Does the false-negative rate for 1 or 2 negative sentinel nodes after neo-adjuvant chemotherapy translate into a high local recurrence rate?

Prospective trials demonstrate that sentinel node (SN) biopsy after neo-adjuvant chemotherapy (NACT) has a significant false-negative rate (FNR) when only 1 or 2 SNs are removed. It is unknown whether this increased FNR correlates with an elevated risk of recurrence. Tumor Registry data at an NCI-Designated Comprehensive Cancer Center were reviewed from 2004 to 2018 for patients having a negative SN biopsy after NACT. Among 190 patients with histologically negative nodes after NACT having 1 (n = 42), 2 (n = 46), and ≥3 (n = 102) SNs, axillary recurrences occurred in 7.14%, 0%, and 1.96% (p = 0.09), breast recurrences occurred in 2.38%, 6.52%, and 0.98% (p = 0.12), and distance recurrences occurred in 16.67%, 8.70%, and 7.84% (p = 0.27), respectively. Time to first recurrence did not differ by SN count (p = 0.41). After adjustment for age, race, clinical stage, and receptor status, there were no differences in the rates of axillary (p = 0.26), breast (p = 0.44), or distance recurrence (p = 0.24) by numbers of SNs harvested. Median follow-up was 46.8 months. Despite higher post-NACT FNRs reported in randomized trials for patients having <3 sentinel nodes, recurrence rates were not significantly different for 1 versus 2 versus ≥3 SNs. This suggests that patients having 1 or 2 post-NACT SNs identified may not necessitate axillary dissection.

Preoperative Delays in the Treatment of DCIS and the Associated Incidence of Invasive Breast Cancer.

BACKGROUND: Although treatment delays have been associated with survival impairment for invasive breast cancer, this has not been thoroughly investigated for ductal carcinoma in situ (DCIS). With trials underway to assess whether DCIS can remain unresected, this study was performed to determine whether longer times to surgery are associated with survival impairment or increased invasion. METHODS: A population-based study of prospectively collected national data derived from women with a clinical diagnosis of DCIS between 2004 and 2014 was conducted using the National Cancer Database. Overall survival (OS) and presence of invasion were assessed as functions of time by evaluating five intervals (≤ 30, 31-60, 61-90, 91-120, 121-365 days) between diagnosis and surgery. Subset analyses assessed those having pathologic DCIS versus invasive cancer on final pathology. RESULTS: Among 140,615 clinical DCIS patients, 123,947 had pathologic diagnosis of DCIS and 16,668 had invasive ductal carcinoma. For all patients, 5-year OS was 95.8% and unadjusted median delay from diagnosis to surgery was 38 days. With each delay interval increase, added relative risk of death was 7.4% (HR 1.07; 95% CI 1.05-1.10; P < 0.001). On final pathology, 5-year OS for noninvasive patients was 96.0% (95% CI 95.9-96.1%) versus 94.9% (95% CI 94.6-95.3%) for invasive patients. Increasing delay to surgery was an independent predictor of invasion (OR 1.13; 95% CI 1.11-1.15; P < 0.001). CONCLUSIONS: Despite excellent OS for invasive and noninvasive cohorts, invasion was seen more frequently as delay increased. This suggests that DCIS trials evaluating nonoperative management, which represents infinite delay, require long term follow up to ensure outcomes are not compromised.

Time to Surgery and the Impact of Delay in the Non-Neoadjuvant Setting on Triple-Negative Breast Cancers and Other Phenotypes.

BACKGROUND: Characterization of breast cancer phenotypes has improved our ability to predict breast cancer behavior. Triple-negative (TN) breast cancers have higher and earlier rates of distant events. It has been suggested that this behavior necessitates treating TNs faster than others, including use of neoadjuvant chemotherapy (NACT) if time to surgery is not rapid. METHODS: A review of women diagnosed with non-inflammatory, invasive breast cancer was conducted using the National Cancer Database for patients not having NACT, diagnosed between 2010 and 2014. Changes in overall survival due to delay were measured by phenotype. RESULTS: Overall, 351,087 patients met the inclusion criteria, including 36,505 (10.4%) TNs, 77.9% hormone receptor-positive (HR+) and 11.7% human epidermal growth factor receptor 2 (HER2)-enriched (HER2+). Phenotype, among other factors, was predictive of treatment delays. Adjusted median days from diagnosis to surgery and chemotherapy were 29.9, 31.6 and 31.5 (p< 0.001), and 72.7, 78.0 and 74.4 (p< 0.001) for TNs, HR+ and HER2+ cancers, respectively. After diagnosis, OS declined for all patients per month of preoperative delay (hazard ratio 1.104; p< 0.001). In models separating or combining surgery and chemotherapy, this survival decline did not vary by breast cancer phenotype (p > 0.3). CONCLUSIONS: Delays cause small but measurable effects overall, but the effect on survival does not differ among breast cancer phenotypes. Our data suggest that urgency between diagnosis and surgery or chemotherapy is similar for breast cancers of different subtypes. Although NACT is sometimes advocated solely to avoid treatment delays, this study does not suggest a greater surgical urgency for TNs compared with other breast cancer phenotypes.

Breast conservation versus mastectomy in patients with T3 breast cancers (> 5 cm): an analysis of 37,268 patients from the National Cancer Database.

PURPOSE: Breast conservation therapy (BCT) is standard for T1-T2 tumors, but early trials excluded breast cancers > 5 cm. This study was performed to assess patterns and outcomes of BCT for T3 tumors. METHODS: We reviewed the National Cancer Database (NCDB) for noninflammatory breast cancers > 5 cm, between 2004 and 2011 who underwent BCT or mastectomy (Mtx) with nodal evaluation. Patients with skin or chest wall involvement were excluded. Patients having clinical T3 tumors were analyzed to determine outcomes based upon presentation, with those having pathologic T3 tumors, subsequently assessed, irrespective of presentation. Overall survival (OS) was analyzed using multivariable Cox proportional hazards models, with adjusted survival curves estimated using inverse probability weighting. RESULTS: After exclusions, 37,268 patients remained. Median age and tumor size for BCT versus Mtx were 53 versus 54 years (p < 0.001) and 6.0 versus 6.7 cm (p < 0.001), respectively. Predictors of BCT included age, race, location, facility type, year of diagnosis, tumor size, grade, histology, nodes examined and positive, and administration of chemotherapy and radiotherapy. OS was similar between Mtx and BCT (p = 0.36). This held true when neoadjuvant chemotherapy patients were excluded (p = 0.39). BCT percentages declined over time (p < 0.001), while tumor sizes remained the same (p = 0.77). Median follow-up was 51.4 months. CONCLUSIONS: OS for patients with T3 breast cancers is similar whether patients received Mtx or BCT, confirming that tumor size should not be an absolute BCT exclusion. Declining use of BCT for tumors > 5 cm in younger patients may be accounted for by recent trends toward mastectomy.

Breast conservation versus mastectomy for patients with T3 primary tumors (>5 cm): A review of 5685 medicare patients.

BACKGROUND: Although breast conservation therapy (BCT) is standard for breast cancer treatment, patients with tumors measuring >5 cm have been excluded from clinical trials. Nevertheless, only a few small retrospective series to date have compared BCT with mastectomy for tumors measuring >5 cm. The current study was performed to determine whether survival is equivalent for BCT versus mastectomy using a large national data set. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked cases were identified for patients aged ≥ 66 years undergoing breast conservation for invasive, noninflammatory, nonmetastatic breast cancer between 1992 and 2009. Propensity score-based adjustment was used to account for demographics and tumor and treatment factors. RESULTS: A total of 5685 patients with tumors measuring >5.0 cm underwent breast surgery, with 15.6% receiving BCT. Mean ages of the patients and tumor sizes were similar. Predictors of BCT included neoadjuvant chemotherapy and postoperative radiotherapy use, higher income, breast cancer as a first malignancy, and a higher Charlson Comorbidity Index. Predictors of mastectomy included younger age, nonductal histology, higher grade, numbers of lymph nodes examined and found to be positive, American Joint Committee on Cancer stage III disease, postoperative chemotherapy use, and residential region of the country. Adjusted overall and breast cancer-specific survival were not different between patients treated with BCT and mastectomy (hazard ratio, 0.934; 95% confidence interval, 0.791-1.103 [P = .419] for overall survival; and subdistribution hazard ratio, 1.042; 95% confidence interval, 0.793-1.369 [P = .769] for breast cancer-specific survival), with each improving over time. The median follow-up was 7.0 years. CONCLUSIONS: For Medicare patients with tumors measuring >5 cm, survival is similar between those treated with BCT and mastectomy as for patients with smaller primary tumors. Despite exclusion from randomized trials, BCT may remain an option for patients with larger tumors when deemed clinically and cosmetically amenable to surgical resection.

Comprehensive compartmental model and calibration algorithm for the study of clinical implications of the population-level spread of COVID-19: a study protocol.

INTRODUCTION: The complex dynamics of the coronavirus disease 2019 (COVID-19) pandemic has made obtaining reliable long-term forecasts of the disease progression difficult. Simple mechanistic models with deterministic parameters are useful for short-term predictions but have ultimately been unsuccessful in extrapolating the trajectory of the pandemic because of unmodelled dynamics and the unrealistic level of certainty that is assumed in the predictions. METHODS AND ANALYSIS: We propose a 22-compartment epidemiological model that includes compartments not previously considered concurrently, to account for the effects of vaccination, asymptomatic individuals, inadequate access to hospital care, post-acute COVID-19 and recovery with long-term health complications. Additionally, new connections between compartments introduce new dynamics to the system and provide a framework to study the sensitivity of model outputs to several concurrent effects, including temporary immunity, vaccination rate and vaccine effectiveness. Subject to data availability for a given region, we discuss a means by which population demographics (age, comorbidity, socioeconomic status, sex and geographical location) and clinically relevant information (different variants, different vaccines) can be incorporated within the 22-compartment framework. Considering a probabilistic interpretation of the parameters allows the model's predictions to reflect the current state of uncertainty about the model parameters and model states. We propose the use of a sparse Bayesian learning algorithm for parameter calibration and model selection. This methodology considers a combination of prescribed parameter prior distributions for parameters that are known to be essential to the modelled dynamics and automatic relevance determination priors for parameters whose relevance is questionable. This is useful as it helps prevent overfitting the available epidemiological data when calibrating the parameters of the proposed model. Population-level administrative health data will serve as partial observations of the model states. ETHICS AND DISSEMINATION: Approved by Carleton University's Research Ethics Board-B (clearance ID: 114596). Results will be made available through future publication.

Treatment times in breast cancer patients receiving neoadjuvant vs adjuvant chemotherapy: Is efficiency a benefit of preoperative chemotherapy?

BACKGROUND/OBJECTIVE: Delays in times to surgery, chemotherapy, and radiotherapy impair survival in breast cancer patients. Neoadjuvant chemotherapy (NAC) confers equivalent survival to adjuvant chemotherapy (AC), but it remains unknown which approach facilitates faster initiation and completion of treatment. METHODS: Women ≥18 years old with nonrecurrent, noninflammatory, clinical stage I-III breast cancer diagnosed between 2004 and 2015 who underwent both surgery and chemotherapy were reviewed from the National Cancer Database. RESULTS: Among 155 606 women overall, 28 241 patients received NAC and 127 365 patients received AC. NAC patients had higher clinical T and N stages (35.8% T3/4 vs 4.9% T3/4; 14.4% N2/3 vs 3.7% N2/3). After adjusting for stage and other factors, NAC patients had longer times to begin treatment (36.1 vs 35.4 days adjusted, P = .15), and took significantly longer to start radiotherapy (240.8 vs 218.2 days adjusted, P < .0001), and endocrine therapy (301.6 vs 275.7 days adjusted, P < .0001). Unplanned readmissions (1.2% vs 1.7%), 30-day mortality (0.04% vs 0.01%), and 90-day mortality (0.30% vs 0.08%) were all low and clinically insignificant between NAC and AC. CONCLUSION: Compared to patients receiving AC, those receiving NAC do not start treatment sooner. In addition, patients receiving NAC do not complete treatment faster. Although there are clear indications for administering NAC vs AC, rapidity of treatment should not be considered a benefit of giving chemotherapy preoperatively.

Patterns of Care and Efficacy of Chemotherapy and Radiotherapy in Skin-Involved Breast Cancers of All Sizes.

BACKGROUND: The management of small skin-involved (SI) invasive breast cancers is controversial because although they are considered unresectable, their prognosis is far better than their stage III classification. This study was undertaken to determine how SI lesions are treated in the United States and to discern the benefit of systemic therapy. PATIENTS AND METHODS: Data of patients diagnosed with stage I-III breast cancer in the National Cancer Data Base between 2004 and 2011 were reviewed. Treatment patterns were examined and overall survival assessed. RESULTS: A total of 3485 patients had SI and 456,287 patients had non-SI breast cancers. Chemotherapy was administered to 68.5% of SI and 45.9% of non-SI tumors (P < .001), including 77.2% of SI and 33% of non-SI tumors < 2 cm (P < .001). After adjusting for patient and tumor characteristics, SI patients were 19.4% more likely to receive chemotherapy than non-SI patients. Radiotherapy was provided to 61.1% of SI and 64.3% of non-SI tumors (P < .001), including 65.5% of SI and 66.5% non-SI tumors < 2 cm (P = .711). After adjusting for patient and tumor characteristics, SI patients were 76.6% more likely to receive radiotherapy than non-SI patients. Chemotherapy and radiotherapy provided an overall survival benefit for stage II and III SI and non-SI tumors. CONCLUSION: Despite controversy regarding staging and prognosis of SI tumors, the majority of patients are provided systemic therapy and radiotherapy. Varied patterns of chemotherapy administration for SI tumors suggests that further treatment guidance and standardization are required, especially because chemotherapy and radiotherapy are equally efficacious in SI and non-SI tumors alike.

THE PPARgamma ligand 15d-PGJ2 modulates macrophage activation after injury in a murine trauma model.

In macrophages, peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to be important for differentiation, and it serves as a negative regulator of activation. Major trauma/injury causes a dramatic host response that disrupts cellular immune homeostasis and initiates an inflammatory cascade that predisposes the injured host to subsequent infections. In prior studies using a murine trauma model consisting of femur fracture and hemorrhage, splenic macrophages from traumatized mice had significantly enhanced LPS-induced cyclooxygenase enzyme (subtype 2) and iNOS production as well as elevated levels of inflammatory cytokines at 1 week after injury compared with uninjured controls. These up-regulated cellular responses corresponded to increased mortality when animals were challenged with LPS or Candida. In the current study, we used the injury model to determine the effect of treatment of injured mice with the endogenous PPARgamma ligand 15-deoxy-Delta(12-, 14)-PGJ2 (15d-PGJ2). It was found that in vivo 15d-PGJ2 treatment significantly reduced the levels of inflammatory mediators produced by splenic macrophages 7 days after injury. The mechanism of inhibition is dependent on PPARgamma because concomitant treatment of animals with the PPARgamma antagonist GW9662 reversed the inhibitory effect of 15d-PGJ2. Endogenous PPARgamma modulated activation of LPS-induced p38 mitogen-activated protein kinase. Furthermore, treatment of injured mice with 15d-PGJ2 conferred a significant survival advantage after infectious challenge induced by cecal ligation and puncture. Thus, this PPARgamma ligands significantly attenuate the postinjury inflammatory response and improve survival after infectious challenge.

Use of mRNA- and protein-destabilizing elements to develop a highly responsive reporter system.

Reporter assays are widely used in applications that require measurement of changes in gene expression over time (e.g. drug screening). With standard reporter vectors, the measurable effect of a treatment or compound (altered reporter activity) is substantially diluted and delayed, compared with its true effect (altered transcriptional activity). This problem is caused by the relatively long half-lives of both the reporter protein and its mRNA. As a result, the activities of compounds, ligands or treatments that have a relatively minor effect, or a substantial but transient effect, often remain undetected. To circumvent this problem, we introduced modular protein- and mRNA-destabilizing elements into a range of commonly used reporters. Our data show that both elements are required for maximal responses to both increases and decreases in transcriptional activity. The double-destabilized reporter vectors showed markedly improved performance in drug screening, kinetic assays and dose-response titrations.

Field electroantennogram and trap assessments of aerosol pheromone dispensers for disrupting mating in Epiphyas postvittana.

An electronically controlled aerosol system for mating disruption was evaluated against Epiphyas postvittana Walker in apple orchards in New Zealand. The area in which male moths were affected by the aerosol system was examined using catches in traps radiating from a central single-point source of either one aerosol can dispenser or 100 polyethylene tubing dispensers, compared with catches in orchard plots without pheromone dispensers. Both pheromone dispensing systems decreased moth catch to similar levels at 5-10 m from the central release point, but there was 5.5-fold more pheromone released from aerosol cans than from polyethylene dispensers over a 24 h period. Trap catches were reduced by about 90% in plots treated with either five aerosol cans per hectare or uniform deployment of polyethylene dispensers. Recordings of electroantennograms in open grassed plots and orchards indicated that the treated cotton pad of an aerosol dispenser and a point source of 100 polyethylene tubing dispensers produced similar electroantennogram recordings. Electroantennogram recordings provided evidence that pheromone plume detection from a single-point source was maintained over a range of 5-40 m downwind in the orchard. On present evidence, aerosol pheromone dispensers could not be recommended for further testing towards control of E. postvittana under New Zealand conditions owing to their higher cost of purchase and operation.

Lysis-deficient bacteriophage therapy decreases endotoxin and inflammatory mediator release and improves survival in a murine peritonitis model.

BACKGROUND: Lysis-deficient (LyD) bacteriophages (phages) kill bacteria without endotoxin (Et) release. This may minimize systemic cytokine responses and limit inflammation in bacterial sepsis. We determined the effects of t amber A3 T4 LyD and virulent wild-type (WT) phages on mouse bacterial peritonitis. METHODS: Balb/c mice were injected with B40sul Escherichia coli, treated intraperitoneally with LyD, WT, or a beta-lactam antibiotic [latamoxef sodium (LMOX)], and followed for survival. We measured Et release, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, as well as bacterial counts and peritoneal exudative cells (PECs) in peritoneal lavage fluid at 6 and 12 hours after infection. RESULTS: LyD mice showed significantly greater survival compared with other groups. Et levels were significantly lower in the LyD mice at 6 and 12 hours after infection. TNF-alpha and IL-6 levels were lower in LyD mice compared with control (untreated) mice at 12 hours. Compared with controls, bacteria counts in peritoneal lavage fluid were lower in all treatment groups (LyD, WT, or LMOX) at 6 and 12 hours. PEC counts were highest in LyD mice at 6 hours but significantly lower than that in WT phage- and LMOX-treated mice at 12 hours. CONCLUSIONS: LyD phage therapy significantly improves survival and attenuates the systemic effects of bacterial sepsis by minimizing Et release and pro-inflammatory mediators in murine bacterial peritonitis. Further studies may find phage therapy useful in treating peritonitis and multidrug-resistant bacterial infections.

Neuroendocrine responses mediate macrophage function after trauma.

BACKGROUND: Clearly understanding the interactions between macrophage (M phi)-generated inflammatory mediators and the neuroendocrine system in regulating immune function after traumatic injury may aid in reversing trauma-mediated immune dysfunction and diminish the incidence and severity of infection in the traumatized patient. METHODS: Trauma consisted of an open femur fracture and 40% retro-orbital hemorrhage (Trauma) or anesthesia alone (Control). Female Balb/C mice (6-8 weeks) with intact adrenal glands (Intact) or a bilateral adrenalectomy (ADX) were used. For glucocorticoid studies, corticosterone or a vehicle was administered via intraperitoneal (ip) injection 2 hours before the trauma. Splenic M phis were harvested and prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) production, and mRNA, cyclooxygenase-2 (COX-2) protein, and nuclear factor kappa B (NF-kappa B) activity were measured. RESULTS: M phi, PGE(2) and IL-6 production in Trauma+Intact mice was significantly increased compared with Control+Intact mice. Adrenalectomy decreased these levels to Control levels. Similar changes were observed for COX-2 and IL-6 expression. M phi nuclear NF-kappa B levels were increased in Trauma+Intact mice compared with controls. Adrenalectomy abrogated this increase. Treating Trauma+Intact mice with RU-486 did not restore PGE(2) and IL-6 production or COX-2 and IL-6 messenger RNA to control levels. Administering exogenous glucocorticoid to Intact mice did not increase PGE(2) and IL-6 production or COX-2 and IL-6 mRNA to Trauma levels. CONCLUSIONS: The neuroendocrine system upregulates certain M phi inflammatory mediators, including PGE(2), IL-6, and NF-kappa B, after trauma. This upregulation does not seem to be mediated via glucocorticoids and possibly may be mediated via catecholamines. Elucidation of the interactions between the neuroendocrine system, the immune system, and inflammatory mediator secretion might provide novel therapeutic strategies for the injured patient.

Effects of limited work hours on surgical training.

BACKGROUND: Legal mandates to reduce resident work hours have prompted changes in the structure of surgical training programs. Such changes have included modification of on-call schedules and the adoption of "night float" resident coverage. Little is known about the effects of these changes on surgical resident education and perceptions of quality of patient care. STUDY DESIGN: The surgical housestaff and faculty at a single institution completed a 21-point Likert survey. Subjects were asked to compare parameters of resident education, patient care, and resident quality of life before and after institution of a strict 80-hour work week resident training schedule. The number of hours worked per week before and after these changes were reported. American Board of Surgery In-Training Examination (ABSITE) scores were compared for the 2 years before and after implementation of this schedule. Total number of surgical cases performed by graduating chief residents were recorded and compared for the 3 years before and after the schedule changes. RESULTS: Resident work hours reduced significantly after schedule changes were implemented. A majority of surgical residents reported an improvement in quality of life, but residents and faculty perceived changes to have a negative impact on continuity of patient care. Mean ABSITE composite percentile scores significantly improved after the reduction of working hours. ABSITE scores for junior residents improved significantly; no significant differences were noted in scores for senior residents. CONCLUSIONS: Reduction in resident work hours has salutary effects on perception of quality of life and basic education for surgical residents. These benefits may come at the expense of patient care, particularly continuity of care. This study did not directly assess patient outcomes but the perceptions of caregivers suggest that patient care may be compromised. Further research is needed to assess the longterm effects of changes on both residents and patients.

NS-398 inhibits tumor growth and liver metastasis of colon cancer through induction of apoptosis and suppression of the plasminogen activation system in a mouse model.

BACKGROUND: Cyclooxygenase-2 (COX-2) is overexpressed in colon cancers. The plasminogen activation (PA) system relates to cancer invasion and metastasis through the degradation of the extracellular matrix. COX-2 also relates to degradation of the extracellular matrix, but the relationship between COX-2 and the plasminogen activator system is unclear. STUDY DESIGN: In vivo: Colon 38 (G0) primary and (G5) metastatic cell lines were implanted in C57BL/6 mice treated with or without COX-2 inhibitor (NS-398). Animal survival and tumor growth were measured. On day 19, tumors were excised and tumor cell apoptosis measured. For metastasis, G5 cells were injected into the spleen, and, after 23 days, liver metastasis was determined. In vitro: G0 or G5 cells were treated with NS-398. Supernatant prostaglandin E2 and mRNA expressions of COX-2, vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (u-PA), u-PA receptor, plasminogen activator inhibitor type-1 (PAI-1), and PAI-2 were measured. Tumor cell proliferation was also determined. RESULTS: In vivo: Mean survival of NS-398-treated animals was higher than controls for both G5 and G0 (G5: p < 0.003, G0: p < 0.02). G5 tumors grew faster than G0 tumors (p < 0.001) and NS-398 significantly inhibited tumor growth (p < 0.001), induced tumor cell apoptosis (p < 0.001), and significantly reduced metastasis (p < 0.003) in G5 animals. In vitro: PGE(2) production was higher in G5 than G0 cells (p < 0.001); NS-398 significantly reduced prostaglandin E(2) levels in G5 cells (p < 0.001). mRNA expression of COX-2, vascular endothelial growth factor, and u-PA receptor was higher in G5 than G0 cells, and NS-398 significantly inhibited u-PA mRNA expression in G5 cells. NS-398 significantly reduced proliferation in G5 cells (p < 0.05). CONCLUSIONS: COX-2 inhibition significantly decreases tumor growth in this model by inducing apoptosis and blocking u-PA production in G5 colon cancer cells, which is associated with significant inhibition of liver metastases.

Decreased peritoneal macrophage NF-kappaB translocation to the nucleus in protein energy malnutrition--a role for the glucocorticoid response?

BACKGROUND & AIMS: Protein energy malnutrition (PEM) induces immune suppression leading to increased morbidity and mortality. The mechanism(s) underlying PEM-mediated immune suppression remain unclear. Plasma glucocorticoid levels are elevated in PEM and it has been postulated that these increased levels may mediate macrophage (MØ) dysfunction in PEM. We have previously shown that nuclear factor kappa B (NF-kappaB) activation in response to LPS stimulation is diminished in peritoneal macrophages (PMØs) from PEM mice. We hypothesized that decreased NF-kappaB activation in lipopolysaccharide (LPS)-stimulated PMØs in PEM is mediated through increased circulating glucocorticoid levels. METHODS: Mice were randomized to six groups of n = 15 each as follows: (1) control diet (24% casein) (C); (2) protein-free diet (PF); (3) mice with subcutaneously implanted corticosterone pellet on the control diet; (4) mice with subcutaneously implanted placebo pellet on the control diet; (5) adrenalectomized mice on the control diet; (6) adrenalectomized mice on the PF diet. Within each group, the mice were pair-fed for 7 days. At the end of the experimental time period, PMØs were harvested and NF-kappaB activation determined by electrophoretic mobility shift assay (EMSA). RESULTS: Elevated circulating glucocorticoids diminished NF-kappaB activation but adrenalectomy failed to restore this diminution in a murine model of PEM. CONCLUSION: NF-kappaB translocation to the nucleus in PEM is independent of elevated circulating glucocorticoid levels.

Serum leptin levels in acute protein deprivation.

BACKGROUND: Protein energy malnutrition (PEM) induces a host neuroendocrine response, reflected by significant elevations in circulating glucocorticoid levels and associated with metabolic and immune dysfunction. Leptin regulates food intake and body mass and has a significant impact on the hypothalamic-pituitary-adrenal axis (HPA). We hypothesized that leptin may be altered by and may play an important role in regulating the effects of PEM. METHODS: Female Balb/c mice were used. In experiment 1, mice were pair-fed either a protein-free (0% casein) or control (24% casein) diet for 7 days. In experiment 2, mice were implanted with either a placebo or corticosterone-releasing pellet and fed the control diet for 7 days. In experiment 3, adrenalectomized mice were pair-fed either the protein-free or control diet for 7 days. Serum corticosterone and leptin levels were measured in all experiments. RESULTS: PEM caused significant reductions in food intake, body weight, and total body fat, but not lean body mass. Serum corticosterone and leptin levels were significantly greater in mice fed the protein-free diet. Subcutaneous implantation of a corticosterone pellet in mice fed the control diet resulted in a significantly elevated serum leptin level compared with placebo-implanted controls. Bilateral adrenalectomy partially blunted the increased serum leptin in PEM. CONCLUSIONS: Leptin may be an important mediator of weight loss and decreased food intake in PEM. Elevated serum leptin in PEM may be secondary to elevated serum corticosterone, with other factors inherent in the host response to protein restriction also contributing to elevated serum leptin.