Error traps in acute pain management in children.

Providing effective acute pain management to hospitalized children can help improve outcomes, decrease length of stay, and increase patient and parental satisfaction. Error traps (circumstances that lead to erroneous actions or undesirable consequences) can result in inadequately controlled pain, unnecessary side effects, and adverse events. This article highlights five error traps encountered when managing acute pain in children. They include failure to appropriately assess pain, optimally utilize regional anesthesia, select suitable systemic analgesics, identify and treat medication-related side effects, and consider patient characteristics when choosing medication or dosing route. These issues are easily addressed when the clinician is cognizant of ways to anticipate, identify, and mitigate or avoid these errors.

Effect of Drug Disposal Kits and Fact Sheets on Elimination of Leftover Prescription Opioids: The DISPOSE Multi-Arm Randomized Controlled Trial.

OBJECTIVE: To determine how passively providing informational handouts and/or drug disposal kits affects rates of leftover prescription opioid disposal. DESIGN: A multi-arm parallel-group randomized controlled trial with masked outcome assessment and computer-guided randomization. SETTING: Johns Hopkins Health System outpatient pharmacies. SUBJECTS: Individuals who filled ≥1 short-term prescription for an immediate-release opioid for themselves or a family member. METHODS: In June 2019, 499 individuals were randomized to receive an informational handout detailing U.S. Food and Drug Administration-recommended ways to properly dispose of leftover opioids (n = 188), the informational handout and a drug disposal kit with instructions on its use (n = 170), or no intervention (n = 141) at prescription pickup. Subjects were subsequently contacted by telephone, and outcomes were assessed by a standardized survey. The primary outcome was the use of a safe opioid disposal method. RESULTS: By 6 weeks after prescription pickup, 227 eligible individuals reported they had stopped taking prescription opioids to treat pain and had leftover medication. No difference in safe disposal was observed between the non-intervention group (10% [6/63]) and the group that received disposal kits (14% [10/73]) (risk ratio = 1.44; 95% confidence interval: 0.55 to 3.74) or the group that received a fact sheet (11% [10/91]) (risk ratio = 1.15; 95% confidence interval: 0.44 to 3.01). CONCLUSIONS: These findings suggest that passive provision of a drug disposal kit at prescription pickup did not increase rates of leftover opioid disposal when compared with provision of a fact sheet alone or no intervention. Active interventions may deserve further investigation.

Pediatric surgeon opioid prescribing behavior: A survey of the American Pediatric Surgery Association membership.

BACKGROUND: The opioid crisis has led to increasing numbers of overdose fatalities in teens and young adults. Surgery, as a common cause of acute pain in children, drives much of the opioid prescribing in pediatrics. Therefore, we sought to characterize opioid prescribing practices of pediatric surgeons by surveying members of the American Pediatric Surgery Association (APSA). STUDY DESIGN: After receiving approval from our institutional review board, we sent an online survey to the entire APSA membership. The survey included four vignettes of common pediatric surgical procedures with questions regarding analgesic prescribing practices, the rationale for these practices, and knowledge about opioid risk mitigation. RESULTS: Of 1127 APSA members contacted, 327 (29%) provided survey responses. For all vignettes, opioid prescribing was within standard ranges for 83% of respondents. Eighty-eight percent of respondents prescribed nonopioid pain medicine. Additionally, 25% reported routinely utilizing a prescription drug monitoring program, 64% did not tell patients how to dispose of opioids, and 37% did not know themselves how to dispose of leftover opioids. CONCLUSIONS: Prescribing by APSA surgeons is largely within standard ranges, but improvement is needed, particularly regarding opioid disposal. Procedure-specific consensus guidelines for opioid prescribing and opioid risk mitigation strategies are warranted. LEVEL OF EVIDENCE: Observational study, level III.

Physicians Prescribe More Opioid Than Needed to Treat Pain in Children After Outpatient Urological Procedures: An Observational Cohort Study.

BACKGROUND: The epidemic of nonmedical use of prescription opioids (NMUPOs) has been fueled in part by the availability of leftover, legitimately prescribed opioids. In children, outpatient urological procedures are among the most common surgeries performed, but data are lacking to guide appropriate postoperative opioid prescribing. The aim of this study was to compare the amount of prescribed opioid medication to the amount taken for acute pain after minor pediatric urological surgery and to determine the disposition of excess opioid. In addition, we explored whether distinct patient characteristics and procedure type influenced opioid prescribing and consumption. METHODS: Of the 139 families of pediatric patients enrolled, 115 were interviewed within 48 hours and/or 10-14 days of discharge to determine the amount of opioid prescribed and consumed, duration of treatment, and disposition of unconsumed opioid. RESULTS: The most common procedures performed were circumcision (n = 58) and orchiopexy (n = 40). Most patients (98%) were male, and 77% were <8 years of age. All opioid prescriptions were for oxycodone dosed every 4 hours as needed (PRN). Median number of doses prescribed was 30 (interquartile range [IQR], 23-31; n = 138) for both respondents who reported doses remaining (IQR, 29-31; n = 83) and those who did not (IQR, 22-32; n = 55). Among those reporting doses remaining, median number of doses consumed was 4.2 (IQR, 0-14). Multivariable linear regression showed no significant association between doses consumed and patient age, type of procedure, discharge pain score, or use of adjuvant analgesics. Median duration of opioid therapy was 2 days (IQR, 0-5; n = 83) with each additional day of opioid use corresponding to an average increase in consumption of 2.3 doses (95% confidence interval [CI], 1.8-2.8). An estimated 75% (95% CI, 69%-81%) of opioid dispensed was not consumed, and 86% (72/83) of patients took ≤18 doses. Forty-four of 65 (68%) families reported receiving no disposal instructions for leftover opioid, and only 7 families disposed of leftover medication. CONCLUSIONS: For minor pediatric urological surgeries in young boys, a 3-day supply (18 doses) of opioid was sufficient to adequately treat acute postoperative pain in most patients. Adjusting opioid dispensing to align with consumption and better educating patients and families on opioid disposal can be used to potentially decrease availability of leftover opioids in homes and communities.

Attitudes and self-reported practices of orthopedic providers regarding prescription opioid use.

OBJECTIVE: Orthopedic surgeons are the third-highest opioid prescribers in the United States. Their prescribing practices can significantly affect the quantity of unconsumed opioids available to fuel the current opioid epidemic. The aim of this study was to identify prescribing patterns and knowledge gaps among orthopedic providers for targeted future interventions and investigation. DESIGN: An online survey describing six common orthopedic surgical scenarios was distributed electronically to determine opioid type and quantity prescribed at discharge, medication disposal instructions, and the use of prescription drug monitoring programs (PDMPs) in the prescription writing process. SETTING: Tertiary care academic hospitals. PARTICIPANTS: Orthopedic physicians and mid-level providers practicing at Johns Hopkins Medical Institutions and University of Maryland Medical System. Of 179 providers contacted, 127 (71 percent) completed the survey. MAIN OUTCOME MEASURES: Quantity of opioid prescribed, utilization of PDMPs, and provision of opioid disposal instructions. RESULTS: While statistically significant associations were identified between quantity of opioid prescribed and surgical procedure, for five of six scenarios 95 percent of respondents recommended prescribing >55 oxycodone 5 mg pill equivalents (PEs) at discharge. An inverse correlation between years of clinical practice and mean number of PEs prescribed was observed. Fewer than 40 percent of respondents modified prescribing when presented with clinically relevant changes in scenario (history of depression or drug abuse). Over 60 percent of respondents do not use PDMPs, and 79 percent do not provide opioid disposal instructions. CONCLUSIONS: Our findings support a need for targeted education to mitigate the role of orthopedic postoperative prescribing practices on the current opioid abuse epidemic.

Opioids in the Management of Acute Pediatric Pain: An Update in a Time of Crisis.

Management of acute pain in children is fundamental to our practice. Its myriad benefits include reduced suffering, improved patient satisfaction, more rapid recovery, and a reduced risk of developing postsurgical chronic pain. Although a multimodal analgesic approach is now routinely used, informed and judicious use of opioid receptor agonists remains crucial in this treatment paradigm, as long as the benefits and risks are fully understood. Further, an ongoing public health response to the current opioid crisis is required to help prevent new cases of opioid addiction, identify opioid-addicted individuals, and ensure access to effective opioid addiction treatment, while at the same time continuing to safely meet the needs of patients experiencing pain.

Opioid Prescribing for the Treatment of Acute Pain in Children on Hospital Discharge.

BACKGROUND: The epidemic of nonmedical use of prescription opioids has been fueled by the availability of legitimately prescribed unconsumed opioids. The aim of this study was to better understand the contribution of prescriptions written for pediatric patients to this problem by quantifying how much opioid is dispensed and consumed to manage pain after hospital discharge, and whether leftover opioid is appropriately disposed of. Our secondary aim was to explore the association of patient factors with opioid dispensing, consumption, and medication remaining on completion of therapy. METHODS: Using a scripted 10-minute interview, parents of 343 pediatric inpatients (98% postoperative) treated at a university children's hospital were questioned within 48 hours and 10 to 14 days after discharge to determine amount of opioid prescribed and consumed, duration of treatment, and disposition of unconsumed opioid. Multivariable linear regression was used to examine predictors of opioid prescribing, consumption, and doses remaining. RESULTS: Median number of opioid doses dispensed was 43 (interquartile range, 30-85 doses), and median duration of therapy was 4 days (interquartile range, 1-8 days). Children who underwent orthopedic or Nuss surgery consumed 25.42 (95% confidence interval, 19.16-31.68) more doses than those who underwent other types of surgery (P < .001), and number of doses consumed was positively associated with higher discharge pain scores (P = .032). Overall, 58% (95% confidence interval, 54%-63%) of doses dispensed were not consumed, and the strongest predictor of number of doses remaining was doses dispensed (P < .001). Nineteen percent of families were informed how to dispose of leftover opioid, but only 4% (8 of 211) did so. CONCLUSIONS: Pediatric providers frequently prescribed more opioid than needed to treat pain. This unconsumed opioid may contribute to the epidemic of nonmedical use of prescription opioids. Our findings underscore the need for further research to develop evidence-based opioid prescribing guidelines for physicians treating acute pain in children.

Long-term tolerability of capnography and respiratory inductance plethysmography for respiratory monitoring in pediatric patients treated with patient-controlled analgesia.

BACKGROUND: The Anesthesia Patient Safety Foundation has advocated the use of continuous electronic monitoring of oxygenation and ventilation to preemptively identify opioid-induced respiratory depression. In adults, capnography is the gold standard in respiratory monitoring. An alternative technique used in sleep laboratories is respiratory inductance plethysmography (RIP). However, it is not known if either monitor is well tolerated by pediatric patients for prolonged periods of time. AIM: The goal of this study was to determine whether capnography or RIP is better tolerated in nonintubated, spontaneously breathing pediatric patients being treated with intravenous patient-controlled analgesia (IVPCA). METHODS: Nasal cannula capnography with oral sampling and thoracic and abdominal inductance plethysmography bands were placed along with the routine monitors on pediatric patients being treated for acute pain with IVPCA. Study monitors were left in place for as long as they were tolerated by the patient, up to a maximum of 24 consecutive hours. If the patient did not wear a particular study monitor for any reason, but tolerated the remaining monitor, participation in the study continued. If the patient would not wear either monitor, participation was terminated. RESULTS: Twenty-six patients (18 female, eight male, average age 10.1 ± 5.5 years) consented to participate, but only 14 patients attempted to wear one or both the devices. Among those who wore either device, median time to device removal was 8.33 h (range 0.3-23.6 h) for capnography and 23.5 h (range 0.7-24 h) for RIP bands. CONCLUSION: Children did not tolerate wearing capnography cannulae for prolonged periods of time, limiting the usefulness of this device as a continuous monitor of ventilation in children. RIP bands were better tolerated; however, they require further assessment of their utility. Until more effective, child-friendly monitors are developed and their utility is validated, guidelines recommended for adult patients cannot be extended to children.

Pain prevalence, intensity, assessment and management in a hospitalized pediatric population.

New research, regulatory guidelines, and practice initiatives have improved pain management in infants, children, and adolescents, but obstacles remain. The aim of this study was to identify the prevalence and demographics of pain, as well as pain management practice patterns in hospitalized children in a tertiary-care university hospital. We prospectively collected data including patient demographics, presence/absence and location of pain, pain intensity, pain assessment documentation, analgesic use, side effects of analgesic therapy, and patient/family satisfaction. Two hundred male (58%) and female, medical and surgical (61%) patients, averaging 9 ± 6.2 years were studied. Pain was common (86%) and often moderate to severe (40%). Surgical patients reported pain more frequently when enrolled than did medical patients (99% vs. 65%). Female gender, age ≥ 5 years, and Caucasian race were all associated with higher mean pain scores. Furthermore, females and Caucasian children consumed more opioids than males and non-Caucasians. Identified obstacles to optimal analgesic management include lack of documented physician pain assessment (<5%), a high prevalence of "as needed" analgesic dosing, frequent opioid-induced side effects (44% nausea and vomiting, 27% pruritus), and patient/family dissatisfaction with pain management (2%-7%). The data demonstrated that despite a concentrated focus on improving pain management over the past decade, pain remains common in hospitalized children. Identification of patient populations and characteristics that predispose to increased pain (e.g., female, Caucasian, postoperative patient) as well as obstacles to analgesic management provide a focus for the development of targeted interventions and research to further improve care.

Opioid therapy in children and adolescents: a physician's guide to risk assessment, monitoring, and mitigation of abuse.

After conducting a thorough literature search of adolescent opioid use from 1990 until present, it became readily apparent that the last decade has witnessed an increase in the number of opioid-related drug overdoses and deaths in the adolescent population, analogous to the epidemic in the adult population. Most of these cases have resulted from prescription medication misuse. Practitioners who use controlled substances to treat pain in pediatric and adolescent patients want to limit harm by carefully assessing their patients' risk of abuse and diversion. In this article, the authors present current knowledge and recommendations for the mitigation of aberrant prescription drug use in the pediatric population.

The relative expression of Mig6 and EGFR is associated with resistance to EGFR kinase inhibitors.

The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).

Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance.

Anti-EGFR therapy is among the most promising molecular targeted therapies against cancer developed in the past decade. However, drug resistance eventually arises in most, if not all, treated patients. Emerging evidence has linked epigenetic changes, such as DNA methylation at CpG islands, to the development of resistance to multiple anticancer drugs. In addition, genes that are differentially methylated have increasingly been appreciated as a source of clinically relevant biomarker candidates. To identify genes that are specifically methylated during the evolution of resistance to anti-EGFR therapeutic agents, we performed a methylation-specific array containing a panel of 56 genes that are commonly known to be regulated through promoter methylation in two parental non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cell lines and their resistant derivatives to either erlotinib or cetuximab. We found that death-associated protein kinase (DAPK) was hypermethylated in drug-resistant derivatives generated from both parental cell lines. Restoration of DAPK into the resistant NSCLC cells by stable transfection re-sensitized the cells to both erlotinib and cetuximab. Conversely, siRNA-mediated knockdown of DAPK induced resistance in the parental sensitive cells. These results demonstrate that DAPK plays important roles in both cetuximab and erlotinib resistance, and that gene silencing through promoter methylation is one of the key mechanisms of developed resistance to anti-EGFR therapeutic agents. In conclusion, DAPK could be a novel target to overcome resistance to anti-EGFR agents to improve the therapeutic benefit, and further evaluation of DAPK methylation as a potential biomarker of drug response is needed.

The optimal dose of prophylactic intravenous naloxone in ameliorating opioid-induced side effects in children receiving intravenous patient-controlled analgesia morphine for moderate to severe pain: a dose finding study.

BACKGROUND: Opioid-induced side effects, such as pruritus, nausea, and vomiting are common and may be more debilitating than pain itself. A continuous low-dose naloxone infusion (0.25 µg/kg/h) ameliorates some of these side effects in many but not all patients without adversely affecting analgesia. We sought to determine the optimal dose of naloxone required to minimize opioid-induced side effects and to measure plasma morphine and naloxone levels in a dose escalation study. METHODS: Fifty-nine pediatric patients (24 male/35 female; average age 14.2 ± 2.2 years) experiencing moderate to severe postoperative pain were started on IV patient-controlled analgesia morphine (basal infusion 20 µg/kg/h, demand dose 20 µg/kg, 5 doses/h) and a low-dose naloxone infusion (initial cohort: 0.05 µg/kg/h; subsequent cohorts: 0.10, 0.15, 0.25, 0.40, 0.65, 1, and 1.65 µg/kg/h). If 2 patients developed intolerable nausea, vomiting, or pruritus, the naloxone infusion was increased for subsequent patients. Dose/treatment success occurred when 10 patients had minimal side effects at a naloxone dose. Blood samples were obtained for measurement of plasma morphine and naloxone levels after initiation of the naloxone infusion, processed, stored, and measured by tandem mass spectrometry with electrospray positive ionization. RESULTS: The minimum naloxone dose at which patients were successfully treated with a <10% side effect/failure rate was 1 µg/kg/h; cohort size varied between 4 and 11 patients. Naloxone was more effective in preventing pruritus than nausea and vomiting. Concomitant use of supplemental medicines to treat opioid-induced side effects was required at all naloxone infusion rates. Plasma naloxone levels were below the level of assay quantification (0.1 ng/mL) for infusion rates ≤0.15 µg/kg/h. At rates >0.25 µg/kg/h, plasma levels increased linearly with increasing infusion rate. In each dose cohort, patients who failed therapy had comparable or higher plasma naloxone levels than those levels measured in patients who did not fail treatment. Plasma morphine levels ranged between 3.52 and 172 ng/mL, and >90% of levels ranged between 10.2 and 61.6 ng/mL. Plasma morphine levels were comparable between patients who failed therapy and those patients who achieved symptom control. CONCLUSIONS: Naloxone infusion rates ≥1 µg/kg/h significantly reduced, but did not eliminate, the incidence of opioid-induced side effects in postoperative pediatric patients receiving IV patient-controlled analgesia morphine. Patients who failed therapy generally had plasma naloxone and morphine levels that were comparable to those who had good symptom relief suggesting that success or failure to ameliorate opioid-induced side effects was unrelated to plasma levels.

Genetic predisposition to natural rubber latex allergy differs between health care workers and high-risk patients.

BACKGROUND: In health care workers, the natural rubber latex (NRL) allergy phenotype has been shown to be associated with promoter polymorphisms in interleukins 13 and 18 (IL13 and IL18) when compared with nonatopic controls. However, it is not known whether high-risk patient populations, such as those born with neural tube defects or genitourinary abnormalities, demonstrate a heightened propensity toward the same genetic/immunologic risk factors that have been reported for health care workers. In this study, we tested the hypothesis that single-nucleotide polymorphisms in genes encoding IL13 and IL18 occur at an increased frequency in NRL allergic patients with spina bifida (SB) or bladder exstrophy (BE). METHODS: One hundred twenty subjects (40 SB, 40 BE, and 40 control) were screened using a clinical history questionnaire and NRL-specific immunoglobulin E (IgE) antibody measurements in the blood. Genomic DNA was extracted from peripheral blood lymphocytes and analyzed for single-nucleotide polymorphisms in candidate genes of interest. Univariate and multivariate analyses were performed to identify significant variables with significance defined as P < 0.05. RESULTS: Sensitization (IgE antibody positivity) to NRL allergens was associated with atopic history and number of prior operations and was prevented by the avoidance of NRL beginning at birth. However, unlike health care workers, the NRL allergy phenotype was not significantly associated with promoter polymorphisms in IL13 or IL18 when comparing NRL allergic SB and BE patients with nonsensitized patients and with atopic and nonatopic controls. CONCLUSIONS: In patients born with SB or BE, environmental factors seem to play a greater role in the development of NRL sensitization and overt allergic symptoms than the IL polymorphisms in IL13 and IL18 previously shown to be associated with NRL allergy in health care workers.

Identification of hypermethylated genes associated with cisplatin resistance in human cancers.

Cisplatin is among the most widely used cytotoxic anticancer agents in solid tumors; however, the development of secondary resistance remains a major obstacle to clinical efficacy. Treatment-related DNA hypermethylation may play a role in creating drug-resistant phenotypes by inactivating genes that are required for cytotoxicity. We applied a pharmacologic unmasking approach to detect hypermethylated genes whose inactivation contributes to cisplatin resistance. Using three pairs of isogeneic, cisplatin-sensitive, and cisplatin-resistant cell lines derived from two parental cell lines (KB-3-1 and SCC25), we identified several hundred genes that were downregulated in each resistant cell line and reactivated by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. Among them, 30 genes were common to two or more cell lines and/or reported to be downregulated in previous studies. Bisulfite sequencing confirmed that 14 genes were hypermethylated in resistant cell lines but not in the sensitive parental cell lines. Six of 14 genes (SAT, C8orf4, LAMB3, TUBB, G0S2, and MCAM) were cisplatin inducible in sensitive but not in resistant cell lines. Small interfering RNA knockdown of two genes, SAT and S100P, increased cell viability with cisplatin treatment in sensitive parental cell lines. S100P knockdown significantly decreased the S-phase fraction of parental sensitive cell lines and slowed cell proliferation, which was associated with decreased sensitivity to cisplatin. Based on these findings, we conclude that DNA methylation is a frequent event in cells that are chronically exposed to cisplatin and that methylation-induced gene silencing may play a role in the development of resistance to cytotoxic chemotherapeutic agents.

A national survey of American Pediatric Anesthesiologists: patient-controlled analgesia and other intravenous opioid therapies in pediatric acute pain management.

BACKGROUND: The influence of patient characteristics, institutional demographics, and published practice guidelines on the provision of IV opioid analgesia, particularly as delivered through a patient-controlled analgesia (PCA) delivery device, to pediatric patients is unknown. METHODS: We sent a national, web-based, descriptive survey of pediatric pain management practice to select members of the Society for Pediatric Anesthesia to assess institutional demographics, availability and implementation of IVPCA and PCA by proxy, and recalled occurrence of serious and life-threatening opioid-related side effects. RESULTS: Data from respondents at 252 institutions throughout the United States were collected and analyzed. Sixty-nine percent of respondents practiced in a children's hospital or children's center within a general hospital, and 51% of institutions had a pediatric pain service. Virtually all pediatric pain services (91%) were administered by departments of anesthesiology. Pediatric pain service availability correlated with the number of pediatric beds. IVPCA was available to pediatric patients at 96% of institutions surveyed, whereas IVPCA by proxy was available at only 38%. Eleven percent of respondents reported that their hospital no longer provided IVPCA by proxy as a result of the 2004 Joint Commission on Accreditation of Hospitals Sentinel Event Warning. Instructional material concerning IVPCA was provided to patients or their families by 40% of institutions. IVPCA orders were handwritten by 55% of respondents, despite 39% having computerized provider order entry systems. Ninety percent of respondents reported using pulse oximetry monitoring when patients were administered IVPCA. Forty-two respondents recalled patients having received naloxone to counteract the cardiopulmonary side effects of opioids during the year before receipt of the survey. Eight respondents recalled patient deaths having occurred over the past 5 years in patients receiving IVPCA, IVPCA by proxy, and continuous non-IVPCA opioid infusions. CONCLUSIONS: Although IVPCA was available to pediatric patients at most institutions surveyed, prescribing practices and supervision of pediatric pain management were influenced by patient characteristics, institutional demographics, and published national guidelines. Recalled life-threatening events were reported in conjunction with all modes of opioid infusion therapy. Interventions that might diminish the incidence of adverse events but are not used to their fullest extent include improved education and implementation of systems designed to minimize human error involved in the prescribing of opioids. Providing a more accurate accounting of complications would require institutions to participate in a prospective data-collecting consortium designed to track both the incidence of therapy and associated complications.

Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells.

The molecular mechanism of lactoferrin-induced cell growth inhibition is incompletely understood. Studying head and neck cancer cells treated with human lactoferrin, we observed growth arrest in three of four cell lines tested. This growth arrest was caused by cell cycle inhibition at the G0-G1 checkpoint. Lactoferrin-induced growth inhibition was associated with a large increase in p27 protein, accompanied by decreased phosphorylation of retinoblastoma protein, and suppression of cyclin E. Decreased levels of phosphorylated Akt were also observed in lactoferrin-sensitive cell lines after treatment. These findings suggest that in head and neck cancer cells the growth inhibitory effects of lactoferrin are mediated through a p27/cyclin E-dependent pathway that may be modulated in part by changes in Akt phosphorylation.

Characterization of a human homologue of proteolysis-inducing factor and its role in cancer cachexia.

Cachexia is an important cause of secondary morbidity and mortality in patients with cancer. Previous studies have suggested that cancer-associated cachexia may be due in part to tumor-specific production and secretion of a glycosylated peptide, proteolysis-inducing factor, originally identified in a murine cancer cachexia model. We report here the cloning of a human cDNA that generates a peptide having high-sequence homology to this proteolysis-inducing factor. Constitutive expression of human proteolysis-inducing factor is low or absent in most normal human tissues but appears to be elevated in some human tumors. Stable forced expression of human proteolysis-inducing factor in multiple murine and human cell lines results in a secreted protein, but no glycosylation of the protein is detected. In addition, tumor xenografts engineered to overexpress human proteolysis-inducing factor protein do not induce cachexia in vivo. These findings raise important questions as to potential cross-species differences in protein sequence and processing of murine proteolysis-inducing factor and human proteolysis-inducing factor, as well as the nature of the relationship between human proteolysis-inducing factor and the development of cancer cachexia.

A neural survival factor is a candidate oncogene in breast cancer.

Using serial analysis of gene expression (SAGE), we identified a SAGE tag that was present only in invasive breast carcinomas and their lymph node metastases. The transcript corresponding to this SAGE tag, dermcidin (DCD), encodes a secreted protein normally expressed only in the pons of the brain and sweat glands. Array comparative genomic hybridization, fluorescence in situ hybridization, and immunohistochemical analyses determined that DCD is overexpressed in approximately 10% of invasive breast carcinomas; in some cases its overexpression is coupled with a focal copy number gain of its locus at 12q13.1, and its expression is associated with advanced clinical stage and poor prognosis. Expression of DCD in breast cancer cells promotes cell growth and survival and reduces serum dependency. Putative high- and low-affinity receptors for DCD are present on the cell surface of breast carcinomas and neurons of the brain. Based on these data we hypothesize that DCD may play a role in tumorigenesis by means of enhancing cell growth and survival in a subset of breast carcinomas.

Genetic contribution to the septic response in a mouse model.

The response to injury is dependent on several factors, including the type and extent of the injury, genetics, and the environment. In the present study, the genetic contribution to sepsis was evaluated in a mouse model. Sepsis was induced in two inbred mouse strains, C57BL/6J (B6) and A/J, by cecal ligation and single puncture (CLP). Frequency of mortality was significantly higher in B6 than A/J mice from 36 to 132 h after CLP. Plasma TNF-alpha, IL-1beta, and IL-6 levels were similar in both strains after CLP. IL-10 plasma levels were significantly higher in B6 mice as opposed to A/J mice after 24 h of CLP. Similarly, hepatic myeloperoxidase activity, an index of polymorphonuclear leukocytes, was elevated in B6 mice as compared with A/J mice after 24 h of CLP. On the contrary, metallothionein mRNA levels were higher in A/J mice compared with B6 mice. Finally, leptin levels were also higher in A/J than B6 mice within 19 h of CLP. This study demonstrates a genetic contribution in the response to sepsis.