Sleep and cancer recurrence and survival in patients with resected Stage III colon cancer: findings from CALGB/SWOG 80702 (Alliance).

BACKGROUND: We sought to assess the influences of sleep duration, sleep adequacy, and daytime sleepiness on survival outcomes among Stage III colon cancer patients. METHODS: We conducted a prospective observational study of 1175 Stage III colon cancer patients enrolled in the CALGB/SWOG 80702 randomised adjuvant chemotherapy trial who completed a self-reported questionnaire on dietary and lifestyle habits 14-16 months post-randomisation. The primary endpoint was disease-free survival (DFS), and secondary was overall survival (OS). Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary and lifestyle factors. RESULTS: Patients sleeping ≥9 h-relative to 7 h-experienced a worse hazard ratio (HR) of 1.62 (95% confidence interval (CI), 1.01-2.58) for DFS. In addition, those sleeping the least (≤5 h) or the most (≥ 9 h) experienced worse HRs for OS of 2.14 (95% CI, 1.14-4.03) and 2.34 (95% CI, 1.26-4.33), respectively. Self-reported sleep adequacy and daytime sleepiness showed no significant correlations with outcomes. CONCLUSIONS: Among resected Stage III colon cancer patients who received uniform treatment and follow-up within a nationwide randomised clinical trial, very long and very short sleep durations were significantly associated with increased mortality. Interventions targeting optimising sleep health among indicated colon cancer patients may be an important method by which more comprehensive care can be delivered. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01150045.

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

BACKGROUND: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

BACKGROUND: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results. METHODS: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025. FINDINGS: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded. INTERPRETATION: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration. FUNDING: US National Cancer Institute.

Impact of Maternal Obesity on Perinatal Outcomes in Preterm Prelabor Rupture of Membranes ≥34 Weeks.

OBJECTIVE: This study aimed to compare pregnancy outcomes in obese and nonobese women with preterm prelabor rupture of membranes (PPROM) ≥34 weeks. STUDY DESIGN: The present study is a secondary analysis of a multicenter retrospective cohort of singletons with PPROM from 2011 to 2017. Women with a delivery body mass index (BMI) ≥30 kg/m2 (obese) were compared with women with a BMI < 30 kg/m2 (nonobese). Pregnancies were stratified based on delivery policies of expectant management until 35 weeks versus immediate delivery ≥34 weeks. The primary outcome was a composite neonatal outcome (neonatal sepsis, antibiotic administration for duration >72 hours after delivery or respiratory support). Univariate analysis and general estimating equations models including maternal age, delivery timing, mode of delivery, hospital, and gestational age were used with p < 0.05 level of significance. RESULTS: Among 259 pregnancies, 47% were obese. Pregnant women with obesity had increased composite neonatal outcome versus nonobese pregnancies (adjusted odds ratio [aOR] = 1.48 [95% confidence interval (CI): 1.01-2.17]). Obesity was also associated with increased neonatal antibiotic administration for a duration >72 hours after delivery, respiratory support, ventilation, oxygen supplementation, and surfactant administration. When stratified by delivery policies there was no significant difference in perinatal outcomes based on obesity. CONCLUSION: Obese women with PPROM ≥34 weeks have an increased odds of adverse neonatal respiratory and infectious outcomes compared with nonobese women.

Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.

BACKGROUND: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. METHODS: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active. FINDINGS: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98-1·57). The primary endpoint was met: 23 (43%, 95% CI 29-56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15-37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3-4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). INTERPRETATION: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. FUNDING: Bayer HealthCare Pharmaceuticals.

A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance).

LESSONS LEARNED: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

Development and validation of a model to predict outcomes of colon cancer surveillance.

PURPOSE: Clinical trials suggest that intensive surveillance of colon cancer (CC) survivors to detect recurrence increases curative-intent treatment, although any survival benefit of surveillance as currently practiced appears modest. Realizing the potential of surveillance will require tools for identifying patients likely to benefit and for optimizing testing regimens. We describe and validate a model for predicting outcomes for any schedule of surveillance in CC survivors with specified age and cancer stage. METHODS: A Markov process parameterized based on individual-level clinical trial data generates natural history events for simulated patients. A utilization submodel simulates surveillance and diagnostic testing. We validate the model against outcomes from the follow-up after colorectal surgery (FACS) trial. RESULTS: Prevalidation sensitivity analysis showed no parameter influencing curative-intent treatment by > 5.0% or overall five-year survival (OS5) by > 1.5%. In validation, the proportion of recurring subjects predicted to receive curative-intent treatment fell within FACS 95% CI for carcinoembryonic antigen (CEA)-intensive, computed tomography (CT)-intensive, and combined CEA+CT regimens, but not for a minimum surveillance regimen, where the model overestimated recurrence and curative treatment. The observed OS5 fell within 95% prediction intervals for all regimens. CONCLUSION: The model performed well in predicting curative surgery for three of four FACS arms. It performed well in predicting OS5 for all arms.

A nomogram for predicting survival and retroperitoneal lymph node dissection treatment in patients with resected testicular germ cell tumors.

BACKGROUND AND OBJECTIVES: To build nomogram incorporating potential prognostic factors for predicting survival outcomes of testicular germ cell tumors (TGCT) patients after resection of the primary tumor. METHODS: Data of TGCT patients from the Surveillance, Epidemiology, and End Results database (2010-2016) who underwent resection of the primary tumor were collected. Overall survival (OS) and cancer-specific survival (CSS) were analyzed by using Cox regression models, nomogram, Kaplan-Meier method, and log-rank test. RESULTS: We identified 7272 TGCT patients. Age at diagnosis, histology, tumor size, American Joint Committee on Cancer (AJCC) staging system, and number of metastases sites were independent prognostic factors and were integrated into nomograms. The nomograms had higher C-indexes for both OS and CSS compared with the AJCC 7th staging system (0.881 vs 0.831 and 0.895 vs 0.856, respectively). Moreover, the new stratification of risk groups based on the nomograms showed a more significant distinction between Kaplan-Meier curves for survival outcomes than the AJCC staging system. Retroperitoneal lymph node dissection was associated with statistically improved survival probability in the nomogram middle-risk group in resected TGCT patients. CONCLUSION: The novel nomogram-based staging system could provide satisfactory risk stratification and survival prediction ability beyond traditional AJCC staging systems.

Preterm Prelabor Rupture of Membranes: Outcomes with Expectant Management until 34 versus 35 Weeks.

OBJECTIVE: To evaluate outcomes with expectant management of preterm prelabor rupture of membranes (PROM) until 35 weeks versus immediate delivery at ≥34 weeks. STUDY DESIGN: This was a multicenter retrospective cohort study of singletons with preterm PROM at >20 weeks from 2011 through 2017. Groups were defined as expectant management until 35 weeks versus immediate delivery at ≥34 weeks. Primary outcome was composite neonatal morbidity: need for respiratory support, culture positive neonatal sepsis, or antibiotic administration for >72 hours. Univariate and general estimating equation models were used with p < 0.05 considered significant. RESULTS: A total of 280 mother-infant dyads were included. There was no difference in composite neonatal outcome in pregnancies managed with expectant management compared with immediate delivery (43.4 vs. 37.5%; p = 0.32). Those with expectant management had shorter length of neonatal intensive care unit (NICU) admission but higher rates of neonatal antibiotics for > 72 hours, endometritis, and histological chorioamnionitis. There were no cases of fetal demise, neonatal death, or maternal sepsis, and only three cases of neonatal sepsis. CONCLUSION: There is no difference in composite neonatal morbidity in pregnancies with preterm PROM managed with expectant management until 35 weeks as compared with immediate delivery at 34 weeks. Expectant management is associated with a decreased length of NICU admission but increased short-term infectious morbidity.

North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic-based dosing of irinotecan, oxaliplatin, and capecitabine as first-line therapy for patients with advanced small bowel adenocarcinoma.

BACKGROUND: Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used as first-line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype-based dosing could optimize tolerability. METHODS: Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2-15) in a 21-day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7). RESULTS: A total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41-77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%-56%), with a median progression-free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype. CONCLUSIONS: UGT1A1 genotype-directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3-drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494-501. © 2017 American Cancer Society.

Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.

BACKGROUND: Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy. METHODS: We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if protocols explicitly pre-specified and solicited for patients with peritoneal involvement in the trial data collection process or had done a formal peritoneum-focused review of individual pre-treatment scans. We used stratified multivariable Cox models to assess the prognostic associations of peritoneal metastatic colorectal cancer with overall survival and progression-free survival, adjusting for other key clinical-pathological factors (age, sex, Eastern Cooperative Oncology Group (ECOG) performance score, primary tumour location [colon vs rectum], previous treatment, and baseline BMI). The primary endpoint was difference in overall survival between populations with and without peritoneal metastases. FINDINGS: Individual patient data were available for 10 553 patients. 9178 (87%) of 10 553 patients had non-peritoneal metastatic colorectal cancer (4385 with one site of metastasis, 4793 with two or more sites of metastasis), 194 (2%) patients had isolated peritoneal metastatic colorectal cancer, and 1181 (11%) had peritoneal metastatic colorectal cancer and other organ involvement. These groups were similar in age, ethnic origin, and use of targeted treatment. Patients with peritoneal metastatic colorectal cancer were more likely than those with non-peritoneal metastatic colorectal cancer to be women (565 [41%] of 1371 vs 3312 [36%] of 9169 patients; p=0·0003), have colon primary tumours (1116 [84%] of 1334 patients vs 5603 [66%]; p<0·0001), and have performance status of 2 (136 [10%] vs 521 [6%]; p<0·0001). We recorded a higher proportion of patients with mutated BRAF in patients with peritoneal-only (eight [18%] of 44 patients with available data) and peritoneal metastatic colorectal cancer with other sites of metastasis (34 [12%] of 289), compared with patients with non-peritoneal metastatic colorectal cancer (194 [9%] of 2230; p=0·028 comparing the three groups). Overall survival (adjusted HR 0·75, 95% CI 0·63-0·91; p=0·003) was better in patients with isolated non-peritoneal sites than in those with isolated peritoneal metastatic colorectal cancer. Overall survival of patients with two of more non-peritoneal sites of metastasis (adjusted HR 1·04, 95% CI 0·86-1·25, p=0.69) and those with peritoneal metastatic colorectal cancer plus one other site of metastasis (adjusted HR 1·10, 95% CI 0·89-1·37, p=0·37) was similar to those with isolated peritoneal metastases. Compared with patients with isolated peritoneal metastases, those with peritoneal metastases and two or more additional sites of metastasis had the shortest survival (adjusted HR 1·40; CI 1·14-1·71; p=0·0011). INTERPRETATION: Patients with peritoneal metastatic colorectal cancer have significantly shorter overall survival than those with other isolated sites of metastases. In patients with several sites of metastasis, poor survival is a function of both increased number of metastatic sites and peritoneal involvement. The pattern of metastasis and in particular, peritoneal involvement, results in prognostic heterogeneity of metastatic colorectal cancer. FUNDING: None.

A guide to critical appraisal of quality improvement reports.

Quality improvement (QI) has become an integral part of healthcare. Despite efforts to improve the reporting of QI through frameworks such as the SQUIRE 2.0 guidelines, there is no standard or well-accepted guide to evaluate published QI for rigor, validity, generalizability, and applicability. User's Guides for evaluation of published clinical research have been employed routinely for over 25 years; however, similar tools for critical appraisal of QI are limited and uncommonly used. In this article we propose an approach to guide the critical review of QI reports focused on evaluating the methodology, improvement results, and applicability and feasibility for implementation in other settings. The resulting Quality Improvement Critical Knowledge (QUICK) Tool can be used by those reviewing manuscripts submitted for publication, as well as healthcare providers seeking to understand how to apply published QI to their local context.

Human milk derived fortifiers are associated with glucose, phosphorus, and calcium derangements.

OBJECTIVE: In 2017, our Level IV NICU switched from providing bovine-derived (BOV-fort) to human milk-derived fortifiers (HM-fort) and donor human milk (DHM) to premature infants born ≤ 30 weeks or ≤1250 g. Following this change, providers anecdotally observed increased hypoglycemia, hypercalcemia, and hyperphosphatemia. This study investigated potential laboratory differences between infants fed Bovine vs. Human milk derived fortifier. METHODS: Lab measurements from 402 infants (232 BOV-fort, 170 HM-fort) born between 2015 and 2019 were compared between groups. RESULTS: The proportion of infants ever having a blood glucose ≤ 45 mg/dL (p < 0.0001) was higher in the HM-fort group. The proportion of infants ever experiencing a phosphorus > 8.0 mg/dL were higher in the HM-fort group (p < 0.0001). The proportion of infants ever experiencing calcium > 11.4 mg/dL was higher in the HM-Fort group (p = 0.019). CONCLUSIONS: Provision of HM-Fort and DHM to extremely premature infants is associated with metabolic derangements.

Building a NICU quality & safety infrastructure.

The American Academy of Pediatrics (AAP) Standards for Levels of Neonatal Care, published in 2023, highlights key components of a Neonatal Patient Safety and Quality Improvement Program (NPSQIP). A comprehensive Neonatal Intensive Care Unit (NICU) quality and safety infrastructure (QSI) is based on four foundational domains: quality improvement, quality assurance, safety culture, and clinical guidelines. This paper serves as an operational guide for NICU clinical leaders and quality champions to navigate these domains and develop their local QSI to include the AAP NPSQIP standards.

Reducing Unplanned Intubations in the Neonatal Intensive Care Unit After Children's Surgery: A Quality Improvement Project.

BACKGROUND: Unplanned intubation following children's surgery is associated with increased postoperative mortality. In response to being a National Surgical Quality Improvement Program - Pediatric (NSQIP-P) high outlier for postoperative unplanned intubation, we aimed to reduce postoperative unplanned intubation events by 25% in one year. METHODS/INTERVENTION: A multidisciplinary team of stakeholders was assembled in 2018. Most unplanned intubation events occurred in the neonatal intensive care unit (NICU). Based on apparent causes of unplanned intubations identified in case reviews, an extubation readiness checklist and a postoperative pain management guideline emphasizing non-opioid analgesics were implemented for NICU patients in September 2019. Postoperative unplanned intubation events were tracked prospectively and evaluated using quality improvement statistical process control methods. RESULTS: Unplanned intubations in the NICU decreased from 0.27 to 0.07 events per patient in the post-intervention group (September 2019-June 2022, n = 145) compared to the pre-intervention group (January 2016-August 2019, n = 200), representing a 76% reduction. Postoperative opioid administration decreased significantly, while acetaminophen usage increased significantly over time. Balancing measures of postoperative pneumonia rate (1.5% vs 0.0%, p = 0.267) and median hospital length of stay [40 (IQR 51) days vs 27 (IQR 60), p = 0.124] were not different between cohorts. The 30-day mortality rate for postoperative patients in the NICU significantly declined [6.5% (n = 13) vs 0.7% (n = 1), p < 0.001]. CONCLUSIONS: Postoperative unplanned intubation rates for NICU patients decreased following a quality improvement effort focused on opioid stewardship and extubation readiness. TYPE OF STUDY: Prospective Quality Improvement. LEVEL OF EVIDENCE: Level III.

Water conservation--whole effluent toxicity paradox.

Total dissolved solids (TDS) management in water has become an increasingly important topic as competition for water supply sources and the intensity of use both increase. Regulatory failure of National Pollutant Discharge Elimination System (NPDES) whole effluent toxicity (WET) tests is one of several potential factors in managing TDS concentrations in effluent. Consequently, WET tests have become a de facto concentration standard that sets the limit for the intensity of water use and the amount of water conservation feasibly obtained for a facility. Conflicting regulations dealing with the application of mixing zones and antidegradation policies can prevent water conservation and actually result in the unintended consequence of causing more water use. The impact of TDS on NPDES-required WET tests, conflicting regulations dealing with the application of mixing zones that are counter-productive to water conservation, alternative practices currently being used, and other means of rectifying this paradox are discussed.

Oral cancer chemotherapy adherence and adherence assessment tools: a report from North Central Cancer Group Trial N0747 and a systematic review of the literature.

Oncologists are now prescribing more oral chemotherapy than ever before, thus placing the onus for taking the right dose at the right time under the right circumstances directly on the patient. This study was undertaken to understand emerging adherence issues and to explore available adherence assessment tools. This two-part study (1) examined N0747, a randomized phase II trial that tested the oral agents, sunitinib and capecitabine, in patients with metastatic esophageal cancer from an adherence standpoint, and (2) conducted a systematic review to compile and assess adherence tools that can be used in future clinical trials. First, in N0747, patients were assigned to sunitinib and capecitabine versus capecitabine; 53 chemotherapy cycles were prescribed to this 12-patient cohort. Nearly all patients denoted that they "always or almost always" took their pills as prescribed, and two patients who reported lack of full adherence suffered from grade 3+ adverse events. Surprisingly, however, over 14 cycles, 9 patients reported grade 3+ toxicity but checked "always or almost always" to describe their adherence. No relationships were observed between adherence and cancer outcomes. Secondly, 21 articles identified the following adherence tools: (1) healthcare providers' interviews, (2) patient-reported adherence with diaries/calendars, (3) patient-completed adherence scales, (4) medication event monitoring, (5) automated voice response, (6) drug/metabolite assays, and (7) prescription databases. Of note, only the automated voice response seems capable of real-time detection of over-adherence, as observed in N0747. Oral chemotherapy adherence should be further studied, particularly from the standpoint of over-adherence.

Human milk-derived fortifiers are linked with feed extension due to Hypoglycemia in infants <1250 g or <30 weeks: a matched retrospective chart review.

OBJECTIVE: To investigate differences in hypoglycemia and extended feed prescriptions among premature infants provided bovine-derived human milk fortifiers (Bov-fort) with mother's milk or formula vs human milk-derived human milk fortifiers (HM-fort) with mother's milk or donor human milk. STUDY DESIGN: This was a retrospective chart review (n = 98). Infants receiving HM-fort were matched with infants receiving Bov-fort. Blood glucose values and feed orders were retrieved from the electronic medical record. RESULTS: Prevalence of ever having blood glucose <60 mg/dL was 39.1% in the HM-fort group vs. 23.9% in the Bov-fort group (p = 0.09). Blood glucose ≤45 mg/dL occurred in 17.4% of HM-fort vs 4.3% in Bov-fort (p = 0.07). Feeds were extended for any reason in 55% of HM-fort vs. 20% of Bov-fort (p < 0.01). Feed extension due to hypoglycemia occurred in 24% of HM-fort vs. 0% of Bov-fort (p < 0.01). CONCLUSION: Predominately HM-based feeds are associated with feed extension due to hypoglycemia. Prospective research is warranted to elucidate underlying mechanisms.

Shift-to-shift handoffs in the NICU: lessons learned from a large scale audit.

OBJECTIVE: Describe the frequency of best practice behaviors during NICU provider and nursing shift-to-shift handoffs and identify strengths and opportunities for improvement. STUDY DESIGN: Observational study of handoff characteristics among 40 centers participating in a learning collaborative over a 10-month period. Data were gathered using a handoff audit tool that outlined best practices. Comparisons of behaviors between nurse-to-nurse and provider-to-provider handoffs were made where appropriate. RESULTS: Overall, 946 audits of shift-to-shift handoffs were analyzed. While many behaviors were demonstrated reliably, differences between nurse-to-nurse vs provider-to-provider handoffs were noted. Families were present for 5.9% of handoffs and, among those who were present, 48.2% participated by contributing information, asking questions, and sharing goals. CONCLUSIONS: Observation and measurement of handoff behaviors can be used to identify opportunities to improve handoff communication, family participation, and human factors that support handoff. Auditing handoffs is feasible and necessary to improve these critical transitions in infants' care.

Value Added from Same-day Discharge after Appendectomy for Children with Simple Appendicitis.

Same-day discharge of children after appendectomy for simple appendicitis is safe and associated with enhanced parent satisfaction. Our general pediatric surgeons aimed to improve the rate of same-day discharge after appendectomy for simple appendicitis. Methods: We implemented a clinical practice guideline in September 2019. A surgeon-of-the-week service model and the urgent operating room started in November 2019 and January 2020, respectively. Data for children with simple appendicitis from our academic medical center were gathered prospectively using National Surgical Quality Improvement Program-Pediatric. Patient outcomes before intervention implementation (n = 278) were compared with patients following implementation (n = 264). Results: The average monthly percentage of patients discharged on the day of surgery increased in the postimplementation group (32% versus 75%). Median postoperative length of stay decreased [16.5 hours (interquartile range, 15.9) versus 4.4 hours (interquartile range, 11.7), P < 0.001], and the proportion of patients discharged directly from the postoperative anesthesia care unit increased (22.8% versus 43.6%; P < 0.001). There were no differences in balancing measures, including the return to the emergency department and readmission. Fewer children were discharged home on oral antibiotics after implementation (6.8% versus 1.5%, P = 0.002), and opioid prescribing at discharge remained low (2.5% versus 1.1%, P = 0.385). Conclusions: Using quality improvement methodology and care standardization, we significantly improved the rate of same-day discharge after appendectomy for simple appendicitis without impacting emergency department visits or readmissions. As a result, our health care system saved 140 hospital days over the first 21 months.