequacy of available theatre sessions, and the under or over-running of available theatre sessions. A detailed time-based evaluation of 810 procedures over a 16-month period is presented. The mean and 80th centile of the time taken for anaesthesia, surgery and other non-clinical activities are described along with the total time spent in theatre for common neurosurgical procedures. The mean times for transit, preparation for anaesthesia, preparation for surgery, recovery in theatre and time between cases were 16, 13, 14, 15 and 8 minutes, respectively. The mean time duration between the end of one surgical procedure and the beginning of the next was 101 minutes. It was found that actual operating time was surprisingly only 56% of the time available. These data could be used to schedule operating theatre sessions for neurosurgery in the UK, as we believe our practice to be representative of a majority of units in the country.

Spontaneous spinal cord herniation.

Spontaneous spinal cord herniation is a rare and under recognized condition. The commonest presentation is a Brown-sequard syndrome. It most commonly occurs in the thoracic region through an anterolateral dural defect, and the pathophysiology is ill understood. We present a case of spontaneous spinal cord herniation along with a review of literature.

Implementation of the STOP protocol for Stroke Prevention in Sickle Cell Anemia by using duplex power Doppler imaging.

PURPOSE: To compare the results of the nonduplex ultrasonography (US) Stroke Prevention Trial in Sickle Cell Anemia (STOP) with those of transcranial duplex power Doppler US by using the STOP protocol and to correlate abnormal transcranial Doppler findings with magnetic resonance (MR) imaging and MR angiographic findings. MATERIALS AND METHODS: One hundred twenty-five asymptomatic patients aged 2-16 years with sickle cell anemia or sickle cell-beta thalassemia were examined by using transcranial duplex power Doppler US with a 2.5-MHz transducer and classified according to STOP criteria. The results were compared with those obtained in the nonduplex STOP study. Eight of 10 patients with abnormal results, as well as one who had normal results and a subsequent stroke, were examined with MR imaging and MR angiography. RESULTS: Ten (8.0%) patients were judged to have abnormal findings by using the duplex Doppler US and STOP criteria compared with 9.4% of patients in the nonduplex US STOP study. Of the eight patients with abnormal transcranial Doppler US results who underwent MR imaging and MR angiography, six had abnormal MR imaging findings and all eight had abnormal MR angiographic findings. CONCLUSION: The STOP protocol can be reproduced by using duplex power Doppler US. Abnormal results with the STOP criteria strongly suggest vascular abnormality.

Marking hypoxia in rat prostate carcinomas with beta-D-[125I]azomycin galactopyranoside and.

UNLABELLED: The purpose of this study was to determine, with a rodent tumor model, if microelectrode measurements of unmodulated tumor oxygenation predict for the avidity of hypoxic markers to tumor tissue. METHODS: The rapidly growing, anaplastic variant of the Dunning rat prostate carcinoma cell line (R3327-AT) was implanted subcutaneously on the upper backs of Fischer X Copenhagen rats. Approximately 100 measurements of PO2 were obtained from tumors of 5-10 g in animals that were restrained and then subjected to different anesthetic procedures. Values of median PO2 (in mm Hg) and percentage of measurements <5 mm Hg obtained from individual tumors were used to define tumor oxygenation status. The radiodiagnostic hypoxic markers beta-D-iodinated azomycin galactopyranoside (IAZGP) and [99mTc]HL-91 were simultaneously administered to 26 animals whose tumor oxygen levels had been measured. Six hours after marker administration, the animals were killed; tumor, blood, and muscle tissues were sampled; and percentage injected dose per gram (%ID/g*), tumor/blood ratio (T/B), and tumor/muscle ratio (T/M) parameters were determined. Parameters of marker avidity to individual tumors were linearly correlated with microelectrode measurements of tumor oxygenation to determine the significance of inverse associations. RESULTS: The median PO2 of 41 tumors varied from 2.0 to 20.9 mm Hg, with an average value of 7.5 +/- 1.4 mm Hg. Six tumors had unusually high values; that is, >10 mm Hg, and when these were excluded from the analysis, the average median PO2 of the remaining 35 was 4.3 +/- 0.7 mm Hg. When electrode measurements of tumor oxygenation were obtained under conditions of halothane anesthesia with the animals breathing O2, carbogen, or air, median PO2 values increased significantly (P = 0.001). When animals were deeply anesthetized by intraperitoneal injection of ketamine-xylazine, median PO2 values were not significantly different (P = 0.13) from those obtained while the animals were restrained and breathing air. There was no inverse correlation of significance between the electrode measurements of median PO2 and the avidity of beta-D-IAZGP nor [99mTc]HL-91 in this tumor model. The range of median PO2 values in these tumors was at least 3 mm Hg, and the range of hypoxic marker avidity was less than twofold. CONCLUSION: These data demonstrate that microelectrode measurements of rat tumor oxygenation did not correlate with the avidity of the two hypoxic markers, at least in this tumor model. The larger dynamic range of tumor oxygen measurements obtained with microelectrodes might be biased to low values by their necrotic fractions, the zones within solid tumors that contain dead cells and debris that will not be labeled by bioreducible hypoxic markers. Hypoxic marker avidity to individual tumors will have to be validated by other assays that can predict for their radiosensitivity.

Gold microspheres: a selective technique for producing biologically effective dose enhancement.

PURPOSE: To investigate dose enhancement and radiosensitization associated with electrons produced and scattered from gold particles suspended in cells in vitro and with tumour cells growing in vivo irradiated with low-energy photons. MATERIALS AND METHODS: CHO-K1, EMT-6 and DU-145 cells were irradiated with kilovoltage X-ray and Cs-137 beams in slowly stirred suspensions in the presence of various concentrations of gold particles ( 1.5-3.0 microm); cell survival was measured by clonogenic assay. Gold particles were injected directly into EMT-6 tumours growing in scid mice prior to their irradiation. Tumour cell killing was assayed by an in vivo-in vitro technique. RESULTS: Dose enhancement was confirmed by both Fricke dosimetry and cell killing for 100, 140, 200 and 240 kVp X-rays, but not for Cs-137 gamma-rays. For the chemical dosimeter, a dose enhancement (DMF) of 1.42 was measured for 1% gold particle solutions irradiated with 200 kVp X-rays. When rodent and human cells were irradiated in the presence of 1% gold particles, DMF values at the 10% survival level ranged from 1.36 to 1.54, with an overall average value of 1.43. Preliminary attempts to deliver these gold particles to tumour cells in vivo by intra-tumour injection resulted in modest radiosensitization but extremely heterogeneous distribution. CONCLUSIONS: An increased biologically effective dose can be produced by gold microspheres suspended in cell culture or distributed in tumour tissue exposed to kilovoltage photon beams. With the increasing use of interstitial brachytherapy with isotopes that produce low-energy photons, high-Z particles might find a role for significantly improving the therapeutic ratio.

Accuracy of the extent of axillary nodal positivity related to primary tumor size, number of involved nodes, and number of nodes examined.

PURPOSE: While a number of studies have evaluated the minimum number of axillary nodes that need to be examined to accurately determine nodal positivity or negativity, there is little information on the number of nodes which must be examined to determine the extent of nodal positivity. This study attempts to determine for patients with 1-3 positive nodes the probability that the number of positive nodes reported is the true number of positive nodes as well as the probability that 4 or more nodes could be positive based on primary tumor size and number of nodes examined. MATERIALS AND METHODS: From 1979 to 1998, 1652 women with Stages I-II invasive breast cancer underwent an axillary dissection as part of their breast conservation therapy and had more than 10 lymph nodes examined. The mean and median number of nodes identified in the dissection was 19 and 17 (range, 11-75). The median age was 55 years. A total of 1155 women had T1 tumors and 497 had T2 tumors. Of the 459 node-positive women, 72% had 1-3 positive nodes, 18% had 4-9 positive nodes, and 10% had 10 or more positive nodes. A mathematical model based on tumor size and number of nodes examined was created using the hypergeometric distribution and Bayes Theorem. The resulting model was used to estimate the accuracy of the reported number of positive nodes and the probability of 4 or more positive nodes based on various observed sampling combinations. RESULTS: For patients with T1 tumors and 1, 2, or 3 positive nodes, the minimum number of nodes examined needed for a 90% probability of accuracy is 19, 20, and 20. For T2 tumors and 1, 2, or 3 positive nodes, a minimum of 20 nodes is required. The probability of 4 or more positive nodes increases as tumor size and the number of reported positive nodes increase and as the number of examined nodes decreases. For a 10% or less probability of 4 or more positive nodes, a patient with a T1 tumor and 1, 2, or 3 observed positive nodes would require a minimum of 8, 15, and 20 nodes removed. For a T2 tumor and 1, 2, or 3 observed positive nodes, the corresponding numbers are 10, 16, and 20. CONCLUSION: The accuracy of the extent of axillary nodal positivity is influenced by the number of observed positive nodes, tumor size, and the number of nodes examined. Underestimation of the number of positive nodes will result in errors in the assessment of an individual's risk for locoregional recurrence, distant disease, and breast cancer death and will adversely impact on treatment recommendations. This model provides the clinician with a means for assessing the accuracy of the number of positive nodes reported in patients with 1-3 positive nodes.

Outcome evaluation of the 1997 American Joint Committee on Cancer staging system for prostate carcinoma treated by radiation therapy.

BACKGROUND: The 1997 American Joint Committee on Cancer (AJCC) staging system condensed unilobular tumors into one entity and continues the use of both imaging and biopsy to alter classification status in T2 and T3 carcinomas. This study analyzes the biochemical freedom from disease recurrence (bNED) outcome in a large database to determine whether these changes reflect outcome differences. METHODS: Five hundred and thirty-seven patients with adenocarcinoma of the prostate were treated with radiation therapy to a median dose of 7180 centigrays (cGy) (range, 6316-8074 cGy) between November 1987 and November 1994. The median age of the patients was 70 years and the median follow-up was 51 months. The median pretreatment prostate specific antigen (PSA) was 11.0 ng/mL. Patients were analyzed using 1992 AJCC stage comparing bNED outcome after radiation therapy for T2a versus T2b versus T2c tumors using Kaplan-Meier estimation and the log rank test. Patients then were analyzed multivariately using Cox regression with the known prognostic variables of dose, pretreatment PSA, palpation stage, and grade in addition to palpation plus imaging stage and palpation plus biopsy stage. The prognostic endpoint was bNED with failure as defined by the 1997 American Society for Therapeutic Radiology and Oncology Consensus Panel. RESULTS: The 1992 AJCC palpation classifications T2a versus T2b versus T2c have a significantly different (P = 0.02) bNED outcome. Prognostic significance is lost by pooling these three classifications in the 1997 AJCC staging system. Adding imaging information to palpation did not improve the ability of palpation alone to assess bNED status (P = 0.33). However, the addition of biopsy information to palpation significantly (P = 0.02) increased the accuracy of palpation stage alone to predict for bNED outcome for T2 and T3 tumors. CONCLUSIONS: The subdivision of T2 tumors in the 1992 AJCC classification (T2a, T2b, and T2c) should be used in the next revision of the 1997 AJCC staging system. The addition of imaging data does not discriminate bNED outcome any better than palpation stage alone in T2 and T3 tumors and should not be used. The addition of biopsy information to palpation stage did significantly improve the predicted outcome compared with palpation alone and should continue to be used.

Preclinical assessment of hypoxic marker specificity and sensitivity.

PURPOSE: In the search for a sensitive, accurate, and noninvasive technique for quantifying human tumor hypoxia, our laboratory has synthesized several potential radiodiagnostic agents. The purpose of this study was to assess and compare the hypoxic marking properties of both radioiodinated and Tc-99m labeled markers in appropriate test systems which can predict for in vivo activity. MATERIALS AND METHODS: Preclinical assessment of hypoxic marker specificity and sensitivity employed three laboratory assays with tumor cells in vitro and in vivo. Radiolabeled marker uptake and/or binding to whole EMT-6 tumor cells under extremely hypoxic and aerobic conditions was measured and their ratio defined hypoxia-specific factor (HSF). Marker specificity to hypoxic tumor tissue was estimated from its selective avidity to two rodent tumors in vivo, whose radiobiologic hypoxic fractions (HF) had been measured. The ratios of % injected dose/gram (%ID/g) of marker at various times in EMT-6 tumor tissue relative to that in the blood and muscle of scid mice were used to quantify hypoxia-specific activity. This tumor in this host exhibited an average radiobiologic HF of approximately 35%. As well, nuclear medicine images were acquired from R3327-AT (HF approximately =15%) and R3327-H (no measurable HF) prostate carcinomas growing in rats to distinguish between marker avidity due to hypoxia versus perfusion. RESULTS: The HSF for FC-103 and other iodinated markers were higher (5-40) than those for FC-306 and other Tc-99m labeled markers. The latter did not show hypoxia-specific uptake into cells in vitro. Qualitative differences were observed in the biodistribution and clearance kinetics of the iodinated azomycin nucleosides relative to the technetium chelates. The largest tumor/blood (T/B) and tumor/muscle (T/M) ratios were observed for compounds of the azomycin nucleoside class in EMT-6 tumor-bearing scid mice. These markers also showed a 3-4 x higher uptake into R3327-AT tumors relative to the well-perfused R3327-H tumors. While both FC-306 and CERETEC rapidly distributed at unique concentrations to different tissues, their avidity to EMT-6 and R3327-AT tumors did not correlate with tumor HF. CONCLUSIONS: The halogenated azomycin nucleosides with the lowest lipid/water partition coefficient values were found to yield the optimal hypoxia-specific signal in these animal tumors. Our Tc-99m-labeled azomycin chelates showed little or no hypoxia-specific uptake and had in vivo biodistribution and clearance kinetics similar to those of CERETEC, a perfusion agent with no known hypoxic binding activity.

A dual hypoxic marker technique for measuring oxygenation change within individual tumors.

Rodent tumour models have been the 'workhorse' for tumour oxygenation research and for investigating radiobiological hypoxic fraction. Because of the intertumour heterogeneity of blood flow and related parameters, most studies have pooled information derived from several different tumours to establish the statistical significance of specific measurements. But it is the oxygenation status of and its modulation in individual tumours that has important prognostic significance. In that regard, the bioreducible hypoxic marker technique was tested for its potential to quantify oxygenation changes within individual tumours. Beta-D-iodinated azomycin galactoside (IAZG) and beta-D-iodinated azomycin xylopyranoside (IAZXP) were each radiolabelled with Iodine-125 and iodine-131 for measurements of animal tumour oxygenation. The tumour-blood (T/B) ratio of marker radioactivity in mice after the renal excretion of unbound marker (at 3 h and longer times) had been shown to be proportional to radiobiological hypoxic fraction. When markers labelled with both radioisotopes were administered simultaneously to EMT-6 tumour-bearing scid mice, T/B ratios were found to vary by up to 300% between different tumours, with an average intratumour variation of only approximately 4%. When the markers were administered 2.5-3.0 h apart, changes in T/B ratios of 8-25% were observed in 10 out of 28 (36%) tumours. Changes to both higher and lower hypoxic fraction were observed, suggestive of acute or cycling hypoxia. When 0.8 mg g(-1) nicotinamide plus carbogen was administered to increase tumour oxygenation, reductions in T/B ratios (mean deltaT/B approximately 38%) were observed in all tumours. Similar results were obtained with Dunning rat prostate carcinomas growing in Fischer x Copenhagen rats whose T/B ratios of IAZG and radiobiological hypoxic fractions are significantly lower. These studies suggest that fluctuating hypoxia can account for at least 25% of the total hypoxic fraction in some tumours and that correlations between bioreducible marker avidity and related tumour properties will be optimal when the independent assays are performed over the same time period. This dual hypoxic marker technique should prove useful for investigating both spontaneous and induced oxygenation changes within individual rodent tumours.

Influence of penicillin prophylaxis on antimicrobial resistance in nasopharyngeal S. pneumoniae among children with sickle cell anemia. The Ancillary Nasopharyngeal Culture Study of Prophylactic Penicillin Study II.

PURPOSE: To evaluate the consequences of prolonged prophylactic penicillin use on the rates of nasopharyngeal colonization with Streptococcus pneumoniae and the prevalence of resistant pneumococcal strains in children with sickle cell anemia. METHODS: Nasopharyngeal specimens were obtained from children with sickle cell anemia (Hb SS or Hb S beta degrees thalassemia) at 10 teaching hospitals throughout the United States. These patients were participating in a prospective, randomized, placebo-controlled trial in which they were prescribed prophylactic penicillin before their fifth birthday and were randomized to prophylactic penicillin or placebo after their fifth birthday (PROPS II). The specimens were cultured for S. pneumoniae, and isolates were analyzed for antimicrobial susceptibility to nine commonly prescribed antimicrobial agents. RESULTS: Of the 226 patients observed, an average of 8.4 specimens were collected per patient. From 1,896 individual culture specimens, 5.5% of the specimens were positive for S. pneumoniae; 27% of patients had at least one positive culture. Nine percent of the study patients had at least one isolate of penicillin intermediate or resistant pneumococci. There was no significant difference in the percent of positive cultures for S. pneumoniae in those patients given penicillin prophylaxis after 5 years of age (4.1%) compared with those patients given placebo after 5 years of age (6.4%). Likewise, there was no significant difference (p = 0.298) in the percent of patients with at least one positive culture for S. pneumoniae in the group given prophylactic penicillin after 5 years of age (21.8%) compared with the group given placebo after 5 years of age (28.3%). There was no difference between the penicillin and placebo groups in the proportion of patients with penicillin intermediate or resistant pneumococci, but there was a trend toward increased carriage of multiply drug-resistant pneumococci in children > 5 years of age receiving prophylactic penicillin compared to children > 5 years of age receiving placebo. The increased colonization rate with multiply drug-resistant organisms of children > 5 years of age receiving penicillin prophylaxis is not statistically significant. CONCLUSIONS: The potential for continued penicillin prophylaxis to contribute to the development of multiply resistant pneumococci should be considered before continuing penicillin prophylaxis in children with sickle cell anemia who are older than 5 years of age. Added to the published data from PROPS II, which demonstrated no apparent advantage to continue prophylaxis, the data support the conclusion that, for children with no history of invasive pneumococcal disease, consideration should be given to discontinue prophylactic penicillin after their fifth birthday.

Serotype-specific immunoglobulin G antibody responses to pneumococcal polysaccharide vaccine in children with sickle cell anemia: effects of continued penicillin prophylaxis.

OBJECTIVES: (1) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and (2) to determine whether continued penicillin prophylaxis had any adverse effects on these responses. STUDY DESIGN: Children with sickle cell anemia, who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday, were randomly selected at age 5 years to continue penicillin prophylaxis or to receive placebo treatment. These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of randomization. RESULTS: Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor; the poorest response was to serotype 6B. The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment, and in subjects who received one or two pneumococcal vaccinations before reimmunization. The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype. CONCLUSIONS: Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies, regardless of previous pneumococcal vaccine history. Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization.

Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II.

OBJECTIVE: To evaluate the consequences of discontinuing penicillin prophylaxis at 5 years of age in children with sickle cell anemia who had received prophylactic penicillin for much of their lives. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Eighteen teaching hospitals throughout the United States. PATIENTS: Children with sickle cell anemia (hemoglobin SS or hemoglobin S beta 0-thalassemia) who had received prophylactic penicillin therapy for at least 2 years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between 2 and 3 years of age and again at the time of randomization. Of 599 potential candidates, 400 were randomly selected and followed for an average of 3.2 years. INTERVENTIONS: After randomization, patients received the study medication twice daily--either penicillin V potassium, 250 mg, or an identical placebo tablet. Patients were either seen in the clinic or contacted every 3 months thereafter for an interval history and dispensing of the study drug. A physical examination was scheduled every 6 months. MAIN OUTCOME MEASURES: The primary end point was a comparison of the incidence of bacteremia or meningitis caused by Streptococcus pneumoniae in children continuing penicillin prophylaxis versus those receiving the placebo. RESULTS: Six children had a systemic infection caused by S. pneumoniae, four in the placebo group (2.0%; 95% confidence interval 0.5%, 5.0%) and two in the continued penicillin prophylaxis group (1.0%; 95% confidence interval 0.1%, 3.6%) with a relative risk of 0.5 (95% confidence interval 0.1, 2.7). All invasive isolates were either serotype 6(A or B) or serotype 23F. Four of the isolates were penicillin susceptible, and two (one from each treatment group) were penicillin and multiply antibiotic resistant. Adverse effects of the study drug were reported for three patients (nausea, vomiting, or both), one of whom was in the placebo group. CONCLUSION: Children with sickle cell anemia who have not had a prior severe pneumococcal infection or a splenectomy and are receiving comprehensive care may safely stop prophylactic penicillin therapy at 5 years of age. Parents must be aggressively counseled to seek medical attention for all febrile events in children with sickle cell anemia.

A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group.

BACKGROUND: Preoperative transfusions are frequently given to prevent perioperative morbidity in patients with sickle cell anemia. There is no consensus, however, on the best regimen of transfusions for this purpose. METHODS: We conducted a multicenter study to compare the rates of perioperative complications among patients randomly assigned to receive either an aggressive transfusion regimen designed to decrease the hemoglobin S level to less than 30 percent (group 1) or a conservative regimen designed to increase the hemoglobin level to 10 g per deciliter (group 2). RESULTS: Patients undergoing a total of 604 operations were randomly assigned to group 1 or group 2. The severity of the disease, compliance with the protocol, and the types of operations were similar in the two groups. The preoperative hemoglobin level was 11 g per deciliter in group 1 and 10.6 g per deciliter in group 2. The preoperative value for hemoglobin S was 31 percent in group 1 and 59 percent in group 2. The most frequent operations were cholecystectomies (232), head and neck surgery (156), and orthopedic surgery (72). With the exception of transfusion-related complications, which occurred in 14 percent of the operations in group 1 and in 7 percent of those in group 2, the frequency of serious complications was similar in the two groups (31 percent in group 1 and 35 percent in group 2). The acute chest syndrome developed in 10 percent of both groups and resulted in two deaths in group 1. A history of pulmonary disease and a higher risk associated with surgery were significant predictors of the acute chest syndrome. CONCLUSIONS: A conservative transfusion regimen was as effective as an aggressive regimen in preventing perioperative complications in patients with sickle cell anemia, and the conservative approach resulted in only half as many transfusion-associated complications.

Clinical characteristics of children with hereditary hemolytic anemias and aplastic crisis: a 7-year review.

We reviewed the clinical courses of children < or = 16 years of age with hereditary hemolytic anemias who were admitted to the University of Mississippi Medical Center for aplastic crisis. Constitutional signs, gastrointestinal complaints, and headache were the most frequent findings. Statistically significant decreases in hemoglobin levels, hematocrit, and reticulocyte counts, but not total white blood cell or platelet counts, were found on admission when compared to other times of determination. For 27 of 49 patients, IgM antibody determinations to human parvovirus (B19) were available, and 15 (56%) had positive values. We conclude that erythroid (but not other) blood cell lines are helpful in establishing a clinical diagnosis, and that both acute and convalescent titers are necessary to assess the immune response to the infection. Physicians should continue to search for agents other than B19 parvovirus in patients in whom B19 antibodies cannot be found.