Robert E. Roses

Injectable tissue-engineered cartilage with different chondrocyte sources

Injectable engineered cartilage that maintains a predictable shape and volume would allow recontouring of craniomaxillofacial irregularities with minimally invasive techniques. This study investigated how chondrocytes from different cartilage sources, encapsulated in fibrin polymer, affected construct mass and volume with time. Swine auricular, costal, and articular chondrocytes were isolated and mixed with fibrin polymer (cell concentration of 40 × 106 cells/ml for all groups). Eight samples (1 cm × 1 cm × 0.3 cm) per group were implanted into nude mice for each time period (4, 8, and 12 weeks). The dimensions and mass of each specimen were recorded before implantation and after explantation. Ratios comparing final measurements and original measurements were calculated. Histological, biochemical, and biomechanical analyses were performed. Histological evaluations (n = 3) indicated that new cartilaginous matrix was synthesized by the transplanted chondrocytes in all experimental groups. At 12 weeks, the ratios of dimension and mass (n = 8) for auricular chondrocyte constructs increased by 20 to 30 percent, the ratios for costal chondrocyte constructs were equal to the initial values, and the ratios for articular chondrocyte constructs decreased by 40 to 50 percent. Constructs made with auricular chondrocytes had the highest modulus (n = 3 to 5) and glycosaminoglycan content (n = 4 or 5) and the lowest permeability value (n = 3 to 5) and water content (n = 4 or 5). Constructs made with articular chondrocytes had the lowest modulus and glycosaminoglycan content and the highest permeability value and water content (p < 0.05). The amounts of hydroxyproline (n = 5) and DNA (n = 5) were not significantly different among the experimental groups (p > 0.05). It was possible to engineer injectable cartilage with chondrocytes from different sources, resulting in neocartilage with different properties. Although cartilage made with articular chondrocytes shrank and cartilage made with auricular chondrocytes overgrew, the injectable tissue-engineered cartilage made with costal chondrocytes was stable during the time periods studied. Furthermore, the biomechanical properties of the engineered cartilage made with auricular or costal chondrocytes were superior to those of cartilage made with articular chondrocytes, in this model.

Differential Production of IL-23 and IL-12 by Myeloid-Derived Dendritic Cells in Response to TLR Agonists

The recently delineated role for IL-23 in enhancing Th-17 activity suggests that regulation of its expression is distinct from that of IL-12. We hypothesized that independent TLR-mediated pathways are involved in the regulation of IL-12 and IL-23 production by myeloid-derived dendritic cells (DCs). The TLR 2 ligand, lipoteichoic acid (LTA), the TLR 4 ligand, LPS, and the TLR 7/8 ligand, resimiquod (R848), induced production of IL-23 by DCs. None of these TLR ligands alone induced significant IL-12 production, except when combined with IFN-γ or other TLR ligands. Notably, IL-23 production in response to single TLR ligands was inhibited by IL-4. DCs treated with single TLR agonists induced IL-17A production by allogeneic and Ag-specific memory CD4+ T cells, an effect that was abrogated by IL-23 neutralization. Moreover, these DCs stimulated IL-17A production by tumor peptide-specific CD8+ T cells. In contrast, DCs treated with dual signals induced naive and memory Th1 responses and enhanced the functional avidity of tumor-specific CD8+ T cells. These results indicate that distinct microbial-derived stimuli are required to drive myeloid DC commitment to IL-12 or IL-23 production, thereby differentially polarizing T cell responses.

HER-2/neu Overexpression as a Predictor for the Transition from In situ to Invasive Breast Cancer

The clinical implications of HER-2/neu (HER2) expression in ductal carcinoma in situ (DCIS) lesions have yet to be clearly elucidated; this despite the more frequent expression of HER2 in high-grade DCIS lesions compared with invasive cancers. We hypothesized that HER2 overexpression in DCIS is associated with more rapid progression to invasive disease. Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 was done on DCIS specimens. Univariate analysis and a multivariate logistic regression were done to determine whether estrogen receptor, progesterone receptor, or HER2 status, comedo necrosis, nuclear grade, lesion size, or patient age predicted the presence of associated invasive disease in patients with DCIS. Invasive foci were found in association with HER2 overexpressing DCIS at a higher frequency than with DCIS that did not overexpress HER2. Although high nuclear grade, large lesion size, and HER2 overexpression were all associated with the presence of invasive disease on univariate analysis, HER2 was the only significant predictor for the presence of invasive disease after multivariate adjustment (odds ratio, 6.4; P = 0.01). These data indicate that HER2 overexpression in DCIS lesions predicts the presence of invasive foci in patients with DCIS and suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1386–9)

HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ.

HER‐2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER‐2/neu expression in DCIS may initiate immunity against invasive cancer.

Cancer in the gastric remnant after gastric bypass: a case report

Gastric cancer in the gastric stump after a Bilroth II subtotal gastrectomy is a well-recognized entity. However, gastric cancer in the bypassed gastric remnant after a gastric bypass operation for morbid obesity has not been well described, and only 2 such cases have been reported in the English literature. This case report presents a patient who developed gastric cancer in the defunctionalized, bypassed stomach 22 years after undergoing an open gastric bypass with a Roux-en-Y gastro-jejunostomy for morbid obesity. The problems of monitoring the defunctionalized bypassed stomach after gastric stapling and gastro-jejunostomy are discussed.

Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer

The identification of pathogen-associated molecular patterns, conserved microbial structures that act on Toll-like receptors, has led to a novel avenue of investigation aimed at developing a new generation of cancer immunotherapies. Ligation of Toll-like receptors results in the induction of robust immune responses that may be directed against tumor-associated antigens. Recent data suggest that such strategies may result in enhanced antitumor immunity. Nonetheless, as clinically effective immunotherapy for cancer remains a somewhat distant goal, attention has shifted toward multimodality approaches to cancer therapy, sometimes combining novel immune interventions and conventional treatments. The traditional view of radiation therapy as immunosuppressive has now been challenged, prompting a re-evaluation of its potential as an adjunct to immunotherapy. Radiation therapy can enhance the expression of tumor-associated antigens, induce immune-mediated targeting of tumor stroma, and diminish regulatory T cell activity. Recent evidence suggests that radiation therapy may also activate effectors of innate immunity through TLR-dependent mechanisms, thereby augmenting the adaptive immune response to cancer. In this paper, we will review evidence for enhanced tumor-directed immunity resulting from radiation exposure and early promising data suggesting synergistic effects of radiation and TLR-targeted immunotherapies.

Reengineering dendritic cell-based anti-cancer vaccines.

Summary: Despite initial enthusiasm, dendritic cell (DC)‐based anti‐cancer vaccines have yet to live up to their promise as one of the best hopes for generating effective anti‐tumor immunity. One of the principal reasons for the generally disappointing results achieved thus far could be that the full potential of DCs has not been effectively exploited. Here, we argue that dramatic improvements in vaccine efficacy will probably require a careful re‐evaluation of current vaccine design. The formulation of new strategies must take into account the natural history of DCs, particularly their role in helping the immune system deal with infection. Equally critical is the emerging importance of soluble factors, notably interleukin‐12, in modulating the quality of immune responses. Vaccines should also be designed to recruit helper T cells and antibody‐producing B cells rather than simply cytotoxic T lymphocytes. Finally, the judicious selection of tumor, target antigen, and disease stage best suited for treatment should serve as the foundation of trial designs. Our discussion addresses a recent clinical vaccine trial to treat early breast cancer, where many elements of this new strategy were put into practice.

The rise in metastasectomy across cancer types over the past decade

Although studies of metastasectomy have been limited primarily to institutional experiences, reports of favorable long‐term outcomes have generated increasing interest. In the current study, the authors attempted to define the national practice patterns in metastasectomy for 4 common malignancies with varying responsiveness to systemic therapy.

Morbidity and mortality after total gastrectomy for gastric malignancy using the American College of Surgeons National Surgical Quality Improvement Program database

BACKGROUND Frequent perioperative morbidity and mortality have been observed in randomized surgical studies for gastric cancer, but specific patient factors associated with morbidity and mortality after total gastrectomy have not been well characterized. METHODS We queried the American College of Surgeons National Surgical Quality Improvement Program database (2005-2011) for all patients with a gastric neoplasm undergoing total gastrectomy. Univariate and multivariate logistic regression analyses were performed to identify factors associated with an increased risk of morbidity or mortality. RESULTS In 1,165 patients undergoing total gastrectomy, 416 patients (36%) experienced a complication, and 55 died (4.7%) within 30 days of operation. In a reduced multivariate model, age >70 years, preoperative weight loss, splenectomy, and pancreatectomy were associated with morbidity, whereas age >70 years, weight loss, albumin <3 g/dL, and pancreatectomy were associated with mortality (P < .05 each). The number of present preoperative risk factors stratified morbidity from 26 to 46%, with an adjacent organ resection (splenectomy, pancreatectomy) associated with 56% morbidity. Similarly, mortality rates ranged from 0.4% in those without risk factors to 5 of 9 patients with all three preoperative factors present. Patients undergoing pancreatectomy had a 13% mortality rate. CONCLUSION Total gastrectomy for malignancy is associated with substantial morbidity and mortality. Identification of high-risk factors may allow more rational patient selection or sequencing of therapy.

Drain Management after Pancreatoduodenectomy: Reappraisal of a Prospective Randomized Trial Using Risk Stratification

BACKGROUND A recent randomized trial used the Fistula Risk Score (FRS) to develop guidelines for selective drainage based on clinically relevant fistula (CR-POPF) risk. Additionally, postoperative day (POD) 1 drain and serum amylase have been identified as accurate postoperative predictors of CR-POPF. This study sought to identify patients who may benefit from selective drainage, as well as the optimal timing for drain removal after pancreatoduodenectomy. STUDY DESIGN One hundred six pancreatoduodenectomies from a previously reported RCT were assessed using risk-adjustment. The incidence of CR-POPF was compared between FRS risk cohorts. Drain and serum amylase values from POD 1 were evaluated using receiver operating characteristic (ROC) analysis to establish cut-offs predictive of CR-POPF occurrence. A regression analysis compared drain removal randomizations (POD 3 vs POD 5). RESULTS Three-quarters of patients had moderate/high CR-POPF risk. This group had a CR-POPF rate of 36.3% vs 7.7% among negligible/low risk patients (p = 0.005). The areas under the ROC curve for CR-POPF prediction using POD 1 drain and serum amylase values were 0.800 (p = 0.000001; 95% CI 0.70-0.90) and 0.655 (p = 0.012; 95% CI 0.55-0.77), respectively. No significant serum amylase cut-offs were identified. Moderate/high risk patients with POD 1 drain amylase ≤ 5,000 U/L had significantly lower rates of CR-POPF when randomized to POD 3 drain removal (4.2% vs 38.5%; p = 0.003); moreover, these patients experienced fewer complications and shorter hospital stays. CONCLUSIONS A clinical care protocol is proposed whereby drains are recommended for moderate/high FRS risk patients, but may be omitted in patients with negligible/low risk. Drain amylase values in moderate/high risk patients should then be evaluated on POD 1 to determine the optimal timing for drain removal. Moderate/high risk patients with POD 1 drain amylase ≤ 5,000 U/L have lower rates of CR-POPF with POD 3 (vs POD ≥ 5) drain removal; early drain removal is recommended for these patients.