To determine whether thyroid surgery in patients ≥80 is associated with higher complication rates.
The incidence of thyroid nodules increases with age and little information is available regarding the risks of thyroid surgery in elderly patients.
Out of 3568 patients undergoing thyroid surgery between July 2001 and October 2007 at a single institution, the records of 90 consecutive patients ≥80 years were retrospectively reviewed and compared to a cohort of 242 randomly selected patients aged 18–79, who underwent thyroid surgery during the same time period, using SAS statistical software. Clinical variables included age group, sex, medical co-morbidities, pre-operative diagnosis, substernal component, previous surgery, final pathology, length of stay (LOS), postoperative complications and mortality.
Preoperative indications for surgery included benign disease in 51.1% vs. 40.9%, suspected malignancy in 18.9% vs. 26% and suspected follicular neoplasms including indeterminate/microfollicular cytology in 30% vs. 33.1% in the octogenarian patient group (≥80 yrs old) vs. the younger patient cohort (p=NS). Octogenarians had a 21.1% rate of significant malignancy on final pathology vs. 28.1% in the younger cohort (p=NS). The overall complication rate in the octogenarian group was 23.3% vs. 9.1% in the younger cohort (p=.0006). Male sex and lung disease were independent risk factors for perioperative complications. Complications unique to octogenarians included heart failure, atrial fibrillation, pneumonia, tracheotomy, urosepsis, blood transfusion, wound infection and ischemic colitis. There was no mortality in either group.
Patients ≥80 years of age can undergo successful thyroid surgery but with significantly higher morbidity. Earlier surgical intervention may be advised in those who are at high risk for disease progression whereas follow-up strategies without surgery may be advised for others.
Papillary thyroid cancer (PTC) recurrence risk is difficult to predict. No current risk classification system incorporates BRAF mutational status. Here, we assess the incremental value of BRAF mutational status in predicting PTC recurrence relative to existing recurrence risk algorithms.
Serial data were collected for a historical cohort having undergone total thyroidectomy for PTC over a five-year period. Corresponding BRAFV600E testing was performed and Cox proportional hazard regression modeling, with and without BRAF status, was used to evaluate existing recurrence risk algorithms.
The five-year cumulative PTC recurrence incidence within our 356 patient cohort was 15%. 205 (81%) of associated archived specimens were successfully genotyped and 110 (54%) harbored the BRAFV600E mutation. The five-year cumulative recurrence incidence among BRAFV600E patients was 20%, versus 8% among BRAF wild type. BRAFV600E was significantly associated with time to recurrence when added to the following algorithms: AMES (HR 2.43 [1.08–5.49]), MACIS category (HR 2.46 [1.09–5.54]), AJCC-TNM (HR 2.51 [1.11, 5.66]), and ATA recurrence-risk category (HR 2.44 [1.08–5.50]), and model discrimination improved (incremental c-index range 0.046–0.109).
Addition of BRAF mutational status to established risk algorithms improves discrimination of recurrence risk in patients undergoing total thyroidectomy for PTC.
The durability of minimally invasive parathyroidectomy (MIP) has been questioned, and some advocate for routine open parathyroidectomy (OP). This study compared outcomes between patients treated with MIP versus OP for primary hyperparathyroidism (PHPT).
A retrospective review was performed to identify cases of PHPT with single adenomas (SA) between 2001 and 2011. Operations were classified as OP when both sides were explored. Kaplan-Meier estimates were plotted and compared by the log-rank test. P<0.05 was considered significant.
We analyzed 1,083 cases of PHPT with SA. 928 (85.7%) were MIP and 155 (14.3%) were OP. There was no difference in the rates of persistence (0.2% MIP vs. 0% OP, p = 0.61) or recurrence (2.5% MIP vs. 1.9% OP, p = 0.68) between the two groups. However, the Kaplan-Meier estimates began to separate beyond eight years follow-up. The OP group did experience a higher incidence of transient hypocalcemia postoperatively (1.9% vs. 0.1%, p = 0.01).
MIP appears equivalent to OP in single-gland disease. While patients undergoing OP experienced more transient hypocalcemia, patients undergoing MIP appear to have a higher long-term recurrence rate. Therefore, proper patient selection and counseling of these risks is necessary for either approach.
Patients with von Hippel-Lindau disease (VHL) commonly develop pancreatic cysts and neuroendocrine tumors (PNETs). Solid microcystic serous adenoma (SMSA), a rare tumor described in VHL patients, can be mistaken for PNET on imaging.
Clinical, pathologic and radiologic data were reviewed on VHL patients who underwent surgery for a pre-operative diagnosis of PNET since 1994 at one institution. Blinded to the pathological diagnoses, radiologists reassessed available imaging.
For 55 patients, 79 pancreatectomies were performed for presumed PNETs. Ten (18.2%) patients underwent 12 (15.2%) resections for tumors diagnosed as SMSA on final pathology. The average size of a SMSA leading to surgery was 3.6 ±0.4 cm. Four out of 11 SMSAs were still mistaken for PNETs when imaging was reassessed. Mean FDG-PET SUV was higher for 17 PNETs (12.1 ±1.2) compared to 6 SMSAs (4.2 ±0.5; p=0.002). The mean doubling time of SMSAs and PNETs was similar. Seven (15.2%) patients with pathologically-proven PNETs had malignant disease.
SMSAs can mimic PNETs on non-functional imaging; FDG-PET may help differentiate them. A high index of suspicion is needed to minimize operations performed for SMSA and to counsel VHL patients of their risks of undergoing surgery for a lesion with no known malignant potential.
Guidelines for post resection surveillance of colorectal cancer recommend a collection of the patient's history and physical examination, testing for carcinoembryonic antigen (CEA), and colonoscopy. No consistent guidelines exist for the use of abdominal computed tomography (CT) and position emission tomography (PET)/PET-CT. The goal of our study was to describe current trends, the impact of oncologic follow-up on guideline adherence, and the patterns of use of nonrecommended tests.
We used Texas Cancer Registry—Medicare-linked data (2000-2009) to identify physician visits, CEA testing, colonoscopy, abdominal CT, and PET/PET-CT scans in patients ≥66 years old with stage I-III colorectal cancer who underwent curative resection. Compliance with guidelines was assessed with a composite measure of physician visits, CEA tests, and colonoscopy use from start of surveillance.
In patients who survived 3 years, the overall compliance with guidelines was 25.1%. In patients seen regularly by a medical oncologist, compliance with guidelines increased to 61.5% compared with 8.8% for those not seen by a medical oncologist regularly (P < .0001). The use of abdominal CTand PET/PET-CT increased from 57.5% and 9.5%, respectively, in 2001 to 65.8% and 24.6% (P <.0001) in 2006. Patients who saw a medical oncologist were more likely to get cross-sectionalimagingthan those whodid not (P <.0001).
Compliance with current minimum guidelines for post treatment surveillance of colorectal cancer is low and the use of nonrecommended testing has increased over time. Both compliance and use of nonrecommended tests are markedly increased in patients seen by a medical oncologist. The comparative effectiveness of CT and PET/PET-CT in the surveillance of colorectal cancer patients needs further examination.
Intracranial hypertension frequently complicates severe traumatic brain injury (TBI) and may be associated with poor outcomes. TBI induces a neuroinflammatory response by microglial activation and upregulation of proinflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α,) and interleukin-6 (IL-6). To elucidate the effect of elevated intracranial pressure on microglial function, we studied the effects of increased extracellular pressure on primary human microglial cell phagocytosis, proliferation, cytokine secretion and total nitrate production. In addition, since many patients receive propofol during anesthesia or intensive care unit sedation, we evaluated whether propofol alters the effects of pressure.
Human microglial cells (HMG030) were pretreated with (2.5–20μg/ml) propofol or intralipid as a vehicle control were incubated at ambient atmospheric pressure or at 15 or 30 mmHg increased pressure for 2 hours for phagocytosis assays or 24 hours for proliferation, cytokine secretion and total nitrate production studies. Phagocytosis was determined by incorporation of intracellular fluorescent latex beads. TNF-α, IL1-β and IL-6 were assayed by sandwich ELISA, and total nitrate by Greiss reagent.
Increased extracellular pressure stimulated phagocytosis vs. untreated microglial cells or cells treated with an intralipid vehicle control. In fact, propofol also stimulated microglial phagocytosis at ambient pressure. However, increased pressure reduced phagocytosis in the presence of propofol. Pressure also increased microglial TNF-α and IL-1β secretion and propofol pretreatment blocked the pressure-stimulated effect. However, IL-6 production was not altered either by pressure or propofol. Pressure also induced total nitrate secretion and propofol pretreatment decreased basal as well as pressure-induced microglial nitrate production.
Extracellular pressures consistent with increased intracranial pressure after head injury activate inflammatory signals in human primary microglial cells in vitro, stimulating phagocytosis, proliferation, and TNF-α, IL-1β, and total nitrate secretion but not affecting IL-6. Such inflammatory events may contribute to the worsened prognosis of traumatic brain injury after increased intracranial pressure. Since propofol alleviated these potentially pro-inflammatory effects, these results raise the possibility that the inflammatory cascade activated by intracranial pressure may be targeted by propofol in patients with increased intracranial pressure after TBI.
traumatic brain injury; microglia; phagocytosis; proliferation; cytokines; extracellular pressure
Cell migration is an integral component of intimal hyperplasia development and proteases are pivotal components in the process. Cell migration in response to urokinase is mediated through the aminoterminal domain (ATF) of the protein. This study examines the role of NAD(P)H oxidase during EGFR transactivation by ATF in human vascular smooth muscle cells (VSMC).
Human VSMCs were cultured in vitro. Linear wound and Boyden microchemotaxis assays of migration in response to ATF were performed in the presence and absence of NAD(P)H oxidase inhibitors (DPI and apocynin) and siRNA to Nox1. Additional assays were performed to examine the upstream pathways that lead to NAD(P)H oxidase activity. Assays were also performed for EGFR activation.
ATF produced concentration-dependent VSMC migration, which was inhibited by increasing concentrations of DPI and apocynin. ATF was shown to induce time-dependent EGFR phosphorylation, which peaked at 4-fold greater than control. This response was inhibited by DPI and apocynin in a concentration-dependent manner. ATF induced a concentration-dependent increase in intracellular oxygen free radical species, which was mitigated by the presence of DPI and apocynin. Inhibition of Gβγ by βARKCT reduced both NAD(P)H oxidase activity and EGFR activation. Inhibition of rac, which allows the NAD(P)H complex to assemble on the membrane, and inhibition of src, which induces assembly of the complex, both reduced ATF-dependent NAD(P)H oxidase activity and EGFR phosphorylation. siRNA to Nox1 prevented ATF-mediated EGFR activation and cell migration.
ATF requires NAD(P)H oxidase activity through a Gβγ, rac and src-mediated pathway to facilitate transactivation of EGFR and VSMC migration.
uPA; growth factor domain; NAD(P)H Oxidase; migration; cell signaling; human coronary smooth muscle cell
Splenic preservation (SP) during distal pancreatectomy can be accomplished by ligating the main splenic artery and vein relying on blood supply from the short gastric vessels. The purpose of this study was to examine the short-term implications of this operation, comparing it to the outcomes following distal pancreatectomy with splenectomy.
The records of 259 patients who underwent distal pancreatectomy with and without SP at Massachusetts General Hospital from 1994 to 2004 were reviewed.
A total of 29% of patients underwent SP with this technique. These patients were more likely to be women (74% vs 56%, P = .008) and to have benign disease (93% vs 54%, P < .0001). Their operative times were shorter (2.5 vs 3.1 h, P < .0001), they had less blood loss (300 vs 500 ml, P < .0001) and a shorter duration of stay (6 days [interquartile range, 5 to 7] vs 7 days [interquartile range, 5 to 8], P = .001). SP was not a significant predictor of complications in either univariate (P = .445) or adjusted analysis (P = .543). One patient (1.4%) in the SP group was reoperated for splenic infarction and two patients (1.1%) in the splenectomy group for abscess and hemorrhage. There were 2 (0.8%) postoperative deaths, both in the splenectomy group.
Splenic preservation relying on blood supply from the short gastric vessels is reliable and safe and does not have a higher incidence of postoperative complications when compared to traditional distal pancreatectomy with splenectomy. The current series validates this approach and provides further evidence of its feasibility and safety.
Pancreatic cancer is the fourth-leading cause of death in the United States and one of the most aggressive known malignancies. New and innovative advances in treatment are desperately needed. One promising area of investigational treatment for pancreatic cancer involves the use of immunotherapy. The development of immunotherapy for pancreatic cancer has been hampered by difficulty in generating tumor-reactive lymphocytes from resected specimens and by a lack of appropriate target antigens expressed on tumor cells. Innovative strategies have been developed with the use of peripheral blood lymphocytes that are genetically engineered to express T-cell receptors targeting common tumor antigens, including cancer-testis antigens, such as the MAGE-A3 antigen. Cancer-testis antigens pose excellent targets for immunotherapy because they are expressed in cancer and in the testis, an immune-privileged site, but have limited expression in normal tissue. An additional advantage in targeting cancer-testis antigens for immunotherapy is that their expression can be selectively up-regulated in tumor cells via epigenetic regulation with chromatin remodeling agents. Current interest in targeting cancer-testis antigens in pancreatic cancer is well-founded because cancer-testis antigens have been shown to be expressed in pancreatic cancer as potential targets for therapy. In our studies, we validated the expression pattern of cancer-testis antigens in resected specimens of pancreatic cancer and tested the hypothesis that treatment of pancreatic cancer cells with chromatin remodeling agents would render them more sensitive to antigen-specific T lymphocytes. We focused predominately on the MAGE-A3 antigen because it is highly expressed in pancreatic cancer, and several immunotherapeutic strategies are in clinical trials targeting this specific antigen. The results of these studies have important translational implications and provide the rationale for combined treatment with chromatin remodeling agents and immunotherapeutic approaches for pancreatic cancer.
Developmental genes are known to regulate cell proliferation, migration, and differentiation; thus, it comes as no surprise that the misregulation of developmental genes plays an important role in the biology of human cancers. One such pathway that has received an increasing amount of attention for its function in carcinogenesis is the Hedgehog (Hh) pathway. Initially the domain of developmental biologists, the Hh pathway and one of its ligands, Sonic Hedgehog (Shh), have been shown to play an important role in body planning and organ development, particularly in the foregut endoderm. Their importance in human disease became known to cancer biologists when germline mutations that resulted in the unregulated activity of the Hh pathway were found to cause basal cell carcinoma and medulloblastoma. Since then, misexpression of the Hh pathway has been shown to play an important role in many other cancers, including those of the pancreas. In many institutions, investigators are targeting misexpression of the Hh pathway in clinical trials, but there is still much fundamental knowledge to be gained about this pathway that can shape its clinical utility. This review will outline the evolution of our understanding of this pathway as it relates to the pancreas, as well as how the Hh pathway came to be a high-priority target for treatment.
Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology.
Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival.
Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins.
Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient’s prognosis.
Since Allen O. Whipple published his seminal paper in 1935, the procedure that bears his name has been performed widely throughout the world and is now a common operation in major medical centers. The goal of this study was to investigate the evolution of pancreatoduodenectomy at the Massachusetts General Hospital (MGH).
We sought to identify all pancreatoduodenectomies performed at the MGH since 1935. Cases were obtained from a computerized database, hospital medical records, and the MGH historical archive. Demographics, diagnosis, intraoperative variables and short-term surgical outcomes were recorded.
The first pancreatoduodenectomy at the MGH was carried out in 1941; since then, 2,050 Whipple procedures have been performed. Pancreatic ductal adenocarcinoma was the most frequent indication (36%). Pylorus preservation has been the most important variation in technique, accounting for 45% of Whipple procedures in the 1980s; observation of frequent delayed gastric emptying after this procedure led to decline in its use. Pancreatic fistula was the most frequent complication (13%). Operative blood replacement and reoperation rates have decreased markedly over time; the most frequent indication for reoperation was intra-abdominal bleeding. Mortality has decreased from 45% to 0.8%, with sepsis and hypovolemic shock being the most frequent causes of death. Mean duration of hospital stay has decreased from >30 to 9.5 days, along with an increasing readmission rate (currently 19%).
The Whipple procedure in the 21st century is a well-established operation. Improvements in operative technique and perioperative care have contributed in making it a safe operation that continues evolving.
The objective of this study was to identify trends in the diagnosis and treatment of cystic neoplasms of the pancreas using a retrospective review of patients from a surgical database at an academic referral center during a 33-year period.
Patient characteristics, including demographics, pathology, and survival, were analyzed over 5 time periods between 1978 and 2011.
A total of 851 consecutive patients underwent resection for a cystic neoplasm of the pancreas during a 33-year period. Sixty-five percent of patients were female, and mean age was 60 years. The most common pathologic diagnoses were intraductal papillary mucinous neoplasm (38%), mucinous cystic neoplasm (23%), serous cystadenoma (16%), and cystic neuroendocrine neoplasm (7%). There was a stepwise increase in the number of resections across time periods (67 between 1978 and 1989; 376 between 2005 and 2011), with a parallel increase in the proportion of incidentally discovered lesions (22% to 50%). Diagnosis of intraductal papillary mucinous neoplasm was very uncommon in the first 2 time periods (before the first recognition of intraductal papillary mucinous neoplasm as a distinct entity) but predominated in the last 2 (41% and 49%), and cystic neuroendocrine neoplasms, which constituted 3% of the cystic neoplasms in the first time-period, now comprise more than 8% of pancreatic cystic neoplasms. The proportion of malignant neoplasms decreased over time (41% between 1978 and 1989; 12% between 2005 and 2011), reflecting probably the earlier diagnosis and treatment of premalignant neoplasms. Although operative mortality was minimal (4/849, 0.5%), the postoperative complication rate was 38%. Overall 5-year survival for all mucinous lesions was 87%.
Cystic neoplasms of the pancreas are being diagnosed and treated with increasing frequency. At present, most are incidentally discovered intraductal papillary mucinous neoplasms. (Surgery 2012;152:S4–12.)
Malignant bowel obstruction is a common result of end-stage abdominal cancer that is a treatment dilemma for many physicians. Little has been reported predicting outcomes or determining the role of surgical intervention. We sought to review our experience with surgical and nonsurgical management of malignant bowel obstruction to identify predictors of 30-day mortality and of who would most likely benefit from surgical intervention.
A chart review of 523 patients treated between 2000 and 2007 with malignant bowel obstruction were evaluated for factors present at admission to determine return to oral intake, 30-day mortality, and overall survival. Propensity score matching was used to homogenize patients treated with and without surgery to identify those who would benefit most from operative intervention.
Radiographic evidence of large bowel obstruction was predictive of return to oral intake. Hypoalbuminemia and radiographic evidence of ascites or carcinomatosis were all predictive of increased 30-day mortality and overall survival. A nomogram of 5 identified risk factors correlated with increased 30-day mortality independent of therapy. Patients with large bowel or partial small bowel obstruction benefited most from surgery. A second nomogram was created from 4 identified risk factors that revealed which patients with complete small bowel obstruction might benefit from surgery.
Two nomograms were created that may guide decisions in the care of patients with malignant bowel obstruction. These nomograms are able to predict 30-day mortality and who may benefit from surgery for small bowel obstruction.
Computed Tomography (CT) has become an essential tool in the assessment of the stable trauma patient. Intravenous (IV) contrast is commonly relied upon to provide superior image quality, particularly for solid organ injury. However, a significant proportion of injured patients have contraindications to IV contrast. Little information exists concerning the repercussions of CT imaging without IV contrast specifically for splenic injury.
We performed a retrospective analysis using data from our trauma registry and chart review as part of a quality improvement project at our institution. All patients with splenic injury, over a 3 year period (2008–2010), where a CT of the abdomen without IV contrast (DRY) early during their admission were selected. All splenic injuries had to have been verified with abdominal CT imaging with IV contrast (CONTRAST) or via intraoperative findings. DRY images were independently read by a single, blinded, radiologist and assessed for parenchymal injury or ‘suspicious’ splenic injury findings and compared with CONTRAST imaging results or intraoperative findings.
Over the time period of the study 319 patients had documented splenic injury with 44 (14%) patients undergoing DRY imaging which was also verified by CONTRAST imaging or operative findings. Splenic parenchymal injury was only visualized in 38% of patients DRY patients. ‘Suspicious’ splenic injury radiographic findings were common. When these less specific findings for splenic injury were incorporated in the radiographic assessment, DRY imaging had over a 93% sensitivity for detecting splenic injury.
DRY imaging is increasingly being performed post-injury and has a low sensitivity in detecting splenic parenchymal injury. However, less specific radiographic findings suspicious for splenic injury in combination provide high sensitivity for splenic injury detection. These results suggest CONTRAST imaging is preferred to detect splenic injury, however, in those patients who have contraindications to IV contrast, DRY imagining may be able to select those who require close monitoring or intervention.
Adoptive immunotherapy for patients with metastatic melanoma has yielded encouraging results. However, methods to expand melanoma-specific T-cells from Stage III are limited. The objective of this study is to determine whether melanoma-specific T-cells could be generated from the melanoma-draining lymph nodes (MDLN) of Stage III patients.
Stage III patients undergoing completion lymphadenectomy were enrolled onto an IRB-approved protocol. MDLN cells were tested for ability to undergo cryopreservation, expand ex vivo in IL-2 or IL-2 and IL-7 and mediate melanoma-specific antitumor responses in vitro.
Cryopreservation produced no significant differences from fresh cultures in terms of cell growth and cellular phenotype. IL-2 and IL-2/IL-7 cultures resulted in similar growth rates, and functional studies revealed the presence of T cells which secreted interferon gamma in response to melanoma antigen peptides. Both IL-2 and IL-2/IL-7 cultured MDLN cells mediated significant apoptosis of human melanoma cell lines as compared to breast and brain tumor lines in vitro. Overall there did not seem to be a benefit of adding IL-7. Both CD4+ and CD8+ T-cells appear to mediate tumor cell apoptosis.
This study demonstrates that melanoma antigen-specific T-cells can be generated from regional melanoma-draining lymph nodes and expanded ex vivo from patients with Stage III disease.
We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, significantly improves survival in a rodent model of lipopolysaccharide (LPS)-induced endotoxic shock. However, the precise mechanisms have not been well defined. The aim of this study was to investigate the impact of SAHA treatment on gene expression profiles at an early stage of shock.
Male C57B1/6J mice were treated with or without SAHA (50 mg/kg, i.p), followed by a lethal dose of LPS (20 mg/kg, i.p) and a second dose of SAHA. Lungs of the animals (LPS and SAHA+LPS groups, n=3/group) were harvested 3 hours post-LPS insult. Sham mice (no LPS and no SAHA) served as controls. RNA was isolated from the tissues and gene expression was analyzed using Affymatrix microarray (23,000 genes). A lower confidence bound (LCB) of fold change was determined for comparison of LPS vs. SAHA+LPS, and genes with LCB >2 were considered to be differentially expressed. RT-PCR, western blotting and tissue staining were performed to verify the key changes. Network graphs were used to determine gene interaction, and biological relevance.
The expression of many genes known to be involved in septic pathophysiology changed after the LPS insult. Interestingly, a number of genes not previously implicated in the septic response were also altered. SAHA treatment attenuated expression of several key genes involved in inflammation. It also reduced neutrophil infiltration in lungs and histological evidence of acute lung injury. Further analysis confirmed genes engaged in the cellular and humoral arms of innate immune system that were specifically inhibited by SAHA. Gene network analysis identified numerous molecules for the potential development of targeted therapies.
Administration of SAHA in a rodent model of LPS shock rapidly modulates gene transcription, with an attenuation of inflammatory mediators derived from both arms (cellular and humoral) of the innate immune system. This may be a novel mechanism responsible for the survival advantage seen with SAHA treatment.
Endotoxic shock; microarray; immune; inflammation; suberoylanilide hydroxamic acid; lung
In the treatment of burns, patients’ own skin is the preferred material to cover burn wounds, resulting in the need to create a donor site wound. Enhancement of healing of the donor site wound would be beneficial in burn patients. Insulin, an anabolic agent, is routinely used to treat hyperglycemia after injury. We investigated whether intensive insulin treatment (INS) increases fractional synthesis rate (FSR) of the donor site wound protein and decreases the length of hospitalization normalized for total body surface area burned (LOS/TBSA).
FSR of the donor site wound protein was measured in pediatric patients randomized to control (CNT) (n = 13) and INS (n = 10) treatments. Depending on the postoperative day when the tracer study was done studies were divided into “Early” (days < 5) and “Late” (days >=5) periods.
FSR of the donor site wound protein was greater in the INS group at the “Early” period of wound healing (CNT vs. INS, 8.2±3.8 vs. 13.1±6.9 %/day, p: < 0.05); but not at the “Late” (CNT vs. INS, 19.7±4.6 vs. 16.6±4.0 %/day, p > 0.05). Despite these differences LOS/TBSA was not decreased in the INS group. Correlation analyses demonstrated that independently of the treatment regimen FSR positively correlated (p < 0.05) with time post creation of the donor site and negatively correlated (p < 0.05) with LOS/TBSA.
Insulin treatment increased FSR of the donor site wound protein in the early period of wound healing; FSR correlated with LOS/TBSA independently of the treatment regimen.
Burn; insulin treatment; donor site wound; protein synthesis; stable isotopes
While cellular therapy has shown promise in the management of traumatic brain injury (TBI), microenvironment interactions between the intracerebral milieu and therapeutic stem cells are poorly understood. We sought to characterize the acute, regional inflammatory response after TBI.
Rats underwent a controlled cortical impact (CCI) injury or sham injury, were sacrificed at 6, 12, 24, 48, and 72 hours, and intracerebral fluid (IF) was isolated from the direct injury, penumbral, ipsilateral frontal, contralateral regions. Cortical and hippocampal areas were also isolated. Regional cytokine levels were measured. PMN oxidative burst and marker expression were assessed after incubation with the IF. Immunohistochemistry identified intracerebral CD68+ cells (microglia/macrophages).
The pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α were significantly elevated after CCI in the injury and penumbral regions. Increases in the same cytokines were localized to the cortex and the hippocampus. Increased PMN expression of CD11b and L-selectin was identified after incubation with injury or penumbral area IF, without change in PMN oxidative burst. CD68+ cells were noted in the direct injury and penumbral areas.
The local cerebral milieu in the first 48 hrs after TBI is highly pro-inflammatory. This response is most pronounced in areas at or proximal to the direct injury. The local, acute pro-inflammatory response after TBI may serve as a therapeutic target of early cell therapy or, conversely, may create an unfavorable local milieu, limiting the efficacy of early cellular therapy.
Traumatic brain injury; inflammation; cellular therapy; cytokine
We hypothesized that IL-12 would enhance the anti-tumor activity of the anti-HER1 antibody cetuximab against squamous cell carcinomas of the head and neck (SCCHN) by activating the FcR effector mechanisms of NK cells. All cell lines showed high expression of HER1 by flow cytometry and immunoblot analysis. NK cell lysis of cetuximab-coated SCCHN cell lines was markedly enhanced by 12 hr pre-treatment of NK cells with IL-12 (p=0.005 vs. cetuximab). Similar levels of lysis were noted for both HPV-positive and HPV-negative cell lines. Other NK cell-activating factors such as IL-2, IL-15 and IL-21 also enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). The stimulus of IL-12 and cetuximab-coated tumor cells induced synergistic production of nanogram levels of interferon-gamma (IFN-γ; >6-fold increase over controls) (p<0.001). A similar effect was seen for NK cell production of the chemokines MIP-1α, RANTES and IL-8. Phosphorylation of ERK (critical for FcR functions) was enhanced in NK cells costimulated with cetuximab and IL-12 compared to controls. Cytokine stimulation of NK cells in the presence of cetuximab-coated SCCHN cells leads to enhanced NK cell-mediated ADCC and cytokine secretion independent of tumor cell HPV-status. Cytokine administration could be a useful adjuvant in the cetuximab treatment of HER1-positive head and neck cancer.
Cetuximab; NK cells; Interleukin-2; Interleukin-12; Interleukin-15; Interleukin-211
Use of neoadjuvant chemotherapy for breast cancer is increasing. The objective was to examine risk of post-operative wound complications in patients receiving neoadjuvant chemotherapy for breast cancer.
Patients undergoing breast surgery from 2005–2010 were selected from the American College of Surgeons National Surgical Quality Improvement Program database. Patients were included if pre-operative diagnosis suggested malignancy and an axillary procedure was performed. A stepwise multivariable regression analysis of predictors of post-operative wound complications, overall and stratified by breast surgery type, was performed. Our primary variable of interest was receipt of neoadjuvant chemotherapy.
Of 44,533 patients, 4.5% received neoadjuvant chemotherapy. Wound complications were infrequent with or without neoadjuvant chemotherapy (3.4% vs. 3.1%, p= 0.4). Smoking, functional dependence, obesity, diabetes, hypertension and mastectomy were associated with wound complications. No association with neoadjuvant chemotherapy was seen (OR 1.01 [CI 0.78–1.32]). However, a trend towards increased complications in neoadjuvant patients undergoing mastectomy with immediate reconstruction (OR 1.58 [CI 0.98–2.58]) was observed.
Breast post-operative wound complications are infrequent and not associated with neoadjuvant chemotherapy. However, given the trend towards increased complications in patients undergoing mastectomy with immediate reconstruction, neoadjuvant chemotherapy should be one of many factors considered when making multidisciplinary treatment decisions.
breast cancer; neoadjuvant chemotherapy; post-operative complications; wound infection
Necrotizing enterocolitis (NEC) is a leading cause of infant mortality and the most common reason for emergent surgery in very low birth weight (VLBW, <1500g) infants. We investigated whether transfer for higher level of surgical care affects mortality in this population.
VLBW infants who underwent NEC surgery were retrospectively reviewed from the California Patient Discharge Linked Birth Cohort Database (1999–2007). Transfer for emergent surgery was defined as surgery ≤2d after transfer. Mortality was analyzed with multivariate logistic regression.
Overall, 1,272 VLBW infants with surgical NEC were identified with a 39% mortality. Transfer for surgery occurred in 406 (32%) infants. Unadjusted mortality was not increased for infants transferred versus not transferred, 37% vs. 40% (p=0.25). Adjusted mortality for infants transferred for surgery did not differ from those who received surgery at their primary NICU (OR 0.75, 95% CI 0.42–1.32). Lower birth weight, lack of prenatal care, peritoneal drainage as sole surgical intervention, and pulmonary interstitial emphysema/pulmonary hemorrhage were associated with increased odds of mortality (p<0.05).
VLBW infants with surgical NEC do not demonstrate increased risk of mortality when transferred emergently for surgery. Future efforts must engage health professionals caring for this vulnerable population in order to maximize resource allocation and safety.
Pancreatic adenocarcinoma is an aggressive malignancy. Oncolytic Ads are genetically modified to target tumor cells while sparing normal cells. We modified the knob domain of the adenovirus (Ad) serotype 5 with a serotype 3 knob domain and incorporated the CXCR4 promoter to regulate Ad E1A gene expression (Ad5/3-CXCR4-E1A). These modifications were made to efficiently infect and lyse pancreatic tumors.
Human pancreatic cancer lines CFPAC-1, PANC-1, AsPC-1, and BxPC-3 were obtained from ATCC. Efficiency of Ad infection in the cells was determined using an Ad construct expressing the green fluorescence protein (GFP) marker in place of the E1A gene (Ad5/3-CXCR4-GFP) and quantified by flow cytometry. Oncolytic activity in the pancreatic cancer cells was determined using the Ad5/3-CXCR4-E1A oncolytic Ad by a crystal violet staining method. To determine the oncolytic effect in vivo, pancreatic cancer cells were implanted on the flanks of 40 SCID mice (4 groups). Tumors were injected intratumorally for 3 days with Ad5/3-CXCR4-E1A, Ad5 wild-type (a positive control), or phosphate buffered saline (a no virus control). Tumor size, overall survival and body condition scale (BCS) were recorded. Statistical analyses included the Kaplan-Meier survival curve, the log-rank test, and ANOVA 1-way.
The serotype 3 fiber-modified Ad with the CXCR4 promoter (Ad5/3-CXCR4-E1A) was most efficient in infecting and lysing pancreatic cancer cells compared with an Ad containing an unmodified fiber knob (Ad5-CXCR4-E1A). Treatment of pancreatic tumor xenografts in vivo with Ad5/3-CXCR4-E1A group resulted in significantly smaller tumors (p = 0.001), higher BCS (p = 0.01), and longer survival time (p = 0.04) than the other treatment groups.
Ad5/3-CXCR4-E1A treatment significantly prolonged survival in SCID mice pancreatic tumor xenografts. This novel construct represents a potential new therapy against pancreatic cancer.
Ad5/3; adenovirus; chemokine receptor; CXCR4; oncolytic virus; fiber chimera; pancreatic adenocarcinoma; serotype; virotherapy