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Background: Our objective was to determine the correlation between preclinical toxicity found in animal models (mouse, rat, dog and monkey) and clinical toxicity reported in patients participating in Phase 1 oncology clinical trials., Methods: We obtained from two major early-Phase clinical trial centres, preclinical toxicities from investigational brochures and clinical toxicities from published Phase 1 trials for 108 drugs, including small molecules, biologics and conjugates. Toxicities were categorised according to Common Terminology Criteria for Adverse Events version 4.0. Human toxicities were also categorised based on their reported clinical grade (severity). Positive predictive values (PPV) and negative predictive values (NPV) were calculated to determine the probability that clinical studies would/would not show a particular toxicity category given that it was seen in preclinical toxicology analysis. Statistical analyses also included kappa statistics, and Matthews (MCC) and Spearman correlation coefficients., Results: Overall, animal toxicity did not show strong correlation with human toxicity, with a median PPV of 0.65 and NPV of 0.50. Similar results were obtained based on kappa statistics and MCC., Conclusions: There is an urgent need to assess more novel approaches to the type and conduct of preclinical toxicity studies in an effort to provide better predictive value for human investigation.

The field of cancer genomics is rapidly evolving and has led to the development of new therapies. Knowledge of commonly involved cellular pathways and genetic mutations is now essential for radiologists reading oncology cases. Radiogenomics is an emerging area of research that seeks to correlate imaging features with cancer genotypes. Such knowledge may extend the utility of multiparametric imaging to yield information regarding cancer prognosis and likelihood of therapeutic response. To date, only a handful of radiogenomics studies have been performed to evaluate solid tumors of the body, and there is much to explore. Before doing so, however, it behooves us to have adequate background knowledge of clinical cancer genomics to design meaningful radiogenomics projects and explore imaging phenotypes. Herein, an up-to-date, detailed overview is provided of well-known and common mutations of solid body tumors (such as human epithelial growth factor receptor 2, breast cancer susceptibility protein), newer genomic alterations with potential for clinical relevance, and a discussion of known related imaging findings, including existing radiogenomics data and other radiologic patterns of disease. © RSNA, 2017 Online supplemental material is available for this article.

Background: Methylnaltrexone (MNTX), a peripherally acting μ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data suggest that MOR activation can play a role in cancer progression and can be a target for anticancer therapy., Patients and Methods: Pooled data from advanced end-stage cancer patients with OIC, despite laxatives, treated in two randomized (phase III and IV), placebo-controlled trials with MNTX were analyzed for overall survival (OS) in an unplanned post hoc analysis. MNTX or placebo was given subcutaneously during the double-blinded phase, which was followed by the open-label phase, allowing MNTX treatment irrespective of initial randomization., Results: In two randomized, controlled trials, 229 cancer patients were randomized to MNTX (117, 51%) or placebo (112, 49%). Distribution of patients' characteristics and major tumor types did not significantly differ between arms. Treatment with MNTX compared with placebo [76 days, 95% confidence interval (CI) 43-109 versus 56 days, 95% CI 43-69; P = 0.033] and response (laxation) to treatment compared with no response (118 days, 95% CI 59-177 versus 55 days, 95% CI 40-70; P < 0.001) had a longer median OS, despite 56 (50%) of 112 patients ultimately crossing over from placebo to MNTX. Multivariable analysis demonstrated that response to therapy [hazard ratio (HR) 0.47, 95% CI 0.29-0.76; P = 0.002) and albumin ≥3.5 (HR 0.46, 95% CI 0.30-0.69; P < 0.001) were independent prognostic factors for increased OS. Of interest, there was no difference in OS between MNTX and placebo in 134 patients with advanced illness other than cancer treated in these randomized studies (P = 0.88)., Conclusion: This unplanned post hoc analysis of two randomized trials demonstrates that treatment with MNTX and, even more so, response to MNTX are associated with increased OS, which supports the preclinical hypothesis that MOR can play a role in cancer progression. Targeting MOR with MNTX warrants further investigation in cancer therapy., Clinical Trials Number: NCT00401362, NCT00672477., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Long wait times are a primary source of dissatisfaction among patients enrolled in early-phase clinical trials. We hypothesized that an automated patient check-in system with readily available display for increasing awareness of waiting intervals would improve patient flow and use of our rooms, with decreased turnover time and increased throughput., Methods: We recorded in-room wait times for patients seen in our clinic and observed the logistics involved in the blood collection process to delineate causes for delays. We then implemented a three-step strategy to alleviate the causes of these delays: (1) changing the collection of materials and the review of faxed orders, (2) improving our LabTracker automated database system that included wait time calculators and real-time information regarding patient status, and (3) streamlining lower complexity appointments., Results: After our intervention, we observed a 19% decrease in mean wait times and a 30% decrease in wait times among patients waiting the longest (95th percentile). We also observed an increase in staff productivity during this process. Modifications in LabTracker provided the biggest reduction in mean wait times (17%)., Conclusion: We observed a significant decrease in mean wait times after implementing our intervention. This decrease led to increased staff productivity and cost savings. Once wait times became a measurable metric, we were able to identify causes for delays and improve our operations, which can be performed in any patient care facility., (Copyright © 2016 by American Society of Clinical Oncology.)

There is limited data on co-expression of FGFR/FGR amplifications and PI3K/ AKT/mTOR alterations in breast cancer. Tumors from patients with metastatic breast cancer referred to our Phase I Program were analyzed by next generation sequencing (NGS). Genomic libraries were selected for all exons of 236 (or 182) cancer-related genes sequenced to average depth of >500× in a CLIA laboratory (Foundation Medicine, Cambridge, MA, USA) and analyzed for all classes of genomic alterations. We report genomic profiles of 112 patients with metastatic breast cancer, median age 55 years (range, 27-78). Twenty-four patients (21%) had at least one amplified FGFR or FGF. Fifteen of the 24 patients (63%) also had an alteration in the PI3K/ AKT/mTOR pathway. There was no association between alterations in FGFR/FGF and PI3K/AKT/mTOR (P=0.49). Patients with simultaneous amplification in FGFR/FGF signaling and the PI3K/AKT/mTOR pathway had a higher rate of SD≥6 months/PR/ CR when treated with therapies targeting the PI3K/AKT/mTOR pathway than patients with only alterations in the PI3K/AKT/mTOR pathway (73% vs. 34%; P=0.0376) and remained on treatment longer (6.8 vs. 3.7 months; P=0.053). Higher response rates were seen in patients with simultaneous amplification in FGFR/FGF signaling and alterations in the PI3K/AKT/mTOR pathway who were treated with inhibitors of that pathway.

Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. The mutated IDH1 and IDH2 proteins have a gain-of-function, neomorphic activity, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis via the abnormal production of the oncometabolite 2-HG. High levels of 2-HG have been shown to inhibit α-KG dependent dioxygenases, including histone and deoxyribonucleic acid (DNA) demethylases, which play a key role in regulating the epigenetic state of cells. Current targeted inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221), and pan-IDH1/2 (AG881) selectively inhibit mutant IDH protein and induce cell differentiation in in vitro and in vivo models. Preliminary results from phase I clinical trials with IDH inhibitors in patients with advanced hematologic malignancies have demonstrated an objective response rate ranging from 31% to 40% with durable responses (>1 year) observed. Furthermore, the IDH inhibitors have demonstrated early signals of activity in solid tumors with IDH mutations, including cholangiocarcinomas and low grade gliomas.

Balamuthia mandrillaris, a free-living ameba, causes rare but frequently fatal granulomatous amebic encephalitis (GAE). Few patients have survived after receiving experimental drug combinations, with or without brain lesion excisions. Some GAE survivors have been treated with a multi-drug regimen including miltefosine, an investigational anti-leishmanial agent with in vitro amebacidal activity. Miltefosine dosing for GAE has been based on leishmaniasis dosing because no data exist in humans concerning its pharmacologic distribution in the central nervous system. We describe results of limited cerebrospinal fluid (CSF) and serum drug level testing performed during clinical management of a child with fatal GAE who was treated with a multiple drug regimen including miltefosine. Brain biopsy specimens, CSF, and sera were tested for B. mandrillaris using multiple techniques, including culture, real-time polymerase chain reaction, immunohistochemical techniques, and serology. CSF and serum miltefosine levels were determined using a liquid chromatography method coupled to tandem mass spectrometry. The CSF miltefosine concentration on hospital admission day 12 was 0.4 μg/mL. The serum miltefosine concentration on day 37, about 80 h post-miltefosine treatment, was 15.3 μg/mL. These are the first results confirming some blood-brain barrier penetration by miltefosine in a human, although with low-level CSF accumulation. Further evaluation of brain parenchyma penetration is required to determine optimal miltefosine dosing for Balamuthia GAE, balanced with the drug's toxicity profile. Additionally, the Balamuthia isolate was evaluated by real-time polymerase chain reaction (PCR), demonstrating genetic variability in 18S ribosomal RNA (18S rRNA) sequences and possibly signaling the first identification of multiple Balamuthia strains with varying pathogenicities.

Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid-induced constipation, can be used to target the mu opioid receptor., (© 2015 American Cancer Society.)

Background: The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes., Case Presentations: We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response., Conclusions: Patients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted.

Background: Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated., Patients and Methods: We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates., Results: Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Twelve of 50 evaluable patients (24%) (median = 3 prior therapies) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR) (n = 5 (10%) with PR/CR): 9 of 32 (28%) with breast cancer (n=5 (16%) with PR/CR); 2 of 10 (20%), ovarian cancer; and 1 of 6 (17%), endometrial cancer. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway: mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All three responders (CR (n = 1); PR (n=2)) who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC., Conclusions: Combination anastrozole and everolimus is well tolerated at full approved doses, and is active in heavily-pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Responses were observed in patients with multiple molecular aberrations. CLINICAL TRAILS INCLUDED: NCT01197170.

Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.

Purpose: Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers., Methods: Bevacizumab was administered at escalating dosages of 2.5-11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3-10 mg/kg on days 1-28 every 28 days to determine the maximum tolerated dose. Pharmacodynamic parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels)., Results: Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease (SD) ≥6 months was reported in 4/57 (7 %) of patients, including two patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with SD ≥6 months showed histone acetylation, while 8 of 36 (22 %) without SD ≥6 months demonstrated histone acetylation (p = 0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 vs. 5.8 months; p = 0.012)., Conclusions: The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction, and prostate cancer. Patients with hypertension had improved overall survival.

Purpose: We have observed severe, but rapidly reversible, hyperbilirubinemia in patients receiving hepatic arterial infusion (HAI) of oxaliplatin. We performed a retrospective analysis to characterize this unusual phenomenon., Methods: We reviewed the electronic medical records of 113 consecutive patients receiving HAI oxaliplatin to describe the associated hyperbilirubinemia., Results: Four of 113 patients (3.5 %) presented with transient, severe (grade 3/4) hyperbilirubinemia post-HAI oxaliplatin. Peak levels of total bilirubin within 10-16 h of starting HAI oxaliplatin were 4.6, 12.2, 12.8, and 21.2 mg/dL and declined rapidly (within 24 after stopping treatment). One out of four patients experienced severe abdominal pain, and another patient had an infusion reaction (hypertension and hypoxemia) that reversed after discontinuation of infusion. Total bilirubin was predominantly direct. No significant decline in hemoglobin or increase in alkaline phosphatase occurred. Increase in liver transaminases post-infusion was mild to moderate (grades 1-3) and was seen after HAI oxaliplatin regardless of the emerged hyperbilirubinemia., Conclusions: Severe hyperbilirubinemia is a rare but rapidly reversible adverse effect of HAI oxaliplatin and may be accompanied by an abdominal pain syndrome or infusion reaction. Treating physicians should be aware for the potential of this reaction. The mechanism of this unusual reaction merits further investigation.

Objectives: In August 2005, the Centers for Disease Control and Prevention was notified of a Ralstonia species outbreak among pediatric patients receiving supplemental oxygen therapy with the Vapotherm 2000i (Vapotherm, Inc, Stevensville, MD). The Vapotherm 2000i is a reusable medical device that was used in >900 hospitals in the United States in 2005. Ralstonia are waterborne bacilli that have been implicated in hospital-acquired infections. We initiated an investigation to determine the source of the outbreak and implement infection control and prevention measures., Patients and Methods: We performed a case-control study at 1 hospital and conducted national case findings to obtain clinical and environmental samples for laboratory analysis. Case-patients had health care-acquired Ralstonia colonization or infection. Isolates were compared by using pulsed-field gel electrophoresis. We tested manufacturer-recommended disinfection protocols for the Vapotherm 2000i under simulated-use conditions., Results: Case-patients at the hospital (n = 5) were more likely to have received Vapotherm therapy than controls. Nationally, Ralstonia mannitolilytica was confirmed in 38 patients (aged 5 days to 7 years); 35 (92%) of the patients were exposed to the Vapotherm 2000i before recovery of the organism. Pulsed-field gel electrophoresis showed related R. mannitolilytica strains from isolates sent from 18 hospitals in 12 states. A Vapotherm machine reprocessed with a protocol proposed by the manufacturer grew Ralstonia spp after 7 days of simulated use. In December 2005, Vapotherm recalled the 2000i., Conclusions: Our findings suggest intrinsic contamination of Vapotherm devices with Ralstonia spp. New medical devices may provide therapy equivalent to current devices yet pose novel reprocessing challenges.

Objective: To determine the ability of neonatal clinical, audiologic, and computed tomography (CT) findings to predict long-term neurodevelopmental outcome in children with symptomatic congenital cytomegalovirus (CMV) infection., Methods: Longitudinal cohort study of children (n = 41) with symptomatic congenital CMV infection evaluated at birth and followed up with serial age-appropriate neurodevelopmental testing. The performance of birth characteristics as predictors of long-term outcome were determined, and clinical and CT scoring systems were developed and correlated with intellectual outcome., Results: Microcephaly was the most specific predictor of mental retardation (100%; 95% CI 84.5-100) and major motor disability (92.3%; 95% CI 74.8-99). An abnormality detected by CT was the most sensitive predictor for mental retardation (100%; 95% CI 82.3-100) and motor disability (100%; 95% CI 78.2-100). A highly significant (P <.001) positive correlation was found between head size at birth and the intelligence/developmental quotient (IQ/DQ). Approximately 29% of children had an IQ/DQ >90. There was no association between sensorineural hearing loss at birth and cognitive outcome. However, children with sensorineural hearing loss on follow-up (congenital and late-onset) had a lower IQ/DQ (P =.006) than those with normal hearing., Conclusions: The presence of microcephaly at birth was the most specific predictor of poor cognitive outcome in children with symptomatic congenital CMV infection, whereas children with normal findings on head CT and head circumference proportional to weight exhibited a good cognitive outcome.

Objective: To determine the impact of respiratory syncytial virus (RSV) prophylaxis among preterm infants of < or =32 weeks gestation by comparing the severity of illness and cost of RSV-related care during the two winter seasons before (1994 to 1995, 1995 to 1996) with the two seasons after initiation of prophylaxis (1996 to 1997, 1997 to 1998)., Methods: Preterm infants of < or =32 weeks gestation at risk for hospitalization with RSV infection were identified retrospectively from the infants hospitalized in our neonatal units. Infants were included if they (1) were born 6 months before or during four winter seasons (1994 to 1998), (2) were discharged from the neonatal unit and (3) had remained in the university outpatient clinic system during at least the first winter of life. Preterm infants of < or =32 weeks gestation hospitalized with RSV were identified from our RSV database (which includes cost of hospitalization, duration of hospital stay, pediatric intensive care unit stay and intubation). Infants receiving prophylaxis were identified prospectively., Results: The incidence of hospitalization with RSV was significantly lower among the cohort of infants born after initiation of prophylaxis: 8.7% (17 of 195) vs. 22% (35 of 159), P = 0.00049 by two tailed Fisher's exact test. Among the cohort of infants born after initiation of prophylaxis (n = 195), 100 infants received prophylaxis. The gestational and chronologic ages of the prophylaxis-treated infants were significantly lower than those of the non-prophylaxis-treated infants (n = 95). The prophylaxis-treated infants also were more likely to have bronchopulmonary dysplasia. Only 1 (1%) of the prophylaxis-treated infants required hospitalization for RSV. Comparison of the cohort of infants born before initiation of prophylaxis to the cohort born after initiation of prophylaxis (includes prophylaxis-treated and non-prophylaxis-treated infants) revealed a significant reduction in severity of illness and cost. The length of stay in the cohort born before initiation of prophylaxis was reduced 83.8%: 373.6 days per 100 infants at risk vs. 60.5 (P = 0.00055). The length of stay in the pediatric intensive care unit was reduced 92.7%: 218.2 days per 100 infants at risk vs. 15.9 (P = 0.00029). The duration of intubation was reduced 95.6%: 187.4 days per 100 infants at risk vs. 8.2 (P = 0.00024). The dollars spent for RSV-related care (hospitalizations and prophylaxis) per 100 infants at risk for RSV was reduced 65% in the cohort of infants born after prophylaxis: $670,590 per 100 infants at risk vs. $234,596 (P = 0.00056). This reduction remained significant (64.9%) if the cost of ribavirin (drug and administration fees) was excluded from the cost of hospitalization., Conclusions: These data reveal that RSV prophylaxis significantly reduced the incidence of RSV hospitalizations and severity of illness as well as the cost of RSV-related care among these infants.

A preterm breast-fed infant had three episodes of type Ia/c group B streptococcus septicemia. After the second episode rifampin was given to the infant, but further Ia/c exposure to maternal breast milk ensued. We propose rifampin treatment for both the mother and infant in cases of recurrent group B streptococcus disease.

We retrospectively reviewed the medical records of all infants and children (< 18 years of age) with the discharge diagnosis of malaria who were admitted to the four major pediatric teaching hospitals in Houston, Texas from January 1988 through December 1993. Thirty-four cases of pediatric malaria were identified in three newborns, 22 travelers, and nine recent immigrants. The travel destination was West Africa in 68%, Central America in 14%, India in 14%, and unknown in 4%. The location of the child's and parents' birthplace was available in 77% of the travel-related cases and in all cases the destination of travel was the parents' country of origin. The peak incident of the travel-related cases was late summer and early January corresponding to return from summer or Christmas vacation. Sixteen (75%) of the 22 travel-related cases had received either no prophylaxis (12 of 22) or inadequate (4 of 22) chemoprophylaxis. Half of the patients who were given appropriate chemoprophylaxis admitted to poor compliance. The clinical presentation was usually nonspecific. Fever was the most common symptom (97%) and was paroxysmal in one-third. Splenomegaly was the most common physical finding (68%). The malaria species identified included Plasmodium falciparum (56%), P. vivax (23%), P. malariae (3%), and unidentified (18%). Moderate anemia (hemoglobin level = 7.0-10 g/dL) occurred in 38% and severe anemia (hemoglobin level < 7.0 g/dL) in 29%. Three patients required transfusion. There were no end-organ complications. In summary, pediatric malaria in Houston was primarily seen in immigrants or children of immigrants who returned to their native country. Education and preventive strategies should target these families and should be part of the routine well child care of these children.

Objectives: To determine the rate of in utero transmission of cytomegalovirus (CMV) in perinatally HIV-exposed infants and to determine whether coinfection with CMV in early life affects outcome., Methods: Infants born to HIV-infected women between March, 1988, and March, 1995, were evaluated (n = 206). Congenital or in utero CMV infection was defined as a positive CMV culture or shell vial assay on urine obtained in the first 3 weeks of life. HIV-infected infants either had positive serology beyond 18 months of age or, for an infant younger than 18 months, had a positive HIV PCR or HIV culture on at least two separate occasions., Results: There were 30 HIV-infected and 171 uninfected infants (144 who seroreverted and 27 infants with at least 2 negative HIV PCR or culture results and normal immunologic studies during the first 6 months of age). Urine culture for CMV was obtained during the first 3 weeks of life on 154 infants: 24 of 30 (80%) HIV-infected infants; and 130 of 171 (76%) HIV-uninfected infants. Overall 10 of 154 (6.5%) infants were infected with CMV: 5 of 24 (21%) HIV-infected and 5 of 130 (3.8%) HIV-uninfected infants. The rate of in utero CMV infection was significantly higher in HIV-infected infants (P = 0.008). Dually infected infants were more immunosuppressed than their CMV-negative counterparts. At 3 months of age the percentage of CD4+ T lymphocytes (P = 0.0021) and CD4:CD8 ratios (P = 0.0018) were significantly lower in the CMV-infected infants than in the CMV-uninfected infants. At 6 months of age the absolute CD4+ T lymphocyte counts (P = 0.0038), percentage of CD4+ T lymphocytes (P = 0.044) and CD4:CD8 ratios (P = 0.037) were significantly lower in the CMV-infected infants. The mean survival of HIV-infected infants who were coinfected with CMV in early life (5 in utero and 1 perinatally infected infant identified at 7 weeks) was 24.77 months. Kaplan-Meier survival analysis indicated a trend toward decreased survival in the infants who were coinfected with CMV in early life (P = 0.088)., Conclusions: Congenital CMV infection is more common in HIV-infected infants than in HIV-uninfected infants. Infection with CMV in early life is associated with greater immunosuppression and may be associated with a more rapid progression of HIV infection in infants.

Objective: In 1991, we noted the emergence amongst our extremely low birth weight neonates of a new clinical entity, invasive fungal dermatitis, characterized by erosive, crusting lesions and a high rate of subsequent systemic fungal infection. We sought to define this condition and examine potential risk factors., Methods: Sixteen neonates with invasive fungal dermatitis were seen during a 2-year period in three Baylor College of Medicine affiliated intensive care nurseries. Seven were confirmed cases, with skin biopsy evidence of invasion beyond the stratum corneum. Nine had a consistent clinical course and a positive potassium hydroxide examination of skin scrapings or isolation of fungi from skin or systemic cultures. Three controls were matched to each case by hospital, date of admission, and birth weight. Data was collected by retrospective chart review., Results: Invasive fungal dermatitis occurred in 5.9% of at-risk infants. Case patients had a mean birth weight of 635 g and developed skin lesions at a mean age of 9 days (range, 6 to 14). Candida albicans was the most commonly implicated pathogen, but other Candida species, Aspergillus, Trichosporon beigelii, and Curvularia were also seen. Disseminated infection occurred in 69%, all due to Candida sp. Case patients were significantly more premature than controls (mean gestation, 24.4 vs 25.9 weeks) and were more likely to be delivered vaginally (81% vs 50%). Postnatal steroids were administered to cases (81%) more often than controls (46%). Case patients had more prolonged hyperglycemia (as assessed by insulin administration) than controls (mean 4.3 vs 2.0 days)., Conclusions: Invasive fungal dermatitis is a disease of the smallest, most immature neonates and is associated with vaginal birth, steroid administration, and hyperglycemia. We speculate that the skin serves as a portal of entry for colonizing fungal species and may thus lead to disseminated infection. Methods to improve skin barrier function may be useful in preventing this disorder.