Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Patient preferences of chemotherapy treatment options and tolerance of chemotherapy side effects in advanced stage lung cancer.

BACKGROUND: In the U.S., lung cancer accounts for 14% of cancer diagnoses and 28% of cancer deaths annually. Since no cure exists for advanced lung cancer, the main treatment goal is to prolong survival. Chemotherapy regimens produce side effects with different profiles. Coupling this with individual patient's preferred side effects could result in patient-centered choices leading to better treatment outcomes. There are apparently no previous studies of or tools for assessing and utilizing patient chemotherapy preferences in clinical settings. The long-term goal of the study was to facilitate patients' treatment choices for advanced-stage lung cancer. A primary aim was to determine how preferences for chemotherapy side effects relate to chemotherapy choices. METHODS: An observational, longitudinal, open cohort study of patients with advanced-stage non-small cell lung cancer (NSCLC) was conducted. Data sources included patient medical records and from one to three interviews per subject. Data were analyzed using Chi-square, Fisher's Exact and McNamara's test, and logistic regression. RESULTS: Patients identified the top three chemotherapy side effects that they would most like to avoid: shortness of breath, bleeding, and fatigue. These side effects were similar between first and last interviews, although the rank order changed after patients experienced chemotherapy. CONCLUSIONS: Patients ranked drug side effects that they would most like to avoid. Patient-centered clinical care and patient-centered outcomes research are feasible and may be enhanced by stakeholder commitment. The study results are limited to patients with advanced NSCLC. Most of the subjects were White, since patients were drawn from the U.S. Midwest, a predominantly White population.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Self-incompatibility: a self-recognition system in plants.

Self-incompatibility (SI), a genetically controlled mechanism to prevent inbreeding in plants, offers a relatively simple model system for studying the interactions between plant cells or between a plant cell and the secreted product or products of another cell. Examples of two major types of SI, gametophytic and sporophytic, have been studied by cloning cDNAs corresponding to glycoproteins of the female tissues that segregate with particular variants encoded by the putative S locus. These secreted glycoproteins are envisaged to interact with the currently undescribed pollen component to cause arrest of pollen tube growth.

Rice plants overexpressing OsEPF1 show reduced stomatal density and increased root cortical aerenchyma formation.

Stomata are adjustable pores in the aerial epidermis of plants. The role of stomata is usually described in terms of the trade-off between CO2 uptake and water loss. Little consideration has been given to their interaction with below-ground development or diffusion of other gases. We overexpressed the rice EPIDERMAL PATTERNING FACTOR1 (OsEPF1) to produce rice plants with reduced stomatal densities, resulting in lowered leaf stomatal conductance and enhanced water use efficiency. Surprisingly, we found that root cortical aerenchyma (RCA) is formed constitutively in OsEPF1OE lines regardless of tissue age and position. Aerenchyma is tissue containing air-spaces that can develop in the plant root during stressful conditions, e.g. oxygen deficiency when it functions to increase O2 diffusion from shoot to root. The relationship with stomata is unknown. We conclude that RCA development and stomatal development are linked by two possible mechanisms: first that reduced stomatal conductance inhibits the diffusion of oxygen to the root, creating an oxygen deficit and stimulating the formation of RCA, second that an unknown EPF signalling pathway may be involved. Our observations have fundamental implications for the understanding of whole plant gas diffusion and root-to-shoot signalling events.

Author Correction: Rice plants overexpressing OsEPF1 show reduced stomatal density and increased root cortical aerenchyma formation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ABA signalling: a messenger's FIERY fate.

There is considerable circumstantial evidence that the Ca(2+)-mobilizing second messenger IP(3) is involved in plant responses to the drought hormone abscisic acid. More direct evidence for this has now come from studies in which endogenous IP(3) levels have been manipulated in plants.

Action of the Style Product of the Self-Incompatibility Gene of Nicotiana alata (S-RNase) on in Vitro-Grown Pollen Tubes.

The products of the S-locus expressed in female tissues of Nicotiana alata are ribonucleases (S-RNases). The arrest of growth of incompatible pollen tubes in styles may result from entry of the S-RNase into the pollen tube and degradation of pollen tube RNA. We investigated the action of isolated S-RNases on pollen tubes grown in vitro and found that S-RNase is taken up by the pollen without substantial alteration. The S-RNases inhibit incorporation of exogenously added radioactive amino acids into protein by the germinated pollen. The S-RNases also inhibit in vitro translation of pollen tube RNA in a wheat germ cell-free extract. We found no evidence for a specific mRNA substrate for the S-RNases, which implies that if RNase activity is involved in the control of self-incompatibility, allelic specificity is more likely to depend on the selective uptake of S-RNases into pollen tubes or their selective activation or inactivation by pollen factors, rather than cleavage of a specific substrate. Heat treating S2-RNase largely destroys its RNase activity but increases its inhibitory effect on in vitro pollen tube growth. This effect is not due to an increased uptake of S2-RNase by the pollen but is associated with a greatly enhanced accumulation of S2-RNase on the outer surface of the pollen grains.

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

Effect of 1.5 tesla nuclear magnetic resonance imaging scanner on implanted permanent pacemakers.

Patients with a permanent pacemaker are currently restricted from diagnostic nuclear magnetic resonance (NMR) imaging because of potential adverse effects on the pacemaker by the magnet. Previous work has shown that NMR imaging will result in asynchronous pacing of the pulse generator within a given distance of the magnet. The radiofrequency signal generated by the system may also result in rapid cardiac pacing, which may have deleterious effects. This study utilized a 1.5 tesla unit in an in vivo laboratory animal to evaluate the unit's effects on eight different pulse generators from two manufacturers. All pacemakers functioned in an asynchronous mode when placed within a certain distance of the magnet. In addition, transient reed switch inhibition was observed. Seven of the eight pulse generators paced rapidly when exposed to the radiofrequency signal and there was a dramatic decrease in arterial blood pressure. Whether effective rapid cardiac pacing would occur could not be predicted before exposure to the magnetic resonance unit. Nuclear magnetic resonance imaging with high magnetic fields in patients with a pacemaker should continue to be avoided until the mechanism of the rapid cardiac pacing can be further delineated and either predicted or prevented.

Effect of pulsed progressive fluoroscopy on reduction of radiation dose in the cardiac catheterization laboratory.

The increased application of therapeutic interventional cardiology procedures is associated with increased radiation exposure to physicians, patients and technical personnel. New advances in imaging techniques have the potential for reducing radiation exposure. A progressive scanning video system with a standard vascular phantom has been shown to decrease entrance radiation exposure. The effect of this system on reducing actual radiation exposure to physicians and technicians was assessed from 1984 through 1987. During this time, progressive fluoroscopy was added sequentially to all four adult catheterization laboratories; no changes in shielding procedures were made. During this time, the case load per physician increased by 63% and the number of percutaneous transluminal coronary angioplasty procedures (a high radiation procedure) increased by 244%. Despite these increases in both case load and higher radiation procedures, the average radiation exposure per physician declined by 37%. During the same time, the radiation exposure for technicians decreased by 35%. Pulsed progressive fluoroscopy is effective for reducing radiation exposure to catheterization laboratory physicians and technical staff.

Is mandatory outpatient treatment effective?

This paper reviews the major studies of mandatory outpatient treatment (MOT) and examines why there has been inconsistency in some of the findings. Attempts to answer the question "is mandatory treatment effective?" must first clarify the type of mandatory treatment being examined, the type of patient being treated, and the outcome by which effectiveness is measured. There is consistent evidence that various forms of MOT increase follow-up with psychiatric services and that court-ordered outpatient committal decreases victimization of patients in the community. It also appears likely that MOT reduces the use of hospitalization; but, due to methodological problems associated with the research, this conclusion remains controversial.

Characterization, primary structure, and evolution of lamprey plasma albumin.

The most abundant protein found in blood plasma from the sea lamprey (Petromyzon marinus) has the hallmarks of a plasma albumin: namely, high abundance, solubility in distilled water, a small number of tryptophans, and a high content of cysteines and charged residues. As in other vertebrate albumins, not all the cysteines are disulfide bonded. An unusual feature of this protein is its molecular weight of 175,000, roughly 2.5 times the size of other vertebrate albumins. Its amino acid sequence, deduced from a series of overlapping cDNA clones, can be aligned with other members of the gene family including plasma albumin, alpha-fetoprotein, and vitamin-D binding protein, confirming that it is indeed an oversized albumin. An unusual feature of the sequence is a 28-amino acid stretch consisting of a serine-threonine repeat with the general motif (STTT). Lamprey albumin contains a 23-amino acid putative signal peptide and a 6-residue putative propeptide, which, when cleaved, yield a mature protein of 1,394 amino acids with a calculated molecular weight of 157,000. The sequence also includes nine potential N-linked glycosylation sites (Asn-X-Ser/Thr), consistent with observation that lamprey albumin is a glycoprotein. If all the potential glycosylation sites were occupied by clusters of 2,000 molecular weight each, the total molecular weight would be 175,000. Like other members of the gene family, lamprey albumin is composed of a series of 190-amino acid repeats, there being seven such domains all together. Quantitative amino acid sequence comparisons of lamprey albumin with the other members of the gene family indicate that it diverged from an ancestral albumin prior to the gene duplications leading to this diverse group. This notion is confirmed by the pattern of amino acid insertions and deletions observed in a consideration of all domains that compose this family. Furthermore, it suggests that the invention of albumin antedates the vertebrate radiation.

Normal birth weight intensive care unit survivors: outcome assessment.

UNLABELLED: RATIONALE/OBJECTIVE: Although the short- and long-term outcome of low birth weight neonatal intensive care unit (NICU) survivors has been extensively studied, much less information is available for normal birth weight (NBW) infants (greater than or equal to 2500 g) who require NICU care. METHODS: To address this issue, we retrospectively examined the neonatal hospitalizations and 6-month health status of 521 consecutive NBW admissions to a single NICU. Information on the neonatal hospitalization was obtained from a review of medical records. Postdischarge health status was collected by using telephone survey techniques. RESULTS: NBW infants comprised 88.1% of births in this hospital and 35.4% of NICU admissions during the study period. The in-hospital mortality rate for this group was 2%. The median length of stay was 7.7 days (range 1 to 110 days) with median hospital charges of $5222 (range $565 to $317,820). Only 59% of infants required active intensive care therapy; the remainder received only intensive monitoring. The need for intensive therapy on admission day along with the presence of prematurity and congenital anomalies were significant predictors of hospital charges (R2 = 0.31, P < .01). After initial discharge, 10.1% of these infants required rehospitalization in the first 6 to 8 months of life. The rate of readmission among infants with congenital anomalies was over 30%. In addition to its association with neonatal resource consumption, the presence of congenital anomalies along with low 5-minute Apgar scores was associated with higher postdischarge resource use, as measured by frequency of physician visits, need for special medical items, and rate of rehospitalization (P < .05). CONCLUSIONS: NBW infants represent a significant percentage of NICU admissions, but for many of these patients NICU admission could be avoided if alternative care settings that provided intensive monitoring were available. In addition, these infants also incur higher rates of postdischarge use of medical care.

Coagulase-negative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome.

OBJECTIVE: To examine the impact of admission-day illness severity on nosocomial bacteremia risk after consideration of traditional risk determinants such as birth weight and length of stay. METHODS: The hospital courses for 302 consecutive very low birth weight (less than 1500 g) infants admitted to two neonatal intensive care units were examined for the occurrence of nosocomial coagulase-negative staphylococcal bacteremia. Using both cumulative incidence and incidence density as measures of bacteremia risk, we explored the relation between illness severity (as measured by the Score for Neonatal Acute Physiology [SNAP]) and bacteremia both before and after birth weight adjustment. In addition, the effect of bacteremia on hospital resource use was estimated. RESULTS: Coagulase-negative staphylococcus was the most common pathogen noted in blood cultures drawn at 48 hours after admission or later. It was isolated on at least one occasion in 53 patients (cumulative incidence of 17.5 first episodes per 100 patients). These episodes occurred during 7652 days at risk, giving an incidence density of 6.9 initial bacteremias per 1000 patient-days at risk. As expected, when compared with the nonbacteremic group, bacteremic patients were of lower birth weight (888 +/- 231 vs 1127 +/- 258 g; P < .01) and gestational age (26.4 +/- 2.1 vs 28.9 +/- 2.8 weeks; P < .01). In addition, these patients were more severely ill on admission (SNAP 17.3 +/- 6.5 vs 12.2 +/- 5.8; P < .01). Even after birth weight stratification, the risk of bacteremia by both measures increased with higher SNAP scores. For example, among infants with birth weights greater than 1 kg, 25% of the most severely ill patients (SNAP 20 and higher) experienced at least one bacteremic episode, whereas the rates seen in infants with intermediate (SNAP 10 to 19) and low illness severity (SNAP 0 to 9) were 8.6% and 3.0%, respectively (chi 2 for trend = 7.25; P < .01). Multivariate linear regression showed that bacteremia was associated with a prolongation of neonatal intensive care unit stay of 14.0 +/- 4.0 days (P < .01) and an increase in hospital charges of $25,090 +/- 12,051 (P < .05), even after adjustment for birth weight and admission-day SNAP. CONCLUSIONS: Nosocomial coagulase-negative bacteremia is an important complication among very low birth weight infants. Assessment of illness severity with SNAP provides information regarding nosocomial infection risk beyond that available from birth weight alone.

Score for Neonatal Acute Physiology: a physiologic severity index for neonatal intensive care.

The substantial variation in birth weight-adjusted mortality among neonatal intensive care units (NICUs) may reflect differences in population illness severity. Development of an illness severity measure is essential for comparisons of outcomes. The Score for Neonatal Acute Physiology (SNAP) was developed and validated prospectively on 1643 admissions (114 deaths) in three NICUs. SNAP scores the worst physiologic derangements in each organ system in the first 24 hours. SNAP showed little correlation with birth weight and was highly predictive of neonatal mortality even within narrow birth weight strata. It was capable of separating patients into groups with 2 to 20 times higher mortality risk. It also correlated highly with other indicators of severity including nursing workload (r = .59), therapeutic intensity (r = .78), physician estimates of mortality risk (r = .65), and length of stay (R2 = .59). SNAP is an important new tool for NICU research.

Estimating neonatal mortality risk: an analysis of clinicians' judgments.

BACKGROUND: Clinicians' estimates of mortality risk in the neonatal intensive care unit (NICU) have implications for patient triage, transfer, initiation and termination of life support, and allocation of medical resources. The accuracy of these judgments has not been studied, nor the differences between nurses and attending physicians. OBJECTIVES: 1) evaluate the accuracy of subjective judgments of NICU unit mortality risk, 2) identify the key components of clinician judgments, 3) compare accuracy between attending physicians and nurses, and 4) examine the utility of combining an objectively computed risk and clinician judgments to improve predictions. METHODS: We obtained estimates of mortality risk on 544 admissions to two NICUs on the day of admission from the attending physician and primary nurse. These were compared with an objective computed mortality risk based on birth weight and the Score for Neonatal Acute Physiology (SNAP) using a linear judgment analysis model, as well as with actual outcomes. RESULTS: Physicians and nurses had good discriminating power with actual mortality rates ranging from 0% among low risk patients to 67% among those with the highest mortality estimates. Physicians had a tendency to overestimate mortality risk. Clinicians base their estimates on the same factors and similar judgment weights as the empiric mortality risk model (22% birth weight, 62% illness severity (SNAP), 13% low Apgar, and 3% for intrauterine growth restriction). Clinicians place additional emphasis on therapeutic as well as physiologic factors. When the computed risk and physician judgment were combined, both made significant contributions in a logistic mortality risk model. CONCLUSIONS: Clinician judgments of mortality risk are fairly accurate and similar to an objective illness severity index. This simple method provides insight into clinical decision making and has important applications in improving direct patient care, appropriate allocation of medical resources, and medical training.

Neonatal therapeutic intervention scoring system: a therapy-based severity-of-illness index.

Severity-of-illness scales have proven valuable in assessing clinical outcomes and resource consumption in adult and pediatric intensive care, but they have been less extensively developed for neonatal care. The National Therapeutic Intervention Scoring System (NTISS) was created by modifying the Therapeutic Intervention Scoring System (TISS). From the 76 original TISS items, 42 were deleted and 28 added to form the NTISS. Like TISS, NTISS assigns score points from 1 to 4 for various intensive care therapies. Admission-day NTISS scores were calculated for 1643 newborns admitted to three neonatal intensive care units (NICUs) between November 1, 1989, and September 30, 1990. NTISS scores ranged from 0 to 47 with a mean of 12.3 +/- 8.7 (SD). There was little correlation with birth weight (r = -.11) or gestational age (r = -.17), but NTISS scores were highly correlated with expected markers of illness severity, including mortality risk estimates by neonatal attending physicians (r = .70, P < .0001), in-hospital mortality rates (P < .05), and a measure of nursing acuity (Medicus) (r = .69, P < .0001). In addition, admission-day NTISS scores were found to be predictive of both NICU length of stay (r = .37, P < .0001) and total hospital charges for survivors (r = .65, P < .0001). It is concluded that NTISS is a valid measure of therapeutic intensity that is independent of birth weight and can be used as an indicator of neonatal illness severity and resource utilization. Further validation in other NICUs is required.

Birth weight and illness severity: independent predictors of neonatal mortality.

BACKGROUND: Low birth weight is a major determinant of neonatal mortality. Yet birth weight, even in conjunction with other demographic markers, is inadequate to explain the large variations in neonatal mortality between intensive care units. This variation probably reflects differences in admission severity. The authors have recently developed the Score for Neonatal Acute Physiology (SNAP), an illness severity index specific for neonatal intensive care, and demonstrated illness severity to be a major determinant of neonatal mortality. OBJECTIVE: To define the relative contributions of birth weight and illness severity to the risk of neonatal mortality and to identify other significant independent risk factors. METHODS: Logistic regression was used to analyze data from a cohort of 1621 consecutive admissions to three neonatal intensive care units (92 deaths), to test six alternative predictive models. The best logistic model was then used to develop a simple additive clinical score, the SNAP Perinatal Extension (SNAP-PE). RESULTS: These analyses demonstrated that birth weight and illness severity are powerful independent predictors across a broad range of birth weights and that their effects are additive. Below 750 g, there is an interaction between birth weight and SNAP. Other factors that showed independent predictive power were low Apgar score at 5 minutes and small size for gestational age. Separate derivation and test samples were used to demonstrate that the SNAP-PE is comparable to the best logistic model and has a sensitivity and specificity superior to either birth weight or SNAP alone (receiver-operator characteristic area .92 +/- .02) as well as excellent goodness of fit. CONCLUSION: This simplified clinical score provides accurate mortality risk estimates for application in a broad array of clinical and research settings.

Declining severity adjusted mortality: evidence of improving neonatal intensive care.

OBJECTIVES: Declines in neonatal mortality have been attributed to neonatal intensive care. An alternative to the "better care" hypothesis is the "better babies" hypothesis; ie, very low birth weight infants are delivered less ill and therefore have better survival. DESIGN: We ascertained outcomes of all live births <1500 g in two prospective inception cohorts. We estimated mortality risk from birth weight and illness severity on admission and measured therapeutic intensity. We calculated logistic regression models to estimate the changing odds of mortality between cohorts. PATIENTS AND SETTING: Two cohorts in the same two hospitals, 5 years apart (1989-1990 and 1994-1995) (total n = 739). RESULTS: Neonatal intensive care unit mortality declined from 17.1% to 9.5%, and total mortality declined from 31.6% to 18.4%. Cohort 2 had lower risk (higher birth weight, gestational age, and Apgar scores and lower admission illness severity for newborns >/=750 g). Risk-adjusted mortality declined (odds ratio, 0.52; confidence interval, 0.29-0. 96). One third of the decline was attributable to "better babies" and two thirds to "better care." Use of surfactant, mechanical ventilation, and pressors became more aggressive, but decreases in monitoring, procedures, and transfusions resulted in little change in therapeutic intensity. CONCLUSIONS: Mortality decreased nearly 50% for infants <1500 g in 5 years. One third of this decline is attributable to improved condition on admission that reflects improving obstetric and delivery room care. Two thirds of the decline is attributable to more effective newborn intensive care, which was associated with greater aggressiveness of respiratory and cardiovascular treatments. Attribution of improved birth weight specific mortality solely to neonatal intensive care may underestimate the contribution of high-risk obstetric care in providing "better babies."