Long-term outcome, including school-age function, has been infrequently reported in infants born at ages as young as 23-26 weeks' gestation. The objective of this study is to report outcome on a ...large cohort of these infants to understand better the risks and factors that affect survival and long-term prognosis.
Records from 1036 infants who were born between January 1, 1986, and December 31, 2000, were analyzed retrospectively by logistic regression to correlate multiple factors with both survival and long-term outcome. A total of 675 surviving infants were analyzed at a mean age of 47.5 months for developmental outcome. A subset of 147 surviving infants who were born before 1991 were followed through school-age years using the University of Vermont Achenbach Child Behavioral Checklist and Teachers Report Form. Longitudinal follow-up was performed comparing 1-year outcome with school-age performance.
Gestational age and recent year of birth correlated highly with survival. Maternal nonwhite race, female sex, inborn status, surfactant therapy, single gestation, and secondary sepsis also correlated positively with survival. Normal cranial ultrasound results, absence of chronic lung disease, female sex, cesarean delivery, and increased birth weight correlated favorably with long-term outcome. Infants who were born at 23 weeks were more likely to have severe impairments compared with those who were born at 24-26 weeks. Early follow-up identified most subsequent physical impairments but correlated poorly with school-age function.
Survival continues to improve for infants who are born at extremely early gestational ages, but long-term developmental concerns continue to be prevalent. Early outcomes do not reliably predict school-age performance. Strategies that reduce severe intraventricular hemorrhage and chronic lung disease will likely yield the best chances to improve long-term outlook.
ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with ...advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis.
ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles.
Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations > 100 ng/mL > 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients.
ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.
Purpose: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective
epidermal growth factor receptor tyrosine kinase inhibitor PKI166 ...in patients with advanced solid malignancies.
Experimental Design: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to
establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information
and characterize the effect of food intake on PKI166 pharmacokinetics. Pharmacokinetics of PKI166 were characterized after
single and multiple doses at all dose levels.
Results: Fifty-four patients received a total of one hundred sixteen 28-day cycles of PKI166. Dose-limiting transaminase elevations
were observed in two of seven and two of eight patients using 50 and 100 mg PKI166 continuously. In the second part with PKI166
once daily for 2 weeks every 4 weeks, MTD was set at 750 mg. Dose-limiting toxicity consisted of diarrhea, skin rash, and
transaminase elevations. Pharmacokinetic analysis revealed fast absorption, a linear dose-response relationship without drug
accumulation after multiple doses. At MTD, no significant influence of food intake on PKI166 pharmacokinetics was observed.
Stable disease for more than two cycles was observed in 11 patients.
Conclusions: PKI166 given once daily for 2 weeks every 4 weeks is well tolerated with linear pharmacokinetics, compatible with once daily
dosing, and without significant effect of food intake on absorption. The recommended dose for further studies is 750 mg once
daily for 2 weeks every 4 weeks.
Abstract Background The microbiome has been associated with chemotherapy and immune checkpoint inhibitor efficacy. How this pertains to resectable esophageal carcinoma is unknown. Our aim was to ...identify microbial signatures in resectable esophageal carcinoma associated with response to neoadjuvant chemoradiotherapy with or without an immune checkpoint inhibitor. Methods From 2 prospectively collected esophageal carcinoma cohorts (n = 172 in total) treated with neoadjuvant chemoradiotherapy alone (n = 132) or a combination of neoadjuvant chemoradiotherapy and an immune checkpoint inhibitor (n = 40), fecal samples were available at baseline, during treatment, and presurgery. Additionally, in the immune checkpoint inhibitor–treated patients, tumor and duodenal snap frozen biopsies were collected over time. Fecal, tumor, and duodenal DNA were extracted for 16S ribosomal RNA sequencing. Associations were investigated between microbiome composition pathological complete response and progression-free survival (PFS). Results There was a statistically significant shift in the microbiota profile of the fecal, tumor, and duodenal microbiota over time. In the total cohort, patients with a pathological complete response had a stable fecal alpha diversity, while the diversity of poor responders decreased during treatment (P = .036). Presurgery, lower alpha diversity (<4.12) was related to worse PFS (log-rank P = .025). Baseline tumor biopsies of patients with short PFS had more Fusobacterium. A low baseline duodenal alpha diversity (<3.96) was associated with worse PFS (log-rank P = .012). Conclusions Lower intestinal alpha diversity was associated with worse response and survival of esophageal carcinoma patients. In tumor biopsies, Fusobacterium was more abundant in patients with poor PFS. After further mechanistic validation, these findings may aid in response prediction and the design of novel microbiome modulating treatments for esophageal carcinoma patients.
Purpose: To determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics of a fixed dose of paclitaxel followed by
increasing doses of carboplatin, given weekly to patients with ...advanced esophageal or gastric junction cancer.
Experimental Design: Paclitaxel was administered on day 1 as a 1-h infusion at a fixed dose of 100 mg/m 2 followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2–5 mg × min/ml, with cycles repeated
on days 8, 15, 29, 36, and 43.
Results: Forty patients 36 males; median (range) age, 57 (40–74) years were enrolled. Dose-limiting toxicity was observed at a carboplatin
AUC of 5 mg × min/ml and consisted of treatment delay attributable to myelosuppression. No grade 3/4 treatment-related nonhematological
toxicity was observed. The highest dose intensity (>95% of the planned dose over time) was achieved with a carboplatin AUC
of 4 mg × min/ml. The mean (±SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 ± 0.186 and 7.37 ± 1.33 μ m × h, respectively. Clearance of Cu was 188 ± 44.6 liter/h/m 2 , which is not significantly different from historical data ( P = 0.52). Cremophor EL clearance was 123 ± 23 ml/h/m 2 , similar to previous findings. Of 37 patients evaluable for response, 1 had complete response, 19 had partial response, and
10 had stable disease, accounting for an overall response rate of 54%.
Conclusions: This regimen is very tolerable and effective, and the recommended doses for additional studies are paclitaxel (100 mg/m 2 ), with carboplatin targeting an AUC of 4 mg × min/ml.
Purpose: BMS-214662 is a potent and selective inhibitor of the farnesyl transferase enzyme with in vitro and in vivo antitumor activity. The aims of this study were to characterize the toxicities and ...to determine the pharmacokinetic profiles
of BMS-214662 when administered in combination with cisplatin, and to determine the constitutive farnesyltransferase activity
as a surrogate pharmacodynamic end point.
Experimental Design: Twenty-nine patients with advanced solid malignancy, refractory to conventional therapy, and with adequate hematological,
renal, and hepatic function were treated with escalating doses of BMS-214662 administered as a 1-h infusion, followed after
an interval of 30 min by 75 mg/m 2 cisplatin administered as a 4-h infusion and repeated every 21 days. Blood and urine samples for pharmacokinetic and pharmacodynamic
analyses were collected during the first cycle of treatment only.
Results: Dose-limiting toxicities occurred in 4 of 9 patients enrolled at the 225 mg/m 2 BMS-214662 dose cohort, and included elevation of hepatic transaminases, nausea, vomiting, diarrhea, and renal failure. There
was no apparent pharmacokinetic interaction between the two drugs at the recommended dose levels, and a dose-dependent inhibition
of farnesyltransferase activity was observed, which returned to control levels within 24 h of drug administration. There were
no objective responses, but disease stabilization was observed in 15 patients, including 4 patients with stable disease after
6 cycles of treatment.
Conclusions: A dose of 200 mg/m 2 of BMS-214662 administered as a 1-h infusion with 75 mg/m 2 cisplatin over 4 h is the recommended dose for additional studies.
The aim of this nationwide cohort study was to examine the course of symptoms and trajectories of health-related quality of life (HR-QoL) and psychological distress during follow-up and to identify ...vulnerable patients.
Patients with pathological stage I–III colorectal cancer (CRC) between 2013 and 2018 were included. Baseline characteristics were collected from the Netherlands Cancer Registry, and patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30/CR29, Hospital Anxiety and Depression Scale and low anterior resection syndrome (LARS) questionnaires at the baseline and subsequently at 3, 6, 12, 18 and 24 months. Latent class growth and multinomial logistic regression analyses were performed to outline 24-month trajectories in HR-QoL and distress and to identify predictive factors.
: A total of 1535 patients with colon cancer or rectal cancer were included. Trajectory analysis of HR-QoL identified three patient classes: high HR-QoL (62.7%), improving HR-QoL (29.0%) and low HR-QoL (8.3%). The following patient groups were identified with having low distress (64.0%), moderate distress (26.9%) and high distress (9.1%). Around 13% of the total cohort had either persistent low HR-QoL or high psychological distress throughout follow-up. Patients belonging to this vulnerable group were significantly more likely to be female, to be younger aged, to have lower education, to have disease stage II–III or to have major LARS.
Although most patients treated for stage I–III CRC fared well, a small but significant proportion of around 13% did not recover during follow-up and reported low HR-QoL and/or high psychological distress levels throughout. This study's findings should be taken into account when organising and selecting patients for tailored follow-up.
•The number of patients with colorectal cancer (CRC) requiring follow-up increased.•Quality of life (QoL) and distress among recently diagnosed patients with CRC are unclear.•Most patients with stage I–III CRC did well and reported high QoL and low distress.•Trajectory analysis revealed vulnerable patient groups and identified predictive factors.•Patient-reported outcome measures should be used when personalising CRC follow-up.
Physical activity (PA) is associated with higher quality of life and probably better prognosis among colorectal cancer (CRC) patients. This study focuses on determinants of PA among CRC patients from ...diagnosis until 5 yr postdiagnosis.
Sociodemographic and disease-related factors of participants of two large CRC cohort studies were combined. Moderate-to-vigorous PA during sport and leisure time (MVPA-SL) was measured at diagnosis (T0) and 6, 12, 24, and 60 months (T6 to T60) postdiagnosis, using the SQUASH questionnaire. Mixed-effects models were performed to identify sociodemographic and disease-related determinants of MVPA-SL, separately for stage I-III colon (CC), stage I-III rectal cancer (RC), and stage IV CRC (T0 and T6 only). Associations were defined as consistently present when significant at ≥4 timepoints for the stage I-III subsets. MVPA-SL levels were compared with an age- and sex-matched sample of the general Dutch population.
In total, 2905 CC, 1459 RC and 436 stage IV CRC patients were included. Patients with higher fatigue scores, and women compared with men had consistently lower MVPA-SL levels over time, regardless of tumor type and stage. At T6, having a stoma was significantly associated with lower MVPA-SL among stage I-III RC patients. Systemic therapy and radiotherapy were not significantly associated with MVPA-SL changes at T6. Compared with the general population, MVPA-SL levels of CRC patients were lower at all timepoints, most notably at T6.
Female sex and higher fatigue scores were consistent determinants of lower MVPA-SL levels among all CRC patients, and MVPA-SL levels were lowest at 6 months postdiagnosis. Our results can inform the design of intervention studies aimed at improving PA, and guide healthcare professionals in optimizing individualized support.
Background and Objectives
Minimally invasive esophagectomy is emerging with comparable short‐term outcomes as open esophagectomies. Neoadjuvant chemoradiotherapy followed by surgery is considered ...standard of care in the Netherlands for patients with esophageal cancer. The aim of this study was to analyze the long‐term oncologic outcome after neoadjuvant chemoradiotherapy followed by totally minimally invasive esophagectomy.
Methods
Neoadjuvant carboplatin and paclitaxel based chemotherapy was concomitantly given with 41.4 Gy radiotherapy. Six weeks after neoadjuvant treatment, totally minimally invasive esophagectomy was performed.
Results
From December 2010 until December 2015 161 patients received this combination of treatment. In 128 male and 33 female patients with median age of 65 years (58‐71), 88 minimally invasive esophagectomies with intrathoracic anastomosis and 73 minimally invasive esophagectomies with cervical anastomosis were carried out. Radical (R0) resection was confirmed in 156 patients (97%). In hospital mortality occurred in 6 patients (3.7%). Overall survival was 79% and 51% at 1 and 5 years, respectively, with a median follow‐up of 24.5 months (13‐38). Disease‐free survival was, respectively, 76% and 55%.
Conclusions
Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy for esophageal cancer is a safe treatment with low postoperative mortality rates and favorable overall and disease‐free survival.
To determine whether multiple doses of bovine surfactant would improve neonatal mortality in very premature neonates, we conducted two multicenter controlled trials under identical protocols; the ...results were combined for analysis. Four hundred and thirty neonates born between 23 and 29 weeks gestation and weighing 600 to 1250 g at birth were assigned randomly at birth to receive either 100 mg of phospholipids/kg of Survanta, a modified bovine surfactant (n = 210), or a sham air placebo (n = 220) within 15 minutes of birth. Neonates who developed respiratory distress syndrome and required mechanical ventilation with at least 30% oxygen could be given up to three more doses in the first 48 hours after birth. Dosing was performed by investigators not involved in the clinical care of the neonates; nursery staff were kept blinded as to the treatment assignment. Cause of death was determined by a panel of three independent, board-certified neonatologists after blindly reviewing case report forms and autopsy reports. Fewer Survanta-treated neonates died of any cause (11.4% vs 18.8%, P = .031), died of respiratory distress syndrome (1.9% vs 15.6%, P less than .001), and either died or developed bronchopulmonary dysplasia due to respiratory distress syndrome (39.5% vs 49.1%, P = .044). The incidence of respiratory distress syndrome was also lower in Survanta-treated neonates (28.0% vs 56.9%, P less than .001), and the Survanta-treated neonates' oxygenation and ventilatory status were improved significantly at 72 hours. Survanta-treated neonates were also at lowered risk of developing pulmonary interstitial emphysema (23.3% vs 36.9%, P = .002) and other forms of pulmonary air leaks (9.6% vs 20.8%, P .002).
PDF
