NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Patient-initiated follow up affects fear of recurrence and healthcare use: a randomised trial in early-stage endometrial cancer.

OBJECTIVE: To test the hypothesis that patient-initiated follow up reduces the fear of cancer recurrence (FCR) and healthcare use when compared with traditional hospital-based follow up. DESIGN: Pragmatic, multicentre randomised trial. SETTING: Four Danish departments of gynaecology between May 2013 and May 2016. POPULATION: One hundred and fifty-six women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I low-intermediate risk endometrial carcinoma. METHODS: Women allocated to the control group attended hospital-based follow up consisting of regular outpatient visits for 3 years after primary treatment. Women in the intervention group were instructed in patient-initiated follow up, which included careful instruction in alarm symptoms and options for self-referral rather than a schedule of examinations. MAIN OUTCOME MEASURES: The primary end point was FCR as measured by the Fear of Cancer Recurrence Inventory (FCRI) after 10 months of follow up. Secondary end points included cancer-related use of primary and secondary health care during the first 10 months after treatment. RESULTS: In the primary analysis, FCR decreased significantly more in the control group from baseline to 10 months of follow up (difference -5.9, 95% CI -10.9 to -0.9). The majority of this improvement happened after only 3 months of follow up. Women receiving the intervention had fewer examinations at the department compared with the control group (0 versus 2 median visits, P < 0.01) and 58% of these examinations were scheduled because of vaginal bleeding. CONCLUSIONS: Hospital-based follow up alleviates FCR significantly more than patient-initiated follow up, though the estimated difference was small. Patient-initiated follow up is a feasible, potentially cost-reducing follow-up approach in a population of endometrial cancer survivors with low risk of recurrence. The decision to use patient-initiated follow up should balance these benefits and harms. TWEETABLE ABSTRACT: Patient-initiated follow up reduces healthcare use but maintains fear of recurrence in endometrial cancer. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? Follow up of women with endometrial cancer is resource consuming and previous research suggests that it is not effective. Even though the women benefit from reassurance at follow up, routine examinations may also remind the women of the disease and induce fear of cancer recurrence. Furthermore, routine follow up may delay recurrence diagnosis, because the women do not report their symptoms until the next scheduled visit. In the research explained in this article, patient-initiated follow up was evaluated as an alternative to traditional follow up. The women were randomly assigned to one of two follow-up programmes: regular gynaecological examinations at the department of gynaecology or self-referral with careful instruction in alarm symptoms, that is, patient-initiated follow up. The level of fear of cancer recurrence in the two groups was obtained by questionnaires. Information on healthcare use was obtained by questionnaires and a chart review. What were the main findings? Regular examinations at the department of gynaecology reduced the fear of cancer recurrence significantly more than patient-initiated follow up, though the difference was small. Women who were instructed in alarm symptoms, under self-referral, were able to monitor their symptoms, and this approach significantly reduced the number of examinations at the department of gynaecology. What are the limitations of the work? Participants in the self-referral group knew that they were examined less than other women, and this may have induced fear of cancer recurrence. Similarly, the regular completion of questionnaires regarding fear of cancer recurrence may have reminded the women of the disease and diminished the difference between the two groups. What are the implications for patients Patient-initiated follow up reduced healthcare use but maintained fear of cancer recurrence in women who had survived early-stage endometrial cancer. Future analyses on quality of life and cost-effectiveness are needed to balance the benefits and harms of patient-initiated follow up.

Reference intervals for stool calprotectin in preterm neonates and their utility for the diagnosis of necrotizing enterocolitis.

OBJECTIVE: Calprotectin is an antimicrobial protein found in stool when released by granulocytes. We sought to create stool calprotectin reference ranges in preterm neonates and to evaluate whether levels exceeding the upper reference interval are diagnostic for necrotizing enterocolitis (NEC). STUDY DESIGN: Stool calprotectin was measured in premature neonates without gastrointestinal pathology to create reference intervals. For comparison, levels from infants undergoing "rule out NEC" evaluations were plotted on these reference intervals. RESULTS: Stool calprotectin reference intervals were created according to gestational age at birth and corrected gestational age. Levels during "rule out NEC" evaluations were more often above the upper reference interval with NEC vs. those without NEC. CONCLUSIONS: Stools from preterm neonates have a higher range of calprotectin than stools from healthy term neonates. In evaluating preterm neonates for NEC with stool calprotectin, a calprotectin upper reference interval that incorporates corrected gestational age best predicts the diagnosis of NEC.

ABO hemolytic disease of the fetus and newborn: thirteen years of data after implementing a universal bilirubin screening and management program.

OBJECTIVE: ABO hemolytic disease occurs among neonates with blood groups A or B delivered to group O women. Extreme neonatal hyperbilirubinemia due to ABO disease has been reported, but its frequency is not well known. We sought to determine the odds of developing severe ABO hemolytic disease in the 13 years since adopting universal bilirubin screening/management in the Intermountain Healthcare system. STUDY DESIGN: We conducted a retrospective analysis of neonates born between 2004 and 2016, defining "severe hemolytic disease" as; (1) total serum bilirubin (TSB) >25 mg/dL, or (2) hospital readmission for jaundice, or (3) bilirubin encephalopathy. Neonates born to group O (+) mothers were included and considered either; (1) Controls (not at risk for ABO disease because they were group O), (2) Study subjects (at risk for ABO disease because they were group A or B). RESULTS: Of 400,531 live births, 47% were to group O women; 86% of whom were group O (+). Overall, 42,529 (27%) neonates born to group O (+) women had their blood group determined; 29,729 (68%) were O, 10,682 (25%) A, and 3109 (7%) B. Peak TSBs during the first 10 days were higher in group A (11.0 ± 4.2 mg/dL) and B (11.5 ± 4.3) than group O neonates (10.3 ± 4.1). However the relative risks of a TSB ≥25 mg/dL, readmission for jaundice, or kernicterus, were the same in the control vs. study groups. CONCLUSIONS: In our health system, severe hemolytic disease in neonates born to group O (+) woman is not more likely in group A or B neonates than in controls (group O). We recognize that in other practices, particularly those who do not have a universal bilirubin screening/management program, ABO hemolytic disease severity might be different than in our system.

The immature platelet fraction: creating neonatal reference intervals and using these to categorize neonatal thrombocytopenias.

OBJECTIVE: The immature platelet fraction (IPF) is a laboratory measurement analogous to the reticulocyte count, but reflecting the thrombopoietic state. Similar to a reticulocyte count, it can be expressed as a percent (IPF%=percent of platelets that are immature) or as an absolute number per µl blood; the immature platelet count (IPC=IPF% × platelets per µl of blood). STUDY DESIGN: Using a retrospective analysis of de-identified data from non-thrombocytopenic neonates, we created reference intervals for IPF% and IPC. We then tested the value of these measurements for categorizing thrombocytopenic neonates. RESULTS: New charts display reference intervals for IPF% and IPC on the day of birth according to gestational age, and during the first 90 days after birth. Neonates with hyporegenerative varieties of thrombocytopenias (syndromes, small for gestational age, birth asphyxia) had lower IPF% and IPC than did neonates with consumptive thrombocytopenias (immune-mediated, infection, disseminated intravascular coagulation, necrotizing enterocolitis; both P<0.0001). CONCLUSION: The new reference interval charts can be used to recognize abnormal IPFs. The IPF parameters can help clarify the kinetic mechanism responsible for thrombocytopenias in neonates.

The iron status at birth of neonates with risk factors for developing iron deficiency: a pilot study.

OBJECTIVE: Small-for-gestational-age (SGA) neonates, infants of diabetic mothers (IDM) and very-low-birth weight premature neonates (VLBW) are reported to have increased risk for developing iron deficiency and possibly associated neurocognitive delays. STUDY DESIGN: We conducted a pilot study to assess iron status at birth in at-risk neonates by measuring iron parameters in umbilical cord blood from SGA, IDM, VLBW and comparison neonates. RESULTS: Six of the 50 infants studied had biochemical evidence of iron deficiency at birth. Laboratory findings consistent with iron deficiency were found in one SGA, one IDM, three VLBW, and one comparison infant. None of the infants had evidence of iron deficiency anemia. CONCLUSIONS: Evidence of biochemical iron deficiency at birth was found in 17% of screened neonates. Studies are needed to determine whether these infants are at risk for developing iron-limited erythropoiesis, iron deficiency anemia or iron-deficient neurocognitive delay.

Recombinant tissue plasminogen activator to restore catheter patency: efficacy and safety analysis from a multihospital NICU system.

OBJECTIVE: In 2001, the US Food and Drug Administration approved recombinant tissue plasminogen activator (alteplase, Cathflo Activase) to reestablish patency of central catheters occluded, presumably, by a fibrin clot. We conducted a multicenter quality improvement study to determine the value of this procedure in our Neonatal Intensive Care Unit (NICUs), including analyses of efficacy, safety and costs. STUDY DESIGN: We conducted a retrospective quality analysis of neonates in level III NICUs, who received alteplase for the purpose of reestablishing patency of occluded central catheters. RESULTS: Alteplase was administered to 169 neonates, each given one to four doses, totaling 205 episodes of administration. The most common type of catheter where alteplase was used was percutaneously inserted central catheter (PICC) lines (78% of uses), 8% were umbilical venous catheters (UVCs), 6% arterial lines, 5% chest tubes and 3% other catheters. Postnatal age at first dose ranged from 0 to 132 days (median, 12); dosed patients were 22 to 41 weeks gestation at birth (median, 31). Fifty-eight percentage of administrations restored catheter function. Success was more likely at younger postnatal age (10±2 days old in successful vs 14±1 days in unsuccessful treatments; P=0.023). Seventy-two percentage of the re-canalized catheters remained functional until they were no longer needed (2 to 30 days later). Nine percentage of episodes were treated with a second dose 1 to 17 days later for re-occlusion and 50% of those were successful. Bleeding consequences were identified in only one case, where three separate lines were treated (chest tube, PICC and UVC) within a 6-h period. Costs to the health system of doses, minus savings to the system by not needing to replace lines, averaged a net of $34 per dose. CONCLUSIONS: The apparent safety and favorable value analysis prompted us to develop a consistent approach to alteplase usage in the Intermountain Healthcare NICUs, using the data in this report to standardize the guidelines across our health system.

Elevated fecal calprotectin levels during necrotizing enterocolitis are associated with activated neutrophils extruding neutrophil extracellular traps.

OBJECTIVE: Neonates with necrotizing enterocolitis (NEC) have higher calprotectin levels in stool than do healthy neonates. However, it is not known whether high stool calprotectin at the onset of bowel symptoms identifies neonates who truly have NEC vs other bowel disorders. STUDY DESIGN: Neonates were eligible for this study when an x-ray was ordered to 'rule-out NEC'. Stool calprotectin was quantified at that time and in a follow-up stool. Each episode was later categorized as NEC or not NEC. The location of calprotectin in the bowel was determined by immunohistochemistry. RESULTS: Neonates with NEC had higher initial and follow-up stool calprotectin levels than did neonates without NEC. Calprotectin in bowel from neonates with NEC was within neutrophil extracellular traps (NETs). CONCLUSION: At the onset of signs concerning for NEC, fecal calprotectin is likely to be higher in neonates with NEC. Calprotectin in their stools is exported from neutrophils via NETs.

Comparing automated vs manual leukocyte differential counts for quantifying the 'left shift' in the blood of neonates.

OBJECTIVE: The neutrophil 'left shift' can be measured via the immature to total (I/T) neutrophil ratio or the absolute bands per µl using a manual differential count. It can also be measured from an automated differential count by the immature granulocyte percentage (IG%) or the absolute IG per µl. In neonates, it is unknown if the manual or automated differential count is superior. STUDY DESIGN: We directly compared complete blood counts (CBCs) with manual and automated differential counts from infants <90 days old, and documented whether or not each neonate was infected. We developed reference intervals for I/T ratio, bands per µl, IG% and IG per µl using values from non-infected neonates. RESULTS: The database had 10 714 CBCs. The upper reference interval for I/T ratio was 0.29 in the first 48 h and 0.31 thereafter; bands per µl was 3710 µl(-1) in the first 48 h and 1785 µl(-1) thereafter. IG% was 6.2% then 4.2%; IG per µl was 1460 µl(-1) then 613 µl(-1). Statistical performances of the four methods were equivalent for identifying infection. CONCLUSIONS: We developed reference intervals for four methods of quantifying a neonate's 'left shift'. The information from automated differentials is not inferior to that from manual differentials in identifying infections, but automated differentials have the advantages of a larger sample size, being less expensive, and faster performance times.

Medical and non-medical predictors of initiating long-term use of proton pump inhibitors: a nationwide cohort study of first-time users during a 10-year period.

BACKGROUND: Studies of the increasing use of proton pump inhibitors (PPIs) have mainly focused on prevalent long-term use and associations with gastrointestinal morbidity and comedication. Little is known about non-medical characteristics of first-time users of PPI, and predictors of initiating long-term use of PPIs. AIMS: To describe medical and non-medical characteristics of first-time PPI users during a 10-year period and to analyse predictors of initiation of long-term use (>60 defined daily doses (DDDs) within 6 months) of PPIs. METHODS: A nationwide cohort study of first-time users of PPI. Data were collected from Danish national registers. Individuals redeeming their first prescription for a PPI (omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole) in 2001 and 2011 were identified. Redemption of more than 60 DDDs of PPI within 6 months defined long-term use. Logistic regression models were used to determine the associations between previous diagnoses, comedication and socio-economic characteristics and initiation of long-term use of PPIs in 2011. RESULTS: From 2001 to 2011 incidence of first-time users increased with an incidence rate ratio of 1.53 and mean quantity of PPI redeemed at first prescription increased by 44.6%. In 2011 a total of 37.6% redeemed >60 DDDs within 6 months, and 96% of the long-term users did not have a diagnosis registered which indicated treatment. New onset long-term use was significantly associated with low income and low educational level when adjusting for other predisposing variables. CONCLUSIONS: Proton pump inhibitor treatment is increasingly initiated with larger quantities prescribed for indications that are unidentifiable from the registers. Morbidity and comedication seem to be the strongest predictors of new onset long-term use of PPIs. However, there is also an independent social gradient.

General practice variation when initiating long-term prescribing of proton pump inhibitors: a nationwide cohort study.

BACKGROUND: Suggestions of overprescribing of proton pump inhibitors (PPIs) for long-term treatment in primary care have been raised. This study aims to analyse associations between general practice characteristics and initiating long-term treatment with PPIs. METHODS: A nationwide register-based cohort study of patients over 18 years redeeming first-time prescription for PPI issued by a general practitioner in Denmark in 2011. Patients redeeming more than 60 defined daily doses (DDDs) of PPI within six months were defined first-time long-term users. Detailed information on diagnoses, concomitant drug use and sociodemography of the cohort was extracted. Practice characteristics such as age and gender of the general practitioner (GP), number of GPs, number of patients per GP, geographical location and training practice status were linked to each PPI user. Logistic regression analysis was used to determine associations between practice characteristics and initiating long-term prescribing of PPIs. RESULTS: We identified 90 556 first-time users of PPI. A total of 30 963 (34.2 %) met criteria for long-term use at six months follow-up. GPs over 65 years had significantly higher odds of long-term prescribing (OR 1.32, CI 1.16-1.50), when compared to younger GPs (<45 years). Furthermore, female GPs were significantly less likely to prescribe long-term treatment with PPIs (OR 0.87, CI 0.81-0.93) compared to male GPs. CONCLUSIONS: Practice characteristics such as GP age and gender could explain some of the observed variation in prescribing patterns for PPIs. This variation may indicate a potential for enhancing rational prescribing of PPIs.

Reference intervals for reticulocyte parameters of infants during their first 90 days after birth.

OBJECTIVE: The automated reticulocyte parameters (absolute reticulocyte count, immature reticulocyte fraction (IRF) and reticulocyte hemoglobin content (RET-He)) are of value in managing adults and older children with a variety of hematological disorders. However, the lack of reference intervals for these parameters in neonates and young infants has limited their application to that population. STUDY DESIGN: During a span of 12 months (29 May 2014 to 5 May 2015), a convenience sample of reticulocyte parameters were run from clinically ordered complete blood counts (CBCs) of infants within the first 90 days after birth. Measuring the reticulocyte parameters as a research-only adjunct to the CBC did not require any additional blood or generate a patient charge, and the reticulocyte results were not reported to the provided and did not appear in the clinical records. Values from neonates who had a transfusion or a diagnosis of anemia were subsequently excluded from the reference data set. RESULTS: Nine Intermountain Healthcare clinical laboratories contributed 8438 CBCs to the initial reticulocyte parameter database. From these, 1806 were excluded because of a transfusion or a diagnosis of anemia, leaving 6632 in the reference interval database. The parameters charted over the first 90 days after birth were: (1) blood hemoglobin concentration (g dl(-1)), (2) mean corpuscular volume (fL), (3) reticulocyte count (x10(3) per µl), (4) IRF (%) and (5) RET-He (pg). CONCLUSIONS: The new reference interval charts can help clinicians identify abnormalities in the reticulocyte parameters. This information could be of value in identifying and following neonates with various hematological problems including hemolytic disorders, occult hemorrhage, or iron deficiency or other limitations of erythrocyte production.

End-tidal carbon monoxide as an indicator of the hemolytic rate.

In the first days of life, low grade jaundice is essentially universal. The source of the elevated bilirubin level giving rise to "physiological jaundice of the newborn" is only partly known. We hypothesized that it is, at least in part, the result of active and specific hemolysis involving a physiological mechanism to lower the high fetal hematocrit, appropriate for the relatively low oxygen environment in utero, to a lower level appropriate for the state of oxygen abundance after birth. We tested this by quantifying end tidal carbon monoxide (ETCO) as a marker of the rate of heme metabolism to bilirubin. We found that ETCO values of 20 neonates and children with known hemolytic disorders were higher than 20 age-matched healthy controls (p<0.0001), indicating that this instrumentation recognizes hemolysis in neonates and children. We also found that ETCO reference intervals were indeed higher in healthy neonates during the first three days after birth (5th to 95th percentile reference range, 1.4 to 1.7ppm) than after 1month of age (all ≤1.0ppm, p<0.0001). These results suggest to us that hemolysis is physiological during the first days after birth. The cellular and molecular mechanisms responsible for transient hemolysis after birth are topics of current investigation.

Why do four NICUs using identical RBC transfusion guidelines have different gestational age-adjusted RBC transfusion rates?

OBJECTIVE: To compare neonatal red blood cell (RBC) transfusion rates in four large Intermountain Healthcare NICUs, all of which adhere to the same RBC transfusion guidelines. STUDY DESIGN: This retrospective analysis was part of a transfusion-management quality-improvement project. De-identified data included RBC transfusions, clinical and laboratory findings, the anemia-prevention strategies in place in each NICU, and specific costs and outcomes. RESULT: Of 2389 NICU RBC transfusions given during the 4-year period studied, 98.9 ± 2.1% (mean ± S.D.) were compliant with our transfusion guidelines, with no difference in compliance between any of the four NICUs. However, RBC transfusion rates varied widely between the four, with averages ranging from 4.6 transfusions/1000 NICU days to 21.7/1000 NICU days (P < 0.00001). Gestational age-adjusted transfusion rates were correspondingly discordant (P < 0.00001). The lower-transfusing NICUs had written anemia-preventing guidelines, such as umbilical cord milking at very low birth weight delivery, use of cord blood for admission laboratory studies, and darbepoetin dosing for selected neonates. Rates of Bell stage ⩾ 2 necrotizing enterocolitis and grade ⩾ 3 intraventricular hemorrhage were lowest in the two lower-transfusing NICUs (P < 0.0002 and P < 0.0016). Average pharmacy costs for darbepoetin were $84/dose, with an average pharmacy cost of $269 per transfusion averted. With a cost of $900/RBC transfusion, the anemia-preventing strategies resulted in an estimated cost savings to Intermountain Healthcare of about $6970 per 1000 NICU days, or about $282,300 annually. CONCLUSION: Using transfusion guidelines has been shown previously to reduce practice variability, lower transfusion rates and diminish transfusion costs. Based on our present findings, we maintain that even when transfusion guidelines are in place and adhered to rigorously, RBC transfusion rates are reduced further if anemia-preventing strategies are also in place.

Evaluating eosin-5-maleimide binding as a diagnostic test for hereditary spherocytosis in newborn infants.

OBJECTIVE: Neonates with undiagnosed hereditary spherocytosis (HS) are at risk for developing hazardous hyperbilirubinemia and anemia. Making an early diagnosis of HS in a neonate can prompt anticipatory guidance to prevent these adverse outcomes. A recent comparison study showed that a relatively new diagnostic test for HS, eosin-5-maleimide (EMA)-flow cytometry, performs better than other available tests in confirming HS. However, reports have not specifically examined the performance of this test among neonates. STUDY DESIGN: We compared EMA-flow cytometry from blood samples of healthy control neonates vs samples from neonates suspected of having HS on the basis of severe Coombs-negative jaundice and spherocytes on blood film. The diagnosis of HS was later either confirmed or excluded based on clinical findings and next generation sequencing (NGS) after which we correlated the EMA-flow results with the diagnosis. RESULT: EMA-flow was performed on the blood of 31 neonates; 20 healthy term newborns and 11 who were suspected of having HS. Eight of the 11 were later confirmed positive for HS and one was confirmed positive for hereditary elliptocytosis (HE). All nine had persistently abnormal erythroid morphology, reticulocytosis and anemia, and eight of the nine had relevant mutations discovered using NGS. The other was confirmed positive for HS on the basis that a parent had HS, and the neonate's spherocytosis, reticulocytosis and anemia persisted. The 20 healthy controls and the 2 in whom HS was initially suspected but later excluded all had EMA-flow results in the range reported in healthy children and adults. In contrast, all nine in whom HS or HE was confirmed had abnormal EMA-flow results consistent with previous reports in older children and adults with HS. CONCLUSION: Although our sample size is small, our findings are consistent with the literature in older children and adults suggesting that EMA-flow cytometric testing performs well in supporting the diagnosis of HS/HE during the early neonatal period.

Re-resection rates and risk characteristics following breast conserving surgery for breast cancer and carcinoma in situ: A single-centre study of 1575 consecutive cases.

OBJECTIVES: To examine the frequency of re-resections and describe risk characteristics: invasive carcinoma or carcinoma in situ (CIS), palpability of the lesion, and neoadjuvant chemotherapy. RESULTS: 1703 breast conserving surgeries were performed: 1575 primary breast conserving surgeries (BCS), and 128 diagnostic excisions (DE). 176 BCS (11.2% [9.6; 12.7]) and 100 DE had inadequate margins indicating re-resection. The overall re-resection rate was 16.2% [14.5; 18.0]. 10.3% of invasive carcinoma BCS patients, and 28.6% CIS patients underwent re-resection (relative risk (RR) 2.8 [1.9; 4.1]). Invasive lobular carcinoma (ilc) had an RR of re-resection of 2.5 [1.7; 3.8], compared with invasive ductal carcinoma (idc). CONCLUSION: Overall 11.2% of the BCS patients needed a re-resection. For isolated CIS (28.6%), RR of re-resection was almost three times as high compared to invasive carcinoma (10.3%). Ilc had an RR of re-resection of 2.5 compared to idc. Palpability and neoadjuvant chemotherapy did not significantly influence the risk of re-resection.

Redefining high-risk patients with stage II colon cancer by risk index and microRNA-21: results from a population-based cohort.

BACKGROUND: The aim of the present study was to analyse the prognostic value of microRNA-21 (miRNA-21) in patients with stage II colon cancer aiming at a risk index for this group of patients. METHODS: A population-based cohort of 554 patients was included. MicroRNA-21 was analysed by qPCR based on tumour tissue. An index was created using the coefficients obtained from a collective multiple Cox regression. The entire procedure was cross-validated (10-fold). The performance of the index was quantified by time-dependent receiver operating characteristics curves. RESULTS: High miRNA-21 expression was associated with an unfavourable recurrence-free cancer-specific survival (RF-CSS), hazard ratio 1.35 (95% confidence interval, 1.03-1.76) (P=0.028). The generated RF-CSS index divided the traditional high-risk patients into subgroups with 5-year RF-CSS rates of 87% and 73%, respectively (P<0.001). The overall survival (OS) index identified three different subgroups (P<0.001). Cross-validated 5-year OS rates were 88%, 68%, and 50%, respectively. CONCLUSIONS: This population-based study supports miRNA-21 as an additional prognostic biomarker in patients with stage II colon cancer. Furthermore, the introduction of a risk index may guide the use of postoperative adjuvant treatment in a more appropriate way compared with current practice.

Causes of hemolysis in neonates with extreme hyperbilirubinemia.

OBJECTIVE: We instituted a quality improvement process to enhance our capacity to diagnose genetic hemolytic conditions in neonates with extreme hyperbilirubinemia. STUDY DESIGN: During a 1-year period, whenever the total serum bilirubin (TSB) was >25 mg dl(-1) a special evaluation was performed. If we deemed an erythrocyte membrane defect likely, based on red blood cell morphology, EMA-flow cytometry was performed. Otherwise 'next-generation' sequencing was performed using a panel of genes involved in neonatal hyperbilirubinemia. RESULT: Ten neonates had a TSB ⩾ 25 mg dl(-1). Two others were evaluated as part of this process at the request of their attending neonatologists, because each had a TSB >14 mg dl(-1) in the first hours after birth and required phototherapy for ⩾ 1 week. Explanations for the jaundice were found in all 12 neonates. Five had hereditary spherocytosis, three of which also had ABO hemolytic disease. Two had pyruvate kinase deficiency. One had severe G6PD deficiency. The other four had ABO hemolytic disease. CONCLUSION: On the basis of the present small case series, we suggest that among neonates with extreme hyperbilirubinemia, it can be productive to pursue a genetic basis for hemolytic disease.

Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance.

OBJECTIVE: Necrotizing enterocolitis (NEC) is characterized by macrophage infiltration into affected tissues. Because intestinal macrophages are derived from recruitment and in situ differentiation of blood monocytes in the gut mucosa, we hypothesized that increased recruitment of monocytes to the intestine during NEC reduces the blood monocyte concentration and that this fall in blood monocytes can be a useful biomarker for NEC. STUDY DESIGN: We reviewed medical records of very-low-birth-weight (VLBW) infants treated for NEC and compared them with a matched control group comprised of infants with feeding intolerance but no signs of NEC. Clinical characteristics and absolute monocyte counts (AMCs) were recorded. Diagnostic accuracy of AMC values was tested using receiver-operator characteristics (ROC). RESULT: We compared 69 cases and 257 controls (median 27 weeks, range 26 to 29 in both the groups). In stage II NEC, AMCs decreased from median 1.7 × 10(9) l(-1) (interquartile range (IQR) 0.98 to 2.4) to 0.8 (IQR 0.62 to 2.1); P < 0.05. In stage III NEC, monocyte counts decreased from median 2.1 × 10(9) l(-1) (IQR 0.1.5 to 3.2) to 0.8 (IQR 0.6 to 1.9); P < 0.05. There was no change in AMCs in control infants. ROC of AMC values showed a diagnostic accuracy (area under the curve) of 0.76. In a given infant with feeding intolerance, a drop in AMCs of > 20% indicated NEC with sensitivity of 0.70 (95% confidence interval (CI) 0.57 to 0.81) and specificity of 0.71 (95% CI 0.64 to 0.77). CONCLUSION: We have identified a fall in blood monocyte concentration as a novel biomarker for NEC in VLBW infants.

Estimating the nucleated red blood cell 'emergence time' in neonates.

OBJECTIVE: The time between onset of fetal hypoxia and first appearance of nucleated red blood cells (NRBCs) in the blood can conceptually be divided into two periods; (1) the 'erythropoietin (EPO) generation time', which previous fetal studies suggest is 4 to 5 h, and (2) the 'NRBC emergence time'. In this study, we estimated the latter as the time required for NRBC to appear in the blood after administering a dose of recombinant EPO. STUDY DESIGN: This was a retrospective analysis of data from a multihospital healthcare system (Intermountain Healthcare). Data were included only for neonates born ≥34 weeks gestation between the dates 1 January 2005 and 31 October 2012 and only if they received a dose of darbepoetin during their neonatal intensive care unit stay and had one or more complete blood cell counts (CBCs) obtained during the 3-day period before the dose was given and one or more CBCs in the 7-day period after the dose. RESULT: The study involved 31 neonates who received 34 doses of darbepoetin. Seven doses were 4 µg kg(-1) and twenty-seven doses were 10 µg kg(-1). Twenty-six CBCs were obtained during the 24-h period following the darbepoetin dose and none had NRBC identified. NRBC first appeared in the blood between 24 and 36 h after the dose. Recipients of the higher dose generally had a higher peak NRBC count but the NRBC 'emergence time' did not appear to depend on dose. CONCLUSION: Following fetal hypoxia, transcription and translation of the EPO gene result in an elevation in plasma EPO concentration. Previous fetal studies suggest this process requires 4 to 5 h. The present studies suggest that, following the increase in plasma EPO, NRBC emerge into the circulation in ≥24 h. If this model serves as a reasonable estimate, it suggests that neonates with an elevated NRBC count at birth had the onset of hypoxia at least 28 to 29 h before birth.