Downstaging in Pancreatic Cancer: A Matched Analysis of Patients Resected Following Systemic Treatment of Initially Locally Unresectable Disease

Background

Patients with locally unresectable pancreatic cancer (AJCC stage III) have a median survival of 10?C14?months. The objective of this study was to evaluate outcome of initially unresectable patients who respond to multimodality therapy and undergo resection.

Methods

Using a prospectively collected database, patients were identified who were initially unresectable because of vascular invasion and had sufficient response to nonoperative treatment to undergo resection. Overall survival (OS) was compared with a matched group of patients who were initially resectable. Case matching was performed using a previously validated pancreatic cancer nomogram.

Results

A total of 36 patients with initial stage III disease were identified who underwent resection after treatment with either systemic therapy or chemoradiation. Initial unresectability was determined by operative exploration (n?=?15, 42%) or by cross-sectional imaging (n?=?21, 58%). Resection consisted of pancreaticoduodenectomy (n?=?31, 86%), distal pancreatectomy (n?=?4, 11%), and total pancreatectomy (n?=?1, 3%). Pathology revealed T3 lesions in 26 patients (73%), node positivity in 6 patients (16%), and a negative margin in 30 patients (83%). The median OS in this series was 25?months from resection and 30?months since treatment initiation. There was no difference in OS from time of resection between the initial stage III patients and those who presented with resectable disease (P?=?.35).

Conclusions

In this study, patients who were able to undergo resection following treatment of initial stage III pancreatic cancer experienced survival similar to those who were initially resectable. Resection is indicated in this highly select group of patients.     

The invisible trauma patient: emergency department discharges

BACKGROUND: As the malpractice and financial environment has changed, injured patients evaluated by the trauma team and discharged from the emergency department (ED) are now commonplace. The evaluation, care, and disposition of this population has become a significant workload component but is not reported to accrediting organizations and is relatively invisible to hospital administrators. Our objective was to quantify and begin to qualify the evolving picture of the trauma ED discharge population as a work component of trauma service function in an urban, Level I trauma center with an aeromedical program. METHODS: Trauma registry (contacts, mechanism, transport, injuries, and disposition) and hospital databases (ED closure, occupancy rates) were queried for a 5-year period (1999-2003). Trend analysis provided statistical comparisons for questions of interest. RESULTS: During the 5-year study period, the total number of trauma contacts rose by 18.1% (2,220 in 1999 vs. 2,622 in 2003; trend p < 0.05). This increase in total contacts was not a manifestation of an increase in admissions (1,672 in 1999 vs. 1,544 in 2003) but rather a reflection of a marked increase in patients seen primarily by the trauma team and discharged from the ED (473 in 1999 vs. 1,000 in 2003; trend p < 0.05). These ED discharge patients were increasingly transported by helicopter (12.3% in 1999 vs. 29.2% in 2003; trend p < 0.05) and less frequently from urban areas (57.1% in 1999 vs. 48.1% in 2003; trend p < 0.05) over the course of the study period. Average injury severity of this group increased over the study period (Injury Severity Score of 2.7 +/- 0.1 in 1999 vs. 3.3 +/- 0.1 in 2003; trend p < 0.05). ED length of stay for this group increased 19.8% over the study period (trend p < 0.05), averaging nearly 5 hours in 2003. CONCLUSION: The total number, relative percentage, and injury severity of patients evaluated by the trauma team and discharged from the ED has significantly increased over the last 5 years, representing nearly 5,000 patient care hours in 2003. Systems to care for these patients in a cost- and resource-efficient fashion should be put in place. The impact of this growing population of patients on the workload of the trauma center should be recognized by accrediting agencies, hospital administration, and Emergency Medical Services.     

Sacrocolpopexy: is there a consistent surgical technique?

Introduction

Sacrocolpopexy is the gold standard treatment for vault prolapse. Current reported standards regarding surgical approach and technique vary. Our aim was to evaluate the surgical techniques used and identify any consistency.

Methods

Electronic surveys were sent to 148 candidates enrolled in a sacrocolpopexy workshop at the 2012 American Urogynecologic Society (AUGS) annual meeting and as a link in the International Urogynecology Association (IUGA) e-magazine. The survey assessed demographics, specific surgical steps including dissection techniques, number and type of sutures, graft materials, and the approach to intraoperative complications.

Results

Within the AUGS group, 61 candidates responded (41 %). From the IUGA membership, 128 responded for a total of 189. Overall, 59 % identified their primary practice as urogynaecology, 43 % having completed a fellowship. Only 33 % reported performing sacrocolpopexy as the primary surgery for vault prolapse. Technical aspects: 99.4 % used polypropylene mesh, with 57 % attaching it to the vagina using non-absorbable monofilament sutures. An average of 3–4 sutures were used on the anterior and posterior walls respectively. Suture location: 22.5 % reported not placing apical sutures and 55.7 % place their anterior wall sutures midway down the vagina. Posteriorly, 47 (30 %) placed sutures through the uterosacral ligaments, 19 (12.4 %) through the levator ani and 15 % extend the mesh to the perineal body. The mesh was attached to the sacrum using permanent sutures by 75 %. Dissection of the sacrum was deemed the most technically difficult aspect.

Conclusion

Surgical technique varies widely despite the level of expertise and training. This study highlights the need for an evaluation of the effect of surgical technique on outcomes.

     

A comparison of EGF and MAb 528 labeled with 111In for imaging human breast cancer.

Our objective was to compare 111In-labeled human epidermal growth factor (hEGF), a 53-amino acid peptide with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) 528 (IgG2a) for imaging EGFR-positive breast cancer. METHODS: hEGF and MAb 528 were derivatized with diethylenetriamine pentaacetic acid (DTPA) and labeled with 111In acetate. Receptor binding assays were conducted in vitro against MDA-MB-468 human breast cancer cells. Biodistribution and tumor imaging studies were conducted after intravenous injection of the radiopharmaceuticals in athymic mice bearing subcutaneous MCF-7, MDA-MB-231, or MDA-MB-468 human breast cancer xenografts or in severe combined immunodeficiency mice implanted with a breast cancer metastasis (JW-97 cells). MCF-7, MDA-MB-231, JW-97, and MDA-MB-468 cells expressed 1.5 x 10(4), 1.3 x 10(5), 2.7 x 10(5), and 1.3 x 106 EGFR/cell, respectively in vitro. RESULTS: 111In-DTPA-hEGF and 111In-DTPA-MAb 528 bound with high affinity to MDA-MB-468 cells (Ka of 7.5 x 10(8) and 1.2 x 10(8) L/mol, respectively). 111In-DTPA-hEGF was eliminated rapidly from the blood with < 0.2% injected dose/g (%ID/g) circulating at 72 h after injection, whereas 111In-DTPA-MAb 528 was cleared more slowly (3%ID/g in the blood at 72 h). Maximum localization of 111In-DTPA-hEGF in MDA-MB-468 tumors (2.2 %ID/g) was 10-fold lower than with 111In-DTPA-MAb 528 (21.6 %ID/g). There was high uptake in the liver and kidneys for both radiopharmaceuticals. Tumor-to-blood ratios were greater for 111In-labeled hEGF than for MAb 528 (12:1 versus 6:1), but all other tumor-to-normal tissue ratios were higher for MAb 528. MDA-MB-468 and JW-97 tumors were imaged successfully with both radiopharmaceuticals, but tumors were more easily visualized using 111In-labeled MAb 528. There was no direct quantitative relationship between EGFR expression on breast cancer cell lines in vitro, and tumor uptake of the radiopharmaceuticals in vivo, but control studies showed that tumor uptake was receptor mediated. CONCLUSION: Our results suggest that the tumor uptake in vivo of receptor-binding radiopharmaceuticals is controlled to a greater extent by their elimination rate from the blood than by the level of receptor expression on the cancer cells. Radiolabeled anti-EGFR MAbs would be more effective for tumor imaging in cancer patients than peptide-based radiopharmaceuticals such as hEGF, because they exhibit higher tumor uptake at only moderately lower tumor-to-blood ratios.     

A retrospective review of the management of Dupuytren's nodules

PURPOSE: To evaluate the progression of Depuytren's nodules with more than 6 years of follow-up study. METHODS: Fifty-nine patients who presented initially with Dupuytren's nodules returned for physical examination at an average follow-up period of 8.7 years (range, 6-15 y). Patients were questioned regarding family history of Dupuytren's disease, family ethnicity, alcohol consumption, smoking, liver disease, seizures, diabetes, and signs of systemic disease such as knuckle pads and plantar nodules. Physical examination evaluated disease state, loss of extension of the finger joints, and disease location. RESULTS: Thirty of the 59 patients with previously diagnosed isolated nodules developed a cord. Twenty-two percent of patients presented with bilateral disease and another 26% developed bilateral disease. Of those patients whose disease progressed 43% had European heritage, 37% had disease onset before the age of 50 years, 30% had bilateral disease, 23% had a family history of Dupuytren's disease, and 13% had plantar nodules. Five patients lost extension averaging 60 degrees at the metacarpophalangeal joint and 40 degrees at the proximal interphalangeal joint. Three of these 5 had surgical excision because they had a flexion contracture of the metacarpophalangeal or proximal interphalangeal joints averaging 60 degrees and 43 degrees , respectively. Another 7 patients did not meet standard criteria but had surgery for persistent pain associated with grasping objects (without contracture). All surgically treated patients had at least 1 risk factor and 7 patients had more than 1 risk factor. In 7 patients the Dupuytren's nodule had resolved at the time of follow-up evaluation. CONCLUSIONS: The progression of the nodular form of Dupuytren's disease to cord-like disease is common but not inevitable. This evaluation of Dupuytren's nodules has shown that at an average of 8.7 years after diagnosis 5 patients met standard surgical criteria of metacarpophalangeal contracture of greater than 30 degrees or any proximal interphalangeal contracture. Age of onset (before 50 years) is correlated most closely with disease progression, and the disease regressed in 7 patients (12%).     

Gene Profiling of Human Adipose Tissue During Evoked Inflammation In Vivo

OBJECTIVE

Adipose inflammation plays a central role in obesity-related metabolic and cardiovascular complications. However, few human adipose-secreted proteins are known to mediate these processes. We hypothesized that microarray mRNA profiling of human adipose during evoked inflammation could identify novel adipocytokines.

RESEARCH DESIGN AND METHODS

Healthy human volunteers (n = 14) were treated with intravenous endotoxin (3 ng/kg lipopolysaccharide [LPS]) and underwent subcutaneous adipose biopsies before and after LPS. On Affymetrix U133Plus 2.0 arrays, adipose mRNAs modulated >1.5-fold (with P < 0.00001) were selected. SignalP 3.0 and SecretomeP 2.0 identified genes predicted to encode secreted proteins. Of these, 86 candidates were chosen for validation in adipose from an independent human endotoxemia protocol (N = 7, with 0.6 ng/kg LPS) and for exploration of cellular origin in primary human adipocytes and macrophages in vitro.

RESULTS

Microarray identified 776 adipose genes modulated by LPS; 298 were predicted to be secreted. Of detectable prioritized genes, 82 of 85 (96% [95% CI 90–99]) were upregulated (fold changes >1.0) during the lower-dose (LPS 0.6 ng/kg) validation study and 51 of 85 (59% [49–70]) were induced greater than 1.5-fold. Treatment of primary adipocytes with LPS and macrophage polarization to M1 proinflammatory phenotype increased expression by 1.5-fold for 58 and 73% of detectable genes, respectively.

CONCLUSIONS

We demonstrate that evoked inflammation of human adipose in vivo modulated expression of multiple genes likely secreted by adipocytes and monocytes. These included established adipocytokines and chemokines implicated in recruitment and activation of lymphocytes, adhesion molecules, antioxidants, and several novel genes with unknown function. Such candidates may represent biomarkers and therapeutic targets for obesity-related complications.Activation of innate and adaptive immunity is a crucial link between adiposity and its metabolic complications (1–4). In rodents, modulation of toll-like receptor-4 (5), tumor necrosis factor (TNF) receptors (6), chemokines, and downstream kinases (7) attenuate diet-induced obesity and insulin resistance. Further, cross talk between immune cells and adipocytes promotes an inflammatory, insulin-resistant state in obesity. A key initiating event in adipose inflammation is recruitment of T-lymphocytes (8,9) and monocyte/macrophages (10,11) with elaboration of inflammatory adipocytokines that modulate metabolic signaling (12–15). Despite experimental evidence in rodent models, most evidence supporting these concepts in humans derives from observational and correlative studies (16–18). Indeed, validated adipokines that mediate, or serve as biomarkers for, complications of human adiposity remain limited.Expression of inflammatory, insulin-signaling, and lipid genes are perturbed in adipose of obese humans (19–21). Recently, the in vitro secretome of subcutaneous and visceral primary human adipocytes was described and includes many unexplored proteins modulated during adipogenesis (1,22). Remarkably, less than half of genes found in the human subcutaneous adipocyte secretome were previously found in the murine 3T3-L1 preadipocyte secretome (22), underscoring the importance of studies in human tissue.Experimental human endotoxemia can provide unique insights into the relationship of inflammation to metabolic disturbance in man (23,24). Others and we have shown that endotoxemia induces acute metabolic, lipoprotein, and oxidant responses that resemble the chronic changes in insulin resistance and metabolic syndrome (25,26). Notably, endotoxemia induces adipose inflammation (27) with activation of several adipose inflammatory cascades, including cytokines, chemokines, and suppressor of cytokine signaling (SOCS) molecules (26) that attenuate insulin signaling and are implicated in obesity and type 2 diabetes (28).We applied microarray mRNA profiling of human adipose during endotoxemia to identify novel inflammation-induced adipose genes. We focused on genes predicted to be secreted and validated our findings in vivo through independent experiments of low-grade human inflammation. Finally, we identified in vitro the likely human adipose cellular source of these top candidates.     

Modular branched stent graft for endovascular repair of aortic arch aneurysm and dissection

PURPOSE: We describe a modular stent graft for use in endovascular repair of aneurysms of the aortic arch. METHOD: Carotid-carotid and left carotid-subclavian bypass grafts are created surgically. Two large, fully stented grafts are inserted endoluminally. The proximal component is bifurcated, with a wide proximal trunk and two distal limbs, one long and narrow, the other short and wide. This component is inserted through the carotid artery and deployed with the trunk and short wide limb in the ascending thoracic aorta; the long narrow limb opens into the innominate artery. After delivery system removal and carotid artery repair, a distal component is inserted through a femoral approach to bridge the gap between the short, wide distal limb of the proximal component and the nondilated descending thoracic aorta. The result is a branched stent graft, implanted proximally into the ascending aorta and distally into the innominate artery and descending thoracic aorta. CONCLUSION: The system has been used successfully to treat a large wide-necked pseudoaneurysm of the aortic arch.     

Selected conditions associated with an increased incidence of incisional hernia: A review of molecular biology

BackgroundIncisional hernias (IH) following a laparotomy, on average, occur in 10–20% of patients, however, little is known about its molecular basis. Thus, a better understanding of the molecular mechanisms could lead to the identification of key target(s) to intervene pre-and post-operatively.MethodsWe examined the current literature describing the molecular mechanisms of IH and overlap these factors with smoking, abdominal aortic aneurysm, obesity, diabetes mellitus, and diverticulitis.ResultsThe expression levels of collagen I and III, matrix metalloproteinases, and tissue inhibitors of metalloproteases are abnormal in the extracellular matrix (ECM) of IH patients and ECM disorganization has an overlap with these comorbid conditions.ConclusionUnderstanding the pathophysiology of IH development and associated risk factors will allow physicians to identify patients that may be at increased risk for IH and to possibly act preemptively to decrease the incidence of IH.