First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study.

OBJECTIVE: Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients. METHODS: This analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200 mg Q3W for 35 cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30 days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response. RESULTS: 84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71-11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33-18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25-9.75) points in the overall population and 9.11 (5.24-12.98) points in patients with CR/PR. CONCLUSIONS: Pembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting.

Phase I trial of alpelisib in combination with concurrent cisplatin-based chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Deregulation of the PI3K signalling pathway is frequent in squamous cell carcinoma of the head and neck (SCCHN) and may be implicated in radioresistance. We report on the results from a phase I 3 + 3 dose escalation study of alpelisib, a class I α-specific PI3K inhibitor in combination with concurrent cisplatin-based chemoradiation (CRT) in patients with locoregionally advanced SCCHN (LA-SCCHN). METHODS: Eligible patients had previously untreated LA-SCCHN and were candidates for CRT. The primary objective was to evaluate safety and determine the recommended phase II dose (RP2D). Alpelisib was given orally once daily at two dose levels: 200 mg and 250 mg. CRT consisted of cisplatin 100 mg/m2 IV every three weeks and standard fractionation radiotherapy (IMRT) 70 Gy in 35 fractions. RESULTS: Nine patients were enrolled (six alpelisib 200 mg, three 250 mg). Oropharynx was the primary site in all patients (seven p16-positive; five T1-2N2M0, four T3-4N2-3M0 [AJCC 7th edition]). All patients completed CRT within seven weeks. Grade 3 alpelisib-related toxicities occurred in four patients. No dose-limiting toxicity (DLT) was observed at 200 mg among three DLT-evaluable patients. Two of two DLT-evaluable patients treated at 250 mg experienced DLTs (inability to complete ≥75% alpelisib secondary to radiation dermatitis and febrile neutropenia). Thus, RP2D was declared at 200 mg. After median follow-up of 39.7 months, two patients developed pulmonary metastases despite locoregional control. Three-year overall survival was 77.8% (95% CI 36.5%-93.9%). CONCLUSION: Alpelisib at 200 mg has a manageable safety profile in combination with cisplatin-based CRT in LA-SCCHN.

Real-world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions: Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials.

BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806.

Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review.

BACKGROUND: The majority of published studies in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are single-arm trials. Reliable modelling of progression-free survival (PFS) and overall survival (OS) outcomes, therefore, is difficult. This study aim to analyse existent literature to estimate the relative efficacy of available systemic regimens in RM-NPC, as well as provide estimates of aggregate OS and PFS. METHODS: We conducted a systematic search of MEDLINE, EMBASE and the Cochrane Library to March 2015. Clinical trials (in English only) investigating cytotoxic and molecularly targeted agents in adult patients with RM-NPC were included. All relevant studies were assessed for quality using Downs and Blacks (DB) checklist (maximum quality score of 27). Aggregate data analysis and Student's t-test were performed for all identified studies (model A). For studies that published analysable Kaplan-Meier curves, survival data were extracted and marginal proportional hazards models were constructed (model B). RESULTS: A total of 56 studies were identified and included in model A, 26 of which had analysable Kaplan-Meier curves and were included in model B. The 26 studies in model B had significantly higher mean DB scores than the remaining 30 (17.3 vs 13.7, P=0.002). For patients receiving first line chemotherapy, the estimated median OS was 15.7 months by model A (95% CI, 12.3-19.1), and 19.3 months by model B (95% CI, 17.6-21.1). For patients undergoing second line or higher therapies (2nd+), the estimated median OS was 11.5 months by model A (95% CI 10.1-12.9), and 12.5 months by model B (95% CI 11.9-13.4). PFS estimates for patients undergoing first-line chemotherapy by model A was 7.6 months (95% CI, 6.2-9.0), and 8.0 months by model B (95% CI, 7.6-8.8). For patients undergoing therapy in the 2nd+ setting, the estimated PFS by model A was 5.4 months (95% CI, 3.8-7.0), and 5.2 months by model B (95% CI, 4.7-5.6). CONCLUSIONS: We present the first aggregate estimates of OS and PFS for RM-NPC patients receiving first and second-line or higher treatment settings, which could inform the design of future clinical trials in this disease setting.

Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review.

BACKGROUND: Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class. METHODS: Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ2 tests and multivariable regression models were used to analyse for effect size and associations. RESULTS: We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (OR 6.5, 95% CI 3.0-14.3) and rash (OR 2.0, 95% CI 1.8-2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8) and vitiligo (OR 3.5, 95% CI 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis. DISCUSSION: CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.

An increasing trend in health-care professionals notifying children of unhealthy weight status: NHANES 1999-2014.

BACKGROUND: Pediatric obesity prevalence remains at historically high levels. The objective of this study was to examine secular trends in the percentages of overweight/obese children who received notification from a health-care professional (HCP) about their unhealthy weight. METHODS: We analyzed data of 25 570 (including 8639 overweight/obese) children aged 2-18 years collected from seven cross-sectional biennial surveys (National Health and Nutrition Examination Survey, 1999-2014), in which adolescents (16 years and older) and caregivers, mostly biological mothers, of children (2-15 years) were asked 'Has a doctor or other health professional ever told you that you (or your child) were overweight?' RESULTS: Approximately 90% of overweight/obese children visited HCPs at least once in the past 12 months, but only 22.12% (s.e.=1.92) in 1999 to 34.43% (2.35) in 2014 of the overweight/obese children were notified by HCPs about unhealthy weight. The biennial increase in odds of receipt of notification of unhealthy weight was 1.08 (95% confidence interval=(1.04-1.12)). Greater likelihood for receipt of notification was associated with being obese (odds ratio=5.03 (4.29-5.89) vs overweight); black (1.24 (1.06-1.46)) or Hispanic race/ethnicity (1.72 (1.45-2.04) vs white); female sex (1.22 (1.07-1.11) vs boys); and child's insurance status (1.31 (1.08-1.59) vs uninsured). There were increasing odds of being notified with increasing age: 1.00 (reference), 2.24 (2.06-2.62), 3.22 (2.50-4.13) and 4.87 (3.76-6.32) for children 2-5, 6-11, 12-16 and 16+ year old, respectively. The frequency of medical contact was linearly associated with an increased likelihood of being notified. CONCLUSIONS: Notification of child's unhealthy weight by HCPs increased significantly between 1999 and 2014, but the opportunity of clinical intervention remained substantially under-utilized.

A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors.

BACKGROUND: There are limited data about the quality of immune-related adverse event (irAE) reporting in immune checkpoint inhibitor (ICI) clinical trial publications. METHODS: A systematic search of citations from Medline, EMBASE and Cochrane databases identified prospective clinical trials involving ICIs in advanced solid tumors from 2003 to 2013. A 21-point quality score (QS) was adapted from the CONSORT harms extension statement. Linear regression was used to identify factors associated with quality reporting. RESULTS: After a review of 2628 articles, 50 trial reports were included, with ICIs as either monotherapy (54%) or part of a combination regimen (46%). The mean QS was 11.21 points (range 3.50-17.50 points). The median grade 3/4 AE rate reported was 21% (range 0%-66%) and 29/50 (58%) trials concluded that irAEs were tolerable. Multivariate regression analysis revealed that year of publication (within last 5 years, P = 0.01) and journal impact factor >15 (P = 0.004) were associated with higher QS. Complete reporting of specific characteristics of irAEs including onset, management and reversibility were reported by 14%, 8% and 6% of studies, respectively. The incidence of grade 3/4 adverse events was higher for inhibitors against CTLA-4 compared with other immune checkpoints (P < 0.001). CONCLUSIONS: The reporting of irAEs is suboptimal. A standardized reporting method of irAEs that accounts for tolerability, management and reversibility is needed and would enable a more precise evaluation of the therapeutic risk benefit ratio of ICIs.

An interdisciplinary, family-focused approach to relational learning in neonatal intensive care.

OBJECTIVE: The aim of this study is to show the efficacy of the Program to Enhance Relational and Communication Skills-Neonatal Intensive Care Unit (PERCS-NICU). STUDY DESIGN: In this study, 74 practitioners attended workshops and completed baseline, post-training and follow-up questionnaires. RESULT: On yes/no questions, 93 to 100% reported improved preparation, communication skills and confidence post-training and follow-up. A total of 94 and 83% improved their ability to establish relationships, and 76 and 83% reported reduced anxiety post-training and follow-up, respectively. On Likert items, 59 and 64% improved preparation, 45 and 60% improved communication skills and confidence, 25 and 53% decreased anxiety and 16 and 32% improved relationships post-training and follow-up, respectively. Qualitative themes included integrating new communication and relational abilities, honoring the family perspective, appreciating interdisciplinary collaboration, personal/human connection and valuing the learning. In total, 93% applied skills learned, three-quarters transformed practice and 100% recommended PERCS-NICU. CONCLUSION: After PERCS-NICU, clinicians improved preparation, communication and relational abilities, confidence and reduced anxiety when holding difficult neonatal conversations.

A comparative study of the immunogold labeling on H(2)O(2)-treated and heated epoxy sections.

The purpose of this study was to compare the intensity of the immunogold labeling of H(2)O(2)-treated and heated epoxy sections. Renal swine tissue with glomerular immune complex deposits with reactivity against IgG was embedded in epoxy resin. Immunogold labeling with anti-IgG was performed on sections from these blocks. Some of these sections were treated by H(2)O(2), others were heated in a citrate solution, while some were not treated at all. Some epoxy sections, which had been exposed to both H(2)O(2) and heat, were also exposed to the same immunolabeling. The heated epoxy sections obtained an yield of specific immunogold labeling, which was twice as large as the labeling of the H(2)O(2)-treated sections. The yield of immunolabeling of the sections that had been exposed to both H(2)O(2) and heat was not significantly different from the sections that were only exposed to heat. The non-treated sections were very weakly labeled with anti-IgG. We believe that both H(2)O(2) and heat have the ability to break some chemical bonds between the epoxy resin and the antigens, but heating in citrate buffer has a larger potential in this respect than H(2)O(2). We interpret the results from the combined treatment with H(2)O(2) and heat in the following way; the bonds that are broken by H(2)O(2) will also be broken by heating in citrate solution. The practical significance of these results is that heating in citrate buffer is a more convenient method for enhancing the immunolabeling of epoxy sections than treatment with H(2)O(2).

Plasminogen activator inhibitor-1: defining characteristics in the cerebrospinal fluid of newborns.

We measured plasminogen activator inhibitor-1 levels in the cerebrospinal fluid and plasma of newborns with and without posthemorrhagic hydrocephalus. We found that plasminogen activator inhibitor-1 levels in the cerebrospinal fluid of healthy newborns are <10 mg/mL but are greatly elevated in patients who have posthemorrhagic hydrocephalus and correlate directly with cerebrospinal fluid D-dimer and protein levels.

Very low birthweight Infant's placenta and its relation to pregnancy and fetal characteristics.

Our objective was to relate pathology of the very low birthweight (VLBW) infant's placenta to pregnancy and fetal characteristics. We correlated the pathologic features of 1146 placentas from infants with birth weights of 500-1500 g who were born between 1/1/91 and 12/31/93 to the number of gestations per pregnancy, initiator of preterm delivery, gestational age, birth weight Z score, and duration of rupture of membrane (ROM). Placental correlates of acute inflammation and villous edema were associated with preterm labor (PTL), prelabor premature rupture of membranes (PROM), lower gestational age, and higher birth weight Z score. In PTL pregnancies delivered within 1 h of membrane rupture, 61% of placentas already had membrane inflammation. Placental correlates of pregnancy-induced hypertension (PIH) were seen more commonly with PIH pregnancies, older gestational age, and lower birth weight Z score. We found a more prominent histopathologic signature for singleton than for multiple gestation placentas. The placental pathologic findings associated with the clinical diagnoses of infection, PIH, and low-birth weight Z scores in our VLBW/preterm population are similar to those in the literature regarding term pregnancies. The presence of multiple histologic findings consistent with inflammation in placentas of PTL pregnancies with duration of ROM lasting <1 h suggests that some cases of PTL are precipitated by a more long-standing infection than that previously suspected. Morphologic placental features appear to be correlates of the phenomena leading to premature delivery. Examination of the VLBW infant's placenta provides insight into the etiology and management of VLBW/preterm deliveries.

Very low birthweight placenta: clustering of morphologic characteristics.

Our objective was to use factor analysis as a data reduction tool to organize a large number of placental pathologic features into useful aggregates. We examined 1146 placentas of live-born infants with a birth weight of 500-1500 g. We then conducted analyses of pairs of characteristics and multiple characteristics to identify "associated groups" and "factors," respectively. We found an associated group and factor that had placental features associated with acute inflammation and another associated group and factor that had features associated with vasculopathy. Acute umbilical vasculitis had the strongest correlation with other features of the acute inflammation associated group and factor. Gross evidence of acute inflammation (opacification and green appearance of membrane) was eliminated in the reduction from associated group to factor. Infarcts and syncytial knots were strongly dissociated with features of acute inflammation. The multiple pathologic features of the very low birthweight placenta can be aggregated into two associated groups or two factors. Lack of membrane opacification cannot be used as a criterion for declining microscopic examination. The absence of infarcts and syncytial knots should prompt a search for features of acute inflammation. If a placenta has two or more findings from the acute inflammation factor or the vasculopathy factor, it is unlikely to demonstrate features from the other factor.

Sonographically detected subarachnoid hemorrhage: an independent predictor of neonatal posthemorrhagic hydrocephalus?

Blood from an intraventricular hemorrhage (IVH) can collect in the basilar cisterns and cause ventriculomegaly and eventual need for ventriculoperitoneal (VP) shunt. We looked for sonographic evidence of subarachnoid hemorrhage (SAH) in three basal cisterns and in the Sylvian fissure of 82 infants with IVH, 30 of whom had ventriculomegaly. We found that ultrasonographically diagnosed SAH and measurement of ventricular blood volume predict ventriculomegaly and need for VP shunt.

CNS fibrinolysis: a review of the literature with a pediatric emphasis.

In vitro studies of cerebrospinal fluid indicate that normal cerebrospinal fluid contains very low levels of fibrinolytic enzymes but that fibrinolytic activity is higher in pathologic compared with normal conditions and in older compared with younger patients. Because of the low endogenous fibrinolytic activity of the central nervous system, intraventricular fibrinolytic therapy has been studied in adult and pediatric patients for the treatment of intraventricular hemorrhage/posthemorrhagic hydrocephalus and subarachnoid hemorrhage with secondary cerebral vasospasm. A review of the literature about endogenous and exogenous fibrinolysis studies of animals, adult humans, and pediatric humans reveals a record of predominant safety and efficacy. Although its use in the adult population for the treatment of subarachnoid hemorrhage with secondary vasospasm has become an accepted therapy in some centers, its use in the pediatric population is less common. It is no longer considered in the treatment of meningitis, but its role in the treatment of intraventricular hemorrhage/posthemorrhagic hydrocephalus is still being investigated.

Medical management of neonatal posthemorrhagic hydrocephalus.

Posthemorrhagic hydrocephalus is a relatively common complication of premature birth. One third of patients who do not undergo spontaneous resolution require medical management aimed at normalizing intracranial pressure by correcting the imbalance between cerebrospinal fluid (CSF) production and drainage. Serial lumbar punctures intermittently remove CSF in bulk. Pharmacologic therapy decreases CSF production. Each of these therapies have attendant benefits and risks. For patients whose CSF absorption does not improve with growth and recovery, placement of an indwelling ventricular drain is ultimately required.