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Steven Piantadosi

Publications and source records attributed to Steven Piantadosi.

At least 19 recordsLinked to original sources
PubMed2006

Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naïve prostate cancer.

PURPOSE: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. PATIENTS AND METHODS: A single-institution phase I/II trial was done in hormone therapy-naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 x 10(8) GM-CSF gene-transduced, irradiated, cancer cells (6 x 10(7) LNCaP cells and 6 x 10(7) PC-3 cells) for 8 weeks. RESULTS: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. CONCLUSIONS: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.

Aged↗
PubMed2005

Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype.

PURPOSE: Persistent infection with oncogenic human papillomaviruses (HPV) plays a central etiologic role in the development of squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasias (CIN). We carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables of clinical behavior in women with high-grade cervical lesions. EXPERIMENTAL DESIGN: Our study cohort included healthy women with high-grade cervical lesions (CIN2/3) with residual visible lesions after colposcopically directed biopsy. We prospectively followed 100 women over 15 weeks before standard resection. HPV typing was done using PCR and a reverse line blot detection method. RESULTS: The rate of spontaneous histologic regression, defined as (CIN1 or less at resection) was 28%. The overall rate of HPV infection was 100%. HPV16 was identified in 68% of the lesions. Women with HPV16 only were significantly less likely to regress, compared with women with HPV types other than HPV16 (odds ratio, 0.342; 95% confidence interval, 0.117-0.997; P = 0.049). In the cohort with HPV16 only, patients who had an HLA*A201 allele had similar outcomes to those who did not carry A201. However, among patients with HPV types other than HPV16, the HLA*A201 allele interaction was significant; patients with HLA*A201 were the least likely to resolve. CONCLUSIONS: CIN2/3 lesions associated with HPV16 alone are significantly less likely to resolve spontaneously than those caused by other types. Interactions among HPV type, HLA type, and regression rate support a role for HLA-restricted HPV-specific immune responses in determining disease outcome.

Adolescent↗
PubMed2005

Expression of the caudal-type homeodomain transcription factors CDX 1/2 and outcome in carcinomas of the ampulla of Vater.

PURPOSE: Adenocarcinomas of the ampulla of Vater demonstrate a characteristic histology but vary significantly in outcome. As a consequence, prognostic factors for these cancers are poorly defined. The caudal-type homeodomain transcription factors 1 (CDX1) and 2 (CDX2) regulate axial development and intestinal differentiation. We assessed the expression of these putative intestinal epithelial-specific transcription factors and their influence on patient outcome. PATIENTS AND METHODS: Fifty-three resected carcinomas of the ampulla of Vater, 31 pancreatic ductal adenocarcinomas, and 15 extrahepatic biliary carcinomas were analyzed for CDX1 and CDX2 expression using immunohistochemistry. RESULTS: Forty percent of carcinomas of the ampulla of Vater but less than 5% of pancreatic and biliary adenocarcinomas expressed CDX. Expression of CDX was associated with a better prognosis (P = .0009). Individually, both CDX1 (P = .02) and CDX2 (P = .02) expression were associated with a survival advantage on univariate analysis. Advanced T stage (P = .02), lymph node metastases (P = .004), and vascular space invasion (P = .0009) were associated with a poor prognosis. Multivariate analysis revealed vascular space invasion (P = .01) and CDX expression (P = .01) to be independent prognostic factors. CONCLUSION: Expression of CDX was an independent marker of outcome in patients with resected adenocarcinoma of the ampulla of Vater. Expression of CDX may distinguish good prognosis intestinal-like tumors, which potentially arise within intestinal epithelium, from poorer prognosis pancreatobiliary tumors, which arise in adjacent pancreatic and/or biliary ductal epithelium.

Adenocarcinoma↗
PubMed2005

PIG-A mutations in normal hematopoiesis.

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by phosphatidylinositol glycan-class A (PIG-A) mutations in hematopoietic stem cells (HSCs). PIG-A mutations have been found in granulocytes from most healthy individuals, suggesting that these spontaneous PIG-A mutations are important in the pathogenesis of PNH. It remains unclear if these PIG-A mutations have relevance to those found in PNH. We isolated CD34+ progenitors from 4 patients with PNH and 27 controls. The frequency of PIG-A mutant progenitors was determined by assaying for colony-forming cells (CFCs) in methylcellulose containing toxic doses of aerolysin (1 x 10(-9) M). Glycosylphosphatidylinositol (GPI)-anchored proteins serve as receptors for aerolysin; thus, PNH cells are resistant to aerolysin. The frequency of aerolysin resistant CFC was 14.7 +/- 4.0 x 10(-6) in the bone marrow of healthy donors and was 57.0 +/- 6.7 x 10(-6) from mobilized peripheral blood. DNA was extracted from individual day-14 aerolysin-resistant CFCs and the PIG-A gene was sequenced to determine clonality. Aerolysin-resistant CFCs from patients with PNH exhibited clonal PIG-A mutations. In contrast, PIG-A mutations in the CFCs from controls were polyclonal, and did not involve T cells. Our data confirm the finding that PIG-A mutations are relatively common in normal hematopoiesis; however, the finding suggests that these mutations occur in differentiated progenitors rather than HSCs.

Bacterial Toxins↗
PubMed2005

Durable molecular remissions with a single cycle of timed sequential consolidation chemotherapy in acute promyelocytic leukemia.

In a pilot study to reduce the duration of treatment and potential long-term toxicities, 39 patients with acute promyelocytic leukemia in remission received a single cycle of intensive consolidation therapy, followed by intermittent ATRA maintenance. Consolidation therapy required prolonged hospitalization and was associated with a high incidence of mucositis (43% grade II or greater) and documented infection (45%). No deaths occurred during consolidation. Seven patients have relapsed; all other patients are in molecular remission (median follow-up, 2.75 years). Kaplan-Meier estimate of 3 year disease-free survival is 73% (95% confidence interval 55-91%). The relapse rate (0.06 relapses/patient-year of follow-up) is well within the range of larger published series that administer more prolonged consolidation. One patient has developed secondary myelodysplastic syndrome. These pilot data suggest that decreasing the total duration of consolidation chemotherapy did not compromise disease-free survival for APL patients induced with ATRA/anthracycline and given intermittent ATRA maintenance. However, the toxicity of the consolidation module and the development of secondary myelodysplasia despite decreased total therapy emphasize the need to further improve and refine curative therapy for APL.

Adult↗
PubMed2005

High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement.

The role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age > or =18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated.

Adolescent↗
PubMed2005

Translational clinical trials: an entropy-based approach to sample size.

Translational clinical trials are small studies of therapies emerging from the laboratory. These trials are essential for generating early evidence regarding the effects of treatment on specific targets in the disease pathway and for guiding the next studies to be done. The statistical properties of such studies have been neglected, in part, because they do not fit the well-known clinical trials developmental paradigm. This paper discusses the translational trial setting, and presents an information (entropy) based approach to understanding the properties and use of these trials. The combination of biological knowledge with a designed experiment (albeit a small one) is a powerful device for resolving much of the considerable uncertainty surrounding an emerging therapeutic concept. An approach to motivating the sample size for translational trials is presented.

Animals↗
PubMed2004

Hypermethylation of CpG islands in primary and metastatic human prostate cancer.

Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.

Adult↗
PubMed2004

Safety and efficacy of median sternotomy versus video-assisted thoracic surgery for lung volume reduction surgery.

BACKGROUND: The National Emphysema Treatment Trial, a randomized trial comparing lung volume reduction surgery with medical therapy for severe emphysema, included randomized and nonrandomized comparisons of the median sternotomy and video-assisted thoracoscopic approaches for lung volume reduction surgery. METHODS: Lung volume reduction surgery was performed by median sternotomy only at 8 centers and video-assisted thoracoscopy only at 3 centers; 6 centers randomized the approach to lung volume reduction surgery. Mortality, morbidity, functional status, and costs were assessed. RESULTS: In the nonrandomized comparison, 359 patients received lung volume reduction surgery by median sternotomy, and 152 patients received lung volume reduction surgery by video-assisted thoracoscopy. The 90-day mortality was 5.9% for median sternotomy and 4.6% for video-assisted thoracoscopy (P =.67). Overall mortality was 0.08 deaths per person-year for median sternotomy and 0.10 deaths per person-year for video-assisted thoracoscopy (video-assisted thoracoscopy-median sternotomy risk ratio, 1.18; P =.42). Complication rates were low and not statistically different for the 2 approaches. The median hospital length of stay was longer for median sternotomy than for video-assisted thoracoscopy (10 vs 9 days; P =.01). By 30 days after surgery, 70.5% of median sternotomy patients and 80.9% of video-assisted thoracoscopy patients were living independently (P =.02). Functional outcomes were similar for median sternotomy and video-assisted thoracoscopy at 12 and 24 months. Costs for the operation and the associated hospital stay and costs in the 6 months after surgery were both less for video-assisted thoracoscopy than for median sternotomy (P <.01 in both cases). Similar results were noted for the randomized comparison. CONCLUSIONS: Morbidity and mortality were comparable after lung volume reduction surgery by video-assisted thoracoscopy or median sternotomy, as were functional results. The video-assisted thoracoscopic approach to lung volume reduction surgery allowed earlier recovery at a lower cost than median sternotomy.

Aged↗
PubMed2004

Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.

BACKGROUND & AIMS: Relatives of patients with pancreatic cancer and persons with certain inherited syndromes are at increased risk for developing pancreatic cancer. We prospectively evaluated the feasibility of screening for pancreatic neoplasia in high-risk individuals. METHODS: Individuals from familial pancreatic cancer kindreds and a patient with Peutz-Jeghers syndrome underwent screening endoscopic ultrasound (EUS). If the EUS was abnormal, EUS-guided fine-needle aspiration, endoscopic retrograde cholangiopancreatography (ERCP), and spiral computed tomography (CT) were performed. Patients with abnormalities suggesting neoplasia had surgery. RESULTS: Thirty-eight patients were studied; 31 (mean age, 58 yr; 42% men) from kindreds with > or =3 affected with pancreatic cancer; 6 from kindreds with 2 affected relatives, 1 was a patient with Peutz-Jeghers syndrome. None had symptoms referable to the pancreas or suggestive of malignancy. Six pancreatic masses were found by EUS: 1 invasive ductal adenocarcinoma, 1 benign intraductal papillary mucinous neoplasm, 2 serous cystadenomas, and 2 nonneoplastic masses. Hence, the diagnostic yield for detecting clinically significant pancreatic neoplasms was 5.3% (2 of 38). The 1 patient with pancreatic cancer was treated and still is alive and disease-free >5 years after surgery. EUS changes similar to those associated with chronic pancreatitis were found, which were more common in patients with a history of regular alcohol intake (P = 0.02), but also occurred in patients who did not consume alcohol. Screening also led to a new diagnosis and treatment of symptomatic upper-gastrointestinal conditions in 18.4% of patients. CONCLUSIONS: EUS-based screening of asymptomatic high-risk individuals can detect prevalent resectable pancreatic neoplasia but false-positive diagnoses also occur.

Age Distribution↗
PubMed2004

Oral valacyclovir as prophylaxis against herpes simplex virus reactivation during high dose chemotherapy for leukemia.

Reactivation of herpes simplex virus is a common event in patients undergoing dose-intensive remission induction or consolidation chemotherapy of acute leukemia, for which either intravenous or oral acyclovir provides effective prophylaxis. This drug's short serum half-life and low oral bioavailability make frequent dosing necessary, however, and we therefore sought to determine if the pro-drug valacyclovir, which has improved bioavailability, could be successfully substituted for this indication. Eighty-one patients with leukemia were randomized to receive either 500 mg or 1,000 mg of valacyclovir orally every 8 h and followed clinically, as well as with serial surveillance cultures. Over a total of 1,979 days on study between the groups, and 380 throat cultures, no documented episodes of herpes simplex reactivation were noted. Valacyclovir was tolerated well with no evident drug-related toxicities. We conclude that valacyclovir at either of the two doses studied can be safely substituted for oral or intravenous acyclovir, and that it provides effective prophylaxis against reactivation of herpes simplex virus in this patient population.

Acyclovir↗
PubMed2004

Methodologic issues in terminating enrollment of a subgroup of patients in a multicenter randomized trial.

The National Emphysema Treatment Trial (NETT) was a multicenter randomized controlled trial comparing medical treatment plus lung-volume-reduction surgery (LVRS) to medical treatment alone for the treatment of severe emphysema. The primary outcomes specified for the trial were mortality from all causes and change in functional status as indicated by the change in maximum exercise capacity measured two years after randomization. A secondary objective of the trial was to define criteria to identify subgroups of patients at risk of harm or benefit from LVRS. Stopping guidelines for safety and efficacy based on 30-day mortality and a combination of overall mortality and functional status at two years were specified at the inception of the trial. Although specific subgroups of patients likely to benefit were not identified in advance, several clinical factors were specified as likely to be important in defining subgroups with differential outcome. In May 2001, with 40% of expected deaths accrued, the Data and Safety Monitoring Board determined that a subgroup of patients was at significantly higher risk of 30-day mortality from LVRS without counterbalancing evidence of functional benefit, and recommended that the protocol be modified to exclude further randomization of such patients. The trial's sponsor, the National Heart, Lung and Blood Institute, accepted the recommendation, which was rapidly communicated to participating clinics. This paper describes the operational aspects of identification of the subgroup and implementation of the recommendation to continue the trial, but to terminate enrollment of new patients in the subgroup. These aspects include notification of the investigators, the institutional review boards, the Research Group, the patients and the medical community. We also describe the repercussions of the publication and the misinterpretations of the results based on media coverage.

Clinical Protocols↗
PubMed2003

Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma.

PURPOSE: A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs). EXPERIMENTAL DESIGN: Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of patients (+/-EIA). Groups of >/==" BORDER="0">3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose. RESULTS: Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients. CONCLUSIONS: The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.

Adult↗
PubMed2003

A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema.

BACKGROUND: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of patients have not been established. METHODS: A total of 1218 patients with severe emphysema underwent pulmonary rehabilitation and were randomly assigned to undergo lung-volume-reduction surgery or to receive continued medical treatment. RESULTS: Overall mortality was 0.11 death per person-year in both treatment groups (risk ratio for death in the surgery group, 1.01; P=0.90). After 24 months, exercise capacity had improved by more than 10 W in 15 percent of the patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). With the exclusion of a subgroup of 140 patients at high risk for death from surgery according to an interim analysis, overall mortality in the surgery group was 0.09 death per person-year, as compared with 0.10 death per person-year in the medical-therapy group (risk ratio, 0.89; P=0.31); exercise capacity after 24 months had improved by more than 10 W in 16 percent of patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). Among patients with predominantly upper-lobe emphysema and low exercise capacity, mortality was lower in the surgery group than in the medical-therapy group (risk ratio for death, 0.47; P=0.005). Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was higher in the surgery group than in the medical-therapy group (risk ratio, 2.06; P=0.02). CONCLUSIONS: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain.

Aged↗
PubMed2003

Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study.

We recently reported 3 risk factors (RFs) at diagnosis of chronic graft-versus-host disease (cGVHD) that were significantly associated with increased nonrelapse mortality. These included extensive skin involvement (ESI), thrombocytopenia (TP), and progressive type of onset (PTO). The hazard ratio (HR) for mortality of the patients with prognostic score (PS) between 0 and 2 (intermediate-risk; 1 RF) compared to those with PS 0 (favorable-risk; 0 RF) was 3.7 (95% CI, 1.4, 9.3); the HR for patients with PS equal to or more than 2 (high-risk; > 1 RF) compared with intermediate-risk group was 6.9 (3.8, 12.4). A rare presentation of TP and PTO without ESI yielded a PS of 1.8 (intermediate-risk). This paper reports the performance of the prognostic model and the individual RFs using data from an additional 1105 patients from University of Nebraska (n = 60), International Bone Marrow Transplantation Registry (n = 708), Fred Hutchinson Cancer Research Center (n = 188), and University of Minnesota (n = 149). The extent of skin involvement was quantified in 3 cohorts using the available data collected in different formats before the analysis. Although the HR for mortality of the patients in the intermediate-risk group versus those in the favorable-risk group ranged from 2.3 to 8.9 across the centers, it was between 1.6 to 6.9 for patients in the high-risk group versus those in the intermediate-risk group. Although TP itself was uniformly associated with increased risk of mortality across all test samples, ESI and PTO showed statistically significant associations with mortality in 1 and 2 cohorts, respectively. In conclusion, the model was predictive of cGVHD-specific survival, but the mortality hazard associated with ESI was lower in each of these test samples compared with the learning sample. Although the new clinical grading based on the model is promising because of its utility across multiple independent data sets, prospective validation is needed.

Adolescent↗