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Selective enrichment process of CAR- and CAR+ transgenic sub-populations

Consolidated supplementary tables for nanostring data

BACKGROUND Radiographic assessment of esophageal growth in long-gap esophageal atresia while on traction and associated traction-related complications have not been described. OBJECTIVE To demonstrate how chest radiography can estimate esophageal position while on traction and to evaluate radiography's utility in diagnosing certain traction system complications. MATERIALS AND METHODS In this retrospective evaluation of portable chest radiographs obtained in infants with long-gap esophageal atresia who underwent the Foker process between 2014 and 2020, we assessed distances between the opposing trailing clips (esophageal gap) and the leading and trailing clips for each esophageal segment on serial radiographs. Growth during traction was estimated using longitudinal random-effects regression analysis to account for multiple chest radiograph measurements from the same child. RESULTS Forty-three infants (25 male) had a median esophageal gap of 4.5 cm. Median traction time was 14 days. Median daily radiographic esophageal growth rate for both segments was 2.2 mm and median cumulative growth was 23.6 mm. Traction-related complications occurred in 13 (30%) children with median time of 8 days from traction initiation. Daily change >12% in leading-to trailing clip distance demonstrated 86% sensitivity and 92% specificity for indicating traction-related complications (area under the curve [AUC] 0.853). Cumulative change >30% in leading- to trailing-clip distance during traction was 85% sensitive and 85% specific for indicating traction complications (AUC 0.874). CONCLUSION Portable chest radiograph measurements can serve as a quantitative surrogate for esophageal segment position in long-gap esophageal atresia. An increase of >12% between two sequential chest radiographs or >30% increase over the traction period in leading- to trailing-clip distance is highly associated with traction system complications.

Esophageal atresia with or without tracheoesophageal fistula and tracheobronchomalacia encompass 2 of the most common complex congenital intrathoracic anomalies. Tailoring interventions to address the constellation of problems present in each patient is essential. Due to advances in neonatology, anesthesia, pulmonary, gastroenterology, nutrition and surgery care for patients with complex congenital tracheoesophageal disorders has improved dramatically. Treatment strategies tailored to the individual patient needs are best implimented under the aegis of a comprehensive longitudinal multidisciplinary care team.

Indocyanine green (ICG) is commonly used to assess perfusion, but quality defining features are lacking. We sought to establish qualitative features of esophageal ICG perfusion assessments, and develop an esophageal anastomotic scorecard to risk-stratify anastomotic outcomes.Single institution, retrospective analysis of children with an intraoperative ICG perfusion assessment of an esophageal anastomosis. Qualitative perfusion features were defined and a perfusion score developed. Associations between perfusion and clinical features with poor anastomotic outcomes (PAO, leak or refractory stricture) were evaluated with logistic and time-to-event analyses. Combining significant features, we developed and tested an esophageal anastomotic scorecard to stratify PAO risk.From 2019 to 2021, 53 children (median age 7.4 months) underwent 55 esophageal anastomoses. Median (IQR) follow-up was 14 (10-19.9) months; mean (SD) perfusion score was 13.2 (3.4). Fifteen (27.3%) anastomoses experienced a PAO and had significantly lower mean perfusion scores (11.3 (3.3) vs 14.0 (3.2), p = 0.007). Unique ICG perfusion features, severe tension, and primary or rescue traction-induced esophageal lengthening [Foker] procedures were significantly associated with PAO on both logistic and Cox regression. The scorecard (range 0-7) included any Foker (+2), severe tension (+1), no arborization on either segment (+1), suture line hypoperfusiontwice expected width (+2), and segmental or global areas of hypoperfusion (+1). A scorecard cut-off3 yielded a sensitivity of 73% and specificity of 93% (AUC 0.878 [95%CI 0.777 to 0.978]) in identifying a PAO.A scoring system comprised of qualitative ICG perfusion features, tissue quality, and anastomotic tension can help risk-stratify esophageal anastomotic outcomes accurately.Diagnostic - II.

Addition of en bloc segmental venous reconstruction (VR) to pancreaticoduodenectomy (PD) for venous involvement of pancreatic tumors increases the complexity of the operation and may increase complications. The long-term mesenteric venous patency rate and oncologic outcome has not been well defined.Our prospective database was reviewed to assess 90-day postoperative outcomes for patients who underwent PD or PD + VR (September 2004-June 2016). Two independent observers reviewed CT scans to determine long-term vein patency. In patients with pancreatic ductal adenocarcinoma, the impact of VR on 5-year overall survival was assessed using multivariate Cox proportional hazards regression. Student's t-test was used to evaluate continuous variables and the chi-square test for categorical variables.Three hundred ninety-three patients underwent PD (51 PD + VR). Patients undergoing PD + VR had longer operations (561 ± 119 versus 433 ± 89 min, P 0.00001) and greater blood loss (768 ± 812 versus 327 ± 423 cc, P 0.00001). There was no difference in 90-day mortality, overall postoperative complication rates, complication severity grades, reoperation, readmission, or length of stay. 26.7% experienced venous thrombosis. Most thromboses occurred in the first year after surgery, but we also observed late thrombosis in 1 patient after 89-month follow-up. Among 135 patients with pancreatic ductal adenocarcinoma, survival was significantly longer in the PD-alone group (31.3 months [95% confidence interval: 22.9-40.0] versus 17.0 [95% confidence interval: 13.0-19.1], pPD + VR does not increase short-term morbidity, but venous thrombosis is frequent and can occur long after surgery. Survival is inferior when VR is required especially in the absence of neoadjuvant chemotherapy.

Many pancreatic surgeons continue to use intraperitoneal drains, but others have limited or avoided their use, believing this improves outcomes. We conducted a systematic review and meta-analysis of the literature assessing outcomes in pancreatectomy without drains, selective drainage, and early drain removal. We searched PubMed, Embase, and the Cochrane Library databases and conducted a systematic review of randomized and nonrandomized studies comparing routine intra-abdominal drainage versus no drainage, selective drain use, and early versus late drain removal after pancreatectomy, with major complications as the primary outcome. A meta-analysis of the literature assessing routine use of drains was conducted using the random-effects model. A total of 461 articles met search criteria from PubMed (168 articles), Embase (263 articles), and the Cochrane Library (30 articles). After case reports and articles without primary data on complications were excluded, 14 studies were identified for systematic review. Definitive evidence-based recommendations cannot be made regarding the management of drains following pancreatectomy because of limitations in the available literature. Based on available evidence, the most conservative approach, pending further data, is routine placement of a drain and early removal unless the patient's clinical course or drain fluid amylase concentration suggests a developing fistula.

AIM To characterize incidence and risk factors for delayed gastric emptying (DGE) following pancreaticoduodenectomy and examine its implications on healthcare utilization. METHODS A prospectively-maintained database was reviewed. DGE was classified using International Study Group of Pancreatic Surgery criteria. Patients who developed DGE and those who did not were compared. RESULTS Two hundred and seventy-six patients underwent pancreaticoduodenectomy (PD) (> 80% pylorus-preserving, antecolic-reconstruction). DGE developed in 49 patients (17.8%): 5.1% grade B, 3.6% grade C. Demographic, clinical, and operative variables were similar between patients with DGE and those without. DGE patients were more likely to present multiple complications (32.6% vs 4.4%, ≥ 3 complications, P < 0.001), including postoperative pancreatic fistula (POPF) (42.9% vs 18.9%, P = 0.001) and intra-abdominal abscess (IAA) (16.3% vs 4.0%, P = 0.012). Patients with DGE had longer hospital stay (median, 12 d vs 7 d, P < 0.001) and were more likely to require transitional care upon discharge (24.5% vs 6.6%, P < 0.001). On multivariate analysis, predictors for DGE included POPF [OR = 3.39 (1.35-8.52), P = 0.009] and IAA [OR = 1.51 (1.03-2.22), P = 0.035]. CONCLUSION Although DGE occurred in < 20% of patients after PD, it was associated with increased healthcare utilization. Patients with POPF and IAA were at risk for DGE. Anticipating DGE can help individualize care and allocate resources to high-risk patients.

The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function. Thus, to protect our cells from the immunosuppressive cytokine IL-4, we generated an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL-4 and instead promote T cell proliferation. We now demonstrate the suppressed activity of CAR T cells in tumor-milieu conditions and the ability of CAR/ICR T cells to thrive in an IL-4-rich microenvironment, resulting in enhanced antitumor activity. Importantly, CAR/ICR T cells remained both antigen and cytokine dependent. These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.

Background Risk of progression to various stages of chronic kidney disease (CKD) after endovascular aortic aneurysm repair (EVAR) is unknown. This study estimates progression rates to stage 3 and 4 CKD after EVAR and identifies potential predictors for progression. Methods EVAR cases (2006–2012) were retrospectively reviewed. Freedom of progression to CKD was estimated using Kaplan–Meier analysis, and predictors for progression were identified using Cox proportional hazards model. Results Two hundred and twelve consecutive patients at a single academic institution underwent EVAR for infrarenal aneurysms. Estimated freedom from progression to stage 3 CKD was 80%, 76%, and 63% at 6, 12, and 18 months, respectively, and for stage 4, 97%, 96%, and 93% at 6, 12, and 18 months, respectively. Stage 3 CKD predictors of progression included age (odds ratio (OR): 1.106, p = 0.001), diabetes (OR: 3.052, p = 0.04), perioperative use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers (OR: 3.249, p = 0.02), and operative blood loss (OR: 1.002, p Conclusions Progression to stage 3 CKD after EVAR occurs more frequently and at a higher rate compared with progression to stage 4. Different risk factors are associated with progression to each of those stages of CKD.

The adoptive transfer of chimeric antigen receptor (CAR)–modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in “on-target, off-tumor” toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize prostate stem cell antigen, TGFβ, and IL4, and whose endodomains recapitulate physiologic T-cell signaling by providing signals for activation, costimulation, and cytokine support, produce potent antitumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g., PD-L1, IL10, and IL13). Significance: This proof-of-concept study demonstrates how sophisticated engineering approaches can be utilized to both enhance the antitumor efficacy and increase the safety profile of transgenic T cells by incorporating a combination of receptors that ensure that cells are active exclusively at the tumor site. Cancer Discov; 8(8); 972–87. ©2018 AACR. See related commentary by Achkova and Pule, p. 918. This article is highlighted in the In This Issue feature, p. 899

ObjectivesPancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. The incidence of pancreatic cancer in African Americans is 50% to 90% higher than the incidence in other racial groups. African Americans also have the worst prognosis. This is an evidence-based re

Patient-controlled analgesia (PCA) is often used in children with perforated appendicitis. To prevent urinary retention, some providers also routinely place Foley catheters. This study examines the necessity of this practice.We retrospectively reviewed all children (≤18 years old) with perforated appendicitis and postoperative PCA from 7/2015 to 6/2016 at two academic children's hospitals. Urinary retention was defined as the inability to spontaneously void requiring straight catheterization or placement of a Foley catheter.Of 313 patients who underwent appendectomy for perforated appendicitis (Hospital 1: 175, Hospital 2: 138), 129 patients received an intraoperative Foley (Hospital 1: 22 [13%], Hospital 2: 107 [78%], p 0.001). Age, gender, and BMI were similar between those with an intraoperative Foley and those without. There were no urinary tract infections in either group. Urinary retention rate in patients with an intraoperative Foley following removal on the inpatient unit (n = 3, 2%) and patients without an intraoperative Foley (n = 10, 5%) did not reach significance (p = 0.25). On univariate analysis, demographics, intraoperative findings, PCA specifics, postoperative abscess formation, and postoperative length of stay, were not significant risk factors for urinary retention.The risk of urinary retention in this population is low despite the use of PCA. Children with perforated appendicitis do not require routine Foley catheter placement to prevent urinary retention.II.

The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications.The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported.Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy.A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores.This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.

Sphincter preservation (SP) is an important goal of rectal cancer surgery. We hypothesized that SP rates among veteran patients have increased and are comparable to national rates, and that a subset of patients with early disease still undergo non-SP procedures.Patients with nonmetastatic primary rectal adenocarcinoma who underwent curative-intent rectal resection were identified from the Veterans Affairs Central Cancer Registry (VACCR) database (1995-2010). SP trends over time were described and compared to the Surveillance, Epidemiology, and End-Results (SEER) population. Subset analysis was performed in patients with nonirradiated, pathologic stage 0-I rectal cancers, a population that may qualify for novel SP strategies.Of 5,145 study patients, 3,509 (68 %) underwent SP surgery. The VACCR SP rate increased from 59.9 % in 1995-1999 to 79.3 % in 2005-2010, when it exceeded that of SEER (76.9 %, p = 0.023). On multivariate analysis, recent time period was independently associated with higher likelihood of SP (odds ratio [OR] 2.64, p0.001). Preoperative radiotherapy (OR 0.51, p0.001) and higher pathologic stage (OR 0.37, stage III, p0.001) were negative predictors. In patients with nonirradiated pathologic stage 0-I cancers, SP rates also increased, but 25 % of these patients underwent non-SP procedures. Within this subset, patients with clinical stage 0 and I disease still had significant rates of abdominoperineal resection (7.7 and 17.0 %, respectively).SP rates among veterans have increased and surpass national rates. However, an unacceptable proportion of patients with stage 0-I rectal cancers still undergo non-SP procedures. Multimodal treatment with local excision may further improve SP rates in this subset of patients.

BackgroundAlthough mortality following pancreaticoduodenectomy is decreasing, postoperative morbidity remains high. It was hypothesized that culture-directed treatment of bacteriobilia would decrease the incidence of infectious complications following pancreaticoduodenectomy.MethodsIn a retrospective study of 197 pancreaticoduodenectomy patients, those in the control group (n = 128, 2005–2009) were given perioperative prophylactic antibiotics, whereas those in the treatment group (n = 69, 2009–2011) were continued on antibiotics until intraoperative bile culture results became available. Patients with bacteriobilia received 10 days of antibiotic treatment, which was otherwise discontinued in patients without bacteriobilia. Various complication rates were compared using Fisher's exact test for categorical variables, Wilcoxon rank sum test for ordinal variables, and a two-sample t-test for continuous variables.ResultsDemographics, comorbidities, baseline clinical characteristics, and intraoperative and postoperative variables were similar between the two groups. There were higher incidences of elevated creatinine (19% versus 4%; P = 0.004) and preoperative hyperglycaemia (18% versus 7%; P = 0.053) in the control group. Fewer patients in the control group underwent preoperative biliary stenting (48% versus 67%; P = 0.017) and intraperitoneal drains were placed at the time of resection more frequently in the control group (85% versus 38%; P < 0.001). Bacteriobilia was found in 59% of patients. Treatment of bacteriobilia was associated with a decrease in the rate of postoperative wound infections (12% in the control group versus 3% in the treatment group; P = 0.036) and overall complication severity score (1 in the control group versus 0 in the treatment group; P = 0.027).ConclusionsProlonged antibiotic therapy for bacteriobilia may decrease postoperative wound infection rates after pancreaticoduodenectomy. A randomized prospective trial is warranted to provide evidence to further support this practice.

The success of adoptively transferred tumor-directed T cells requires them to survive and expand in vivo. Most tumors, however, employ immune evasion mechanisms, including the production of inhibitory cytokines that limit in vivo T-cell persistence and effector function. To protect tumor-directed T cells from such negative influences, we generated a chimeric cytokine receptor in which the interleukin (IL) 4 receptor exodomain was fused to the IL7 receptor endodomain. We thereby inverted the effects of tumor-derived IL4 so that the proliferation and activation of tumor directed cytotoxic T cells was enhanced rather than inhibited in the tumor microenvironment, resulting in superior antitumor activity. These transgenic T cells were only activated in the tumor environment since triggering required exposure to both tumor antigen (signal 1) and tumor-derived IL4 (signal 2). This selectivity supports future clinical adaptation.

OBJECTIVE: For patients with genetically triggered thoracic aortic disease, the morbidity and mortality associated with reoperation are high, making endovascular treatment an appealing option. We evaluated the short- and mid-term outcomes of different applications of endovascular intervention in such patients. METHODS: Between January 2003 and April 2013, 60 patients received endovascular or hybrid treatment for genetically triggered thoracic aortic disease. The inclusion criteria were based on those devised by the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. We included patients with thoracic aneurysm or dissection not due to trauma in a patient aged ≤50 years (n= 30), bicuspid aortic valve (BAV) and coarctation (n= 11), Marfan syndrome (n= 10), BAV with thoracic aneurysm (n= 4), Loeys–Dietz syndrome (n= 3), familial thoracic aneurysm or dissection (n= 3) and genetic mutations (n= 2). Some patients met more than one inclusion criterion. Forty-one (68.3%) patients were treated with only endovascular stent grafting. Nineteen (31.7%) patients underwent a hybrid procedure with open proximal or total arch replacement and concomitant endovascular stenting of the aortic arch or the descending thoracic aorta. Twenty-nine (48.3%) had previous cardiovascular operations (mean ± SD, 1.9 ± 1.4) before undergoing hybrid or endovascular therapy. The median follow-up was 2.3 years (interquartile interval 25–75%, 1.4–4.6 years). RESULTS: The technical success rate was 100%. In-hospital mortality was 3.3% (n= 2) and neurological events occurred in 2 patients; 1 (1.6%) had a stroke and 1 (1.6%) suffered paraparesis with partial recovery. Fifteen repeat open or endovascular interventions were required in 10 surviving patients (17.2%). Overall survival during follow-up was 94.8% (55/58). CONCLUSIONS: Endovascular technology can be helpful in treating selected young patients with genetically triggered thoracic aortic disease. Long-term studies and further evolution of endovascular technology will be necessary for it to be incorporated into the armamentarium of surgical options for this challenging patient population.

Objective To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. Background Some surgeons have abandoned the use of drains placed during pancreas resection. Methods We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. Results There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. Conclusions This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.

As the practice of pancreatic surgery evolves to encompass a wider array of clinical indications, incorporate increasingly complex technologies, and provide care to an aging population with many comorbid conditions, systematic assessment of quality and outcomes in an effort to improve the quality of care is imperative. This article discusses the volume-outcomes relationship that exists in pancreatic surgery, trends in centralization of practice within the field, common outcomes measures, and the complexity of assessing quality metrics. It also highlights surgical outcomes from several high-volume institutions and recent developments in quality metrics within pancreatic surgery.

Granulomatous mastitis (GM) is a rare, chronic, inflammatory condition of the breast with unknown etiology that affects women of child-bearing age. It can be mistaken radiographically and clinically for breast cancer and due to its rarity can cause a delay in establishing a definitive diagnosis and subsequent initiation of treatment. Furthermore, GM has a progressive clinical course with multiple recurrences. To date, there is no universally accepted treatment for GM. The goal of this study is to review the experience with granulomatous mastitis at a large inner-city public hospital over a 10-y period.A retrospective review of a prospectively maintained institutional database was queried for all patients with a histopathologic diagnosis of GM between July 1, 2000 and July 1, 2010. A separate database was created for these patients, and data was collected from electronic medical records and paper charts. Demographic, clinical, and outcomes data were analyzed using summary statistics.A total of 41 cases were identified. The median age at time of diagnosis was 34 y. Thirty-three (80%) patients were of Hispanic ethnicity. The most common physical findings were mass (n = 32, 78%), tenderness (n = 17, 41%), and erythema (n = 12, 29%). Three (7%) patients had a previous history of treatment for tuberculosis whereas 12 (29%) patients were human immunodeficiency virus-positive. Mammography and ultrasonography noted mass (n = 14, 34% and n = 15, 37%, respectively) as the most common radiographic finding. Core needle biopsy and incisional biopsy were used with equal frequency (n = 16, 37%) to establish a definitive pathologic diagnosis. The median number of days between onset of symptoms and definitive diagnosis was 73. Thirteen (32%) patients received antibiotics as initial treatment, whereas 23 (56%) underwent surgical procedures and 1 (2%) received steroid therapy. Steroids were used at any point in the clinical course of 7 (17%) patients, and none of these patients required definitive surgical treatment.GM affects women of childbearing age and typically presents as an inflamed breast mass with or without pain. The clinical features of GM among Hispanic patients are similar to those among other study populations in the reported literature. This disease is a diagnostic and therapeutic challenge and a high degree of clinical suspicion is warranted. Treatment with steroids may obviate the need for surgery in some patients. Reported recurrence rates for GM are high, and long-term follow-up is essential.

Perioperative transfusion of packed red blood cells (PRBC) has been associated with negative side effects. We hypothesized that a majority of transfusions in our series of patients who underwent pancreaticoduodenectomy (PD) were unnecessary. A retrospective analysis was performed to determine whether transfusions were indicated based on pre-determined criteria, and the impact of perioperative transfusions on postoperative outcomes was assessed.Our prospectively maintained database was queried for patients who underwent PD between 2004 and 2011. 200 patients were divided into Cohort 1 (no transfusion) and Cohort 2 (transfusion). Rates of various graded 90-day postoperative complications were compared. Categorical values were compared according to the Common Terminology Criteria for Adverse Events. All cases involving intraoperative blood transfusion were reviewed for associated blood loss, intraoperative vital signs, urine output, hemoglobin values, and presence or absence of EKG changes to determine whether the transfusion was indicated based on these criteria.There were 164 patients (82%) in Cohort 1 (no transfusion) and 36 patients (18%) in Cohort 2 (transfused). Both groups had similar demographics. Patients in Cohort 2 had lesser median preoperative values of hemoglobin (12.3 vs 13.1, P = .002), a greater incidence of vein resection (33% vs. 16%, P = .021), longer operative times (518 vs 440 minutes, P.0001), a greater estimated blood loss (850 vs. 300 mL, P.001), and greater intraoperative fluid resuscitation (6,550 vs. 5,300 mL, P = .002). Ninety-day mortality was similar between the 2 groups (3% vs 1%, P = .328). Patients in Cohort 2 (transfused) had increased rates of delayed gastric emptying (36% vs. 20%, P = .031), wound infection (28% vs. 7%, P = .031), pulmonary complications (6% vs. 0%, P = .032), and urinary retention (6% vs. 0%, P = .032). A greater incidence of any complication of grade II severity (67% vs. 35%, P = .0005) or grade III severity (36% vs. 17%, P = .010) was also noted in Cohort 2. Of the 33 intraoperative transfusions, 15 (46%) did not meet any of the predetermined criteria: intraoperative hypotension (90/60 mmHg), tachycardia (110 beats per minute), low urine output (10 mL/hour), decreased oxygen saturation (95%), excessive blood loss (1,000 mL), EKG changes, and low hemoglobin (7.0 g/dL).Perioperative transfusions among patients with PD were associated with increased rates of various postoperative complications. A substantive portion (∼46%) of perioperative transfusions in this patient population did not meet predetermined criteria, indicating a potential opportunity for improved blood product use. Further prospective studies are required to determine whether the implementation of these criteria may a positive impact on perioperative outcomes.

Adoptive transfer of T cells redirected to tumor-associated antigens (TAAs) by expression of chimeric antigen receptors (CARs) can produce tumor responses, even in patients with resistant malignancies. To target pancreatic ductal adenocarcinoma (PDAC), we generated T cells expressing a CAR directed to the TAA prostate stem cell antigen (PSCA). T cells expressing this CAR were able to kill PSCA(+) tumor cell lines CAPAN1 and K562-PSCA but not PSCA(-)293T cells (74±4%, 73±6% and 9±3% specific lysis, respectively, 10:1 E:T, n=3). Although these CAR-T cells had potent anti-tumor activity, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit in vivo CAR-T cell persistence and effector function. Indeed, when we examined the serum of patients with pancreatic cancer (n=8) we found the levels of the immunosuppressive cytokine IL4 to be elevated relative to patients with benign pancreatic disorders or normal healthy controls (14.25±19.48 pg/mL vs 7.28±9.03 vs 1.13±1.42 pg/mL). Thus, to protect our CAR-PSCA T cells from the negative influences of IL-4, we generated a chimeric cytokine receptor in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (IL4/7 ChR). Transgenic expression of this molecule in CAR-PSCA T cells can invert the inhibitory effects of tumor-derived IL4 to instead promote the proliferation of the effector CAR T cells. In preliminary experiments, we successfully co-expressed both CAR-PSCA and IL4/7 ChR (47.5±12.3% double-positive cells, n=4) on primary T cells. These T cells retained their tumor-specific activity (80±8% specific lysis against CAPAN1, 10:1 E:T, n=3) and when cultured in conditions that mimic the tumor milieu (IL4 12.5 ng/ml), CAR-PSCA 4/7R ChR-modified T cells continued to expand (increase from 2×10e6 cells on day 0 to 5.53±8.46×10e10 cells on day 28), unlike unmodified CAR-PSCA T cells which plateaued at 3.84±5.43×10e8 cells (n=4). Indeed, in the presence of IL4, transgenic cells had a selective advantage (comprising 44.8±11.0% of the population on day 0 and 87.6±10.0% on day 28; n=4). However, even after prolonged cytokine exposure these T cells remained both antigen- and cytokine-dependent. In conclusion, CAR-PSCA 4/7 ChR-modified tumor-specific T cells can effectively target pancreatic cancer cells and are equipped to expand, persist, and retain their cytotoxic function even in the presence of high levels of IL4 in the tumor microenvironment.

Adoptive transfer of T cells redirected to tumor-associated antigens (TAAs) by expression of chimeric antigen receptors (CARs) can produce tumor responses, even in patients with resistant malignancies. To target pancreatic ductal adenocarcinoma (PDAC), we generated T cells expressing a CAR directed to the TAA prostate stem cell antigen (PSCA). T cells expressing this CAR were able to kill PSCA(+) tumor cell lines CAPAN1 and K562-PSCA but not PSCA(-)293T cells (74±4%, 73±6% and 9±3% specific lysis, respectively, 10:1 E:T, n = 3). Although these CAR-T cells had potent anti-tumor activity, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit in vivo CAR-T cell persistence and effector function. Indeed, when we examined the serum of patients with pancreatic cancer (n = 8) we found the levels of the immunosuppressive cytokine IL4 to be elevated relative to patients with benign pancreatic disorders or normal healthy controls (14.25±19.48 pg/mL vs 7.28±9.03 vs 1.13±1.42 pg/mL). Thus, to protect our CAR-PSCA T cells from the negative influences of IL-4, we generated a chimeric cytokine receptor in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (IL4/7 ChR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL4 and instead promote the proliferation of the effector CAR T cells. In preliminary experiments we successfully co-expressed both CAR-PSCA and IL4/7 ChR (47.5±12.3% double-positive cells, n = 4) on primary T cells. These T cells retained their tumor-specific activity (80±8% specific lysis against CAPAN1, 10:1 E:T, n = 3) and when cultured in conditions that mimic the tumor milieu (IL4 12.5 ng/ml), CAR-PSCA 4/7R ChR-modified T cells continued to expand (increase from 2×10e6 cells on day 0 to 5.53±8.46×10e10 cells on day 28), unlike unmodified CAR-PSCA T cells which plateaued at 3.84±5.43×10e8 cells (n = 4). Indeed, in the presence of IL4, transgenic cells had a selective advantage (comprising 44.8±11.0% of the population on day 0 and 87.6±10.0% on day 28; n = 4). However, even after prolonged cytokine exposure these T cells remained both antigen- and cytokine-dependent. In conclusion, CAR-PSCA 4/7 ChR-modified tumor-specific T cells can effectively target pancreatic cancer cells and should be equipped to expand, persist, and retain their cytotoxic function even in the presence of high levels of IL4 in the tumor microenvironment. Citation Format: Somala Mohammed, Sujita Sukumaran, Pradip Bajgain, Usanarat Anurathapan, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera. Improving CAR T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4703. doi:10.1158/1538-7445.AM2015-4703

Background: Adoptive transfer of T cells redirected to tumor-associated antigens (TAAs) by expression of chimeric antigen receptors (CARs) can produce tumor responses, even in patients with resistant malignancies. Although these CAR-T cells have potent anti-tumor activity in vitro and in vivo, pancreatic tumors employ immune evasion mechanisms, such as the production of inhibitory cytokines, which limit in vivo CAR-T cell persistence and effector function. Methods: To target pancreatic ductal adenocarcinoma (PDAC), we generated T cells expressing a CAR directed to the TAA prostate stem cell antigen (PSCA). We also engineered a chimeric cytokine receptor in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (IL4/7 ChR). Expansion and selection profiles and short- and long-term anti-tumor activity of these transgenic T cells were assessed. Results: T cells expressing CAR-PSCA kill PSCA(+) tumor cell lines CAPAN1 and K562-PSCA but not PSCA(-) targets, such as 293T (74±4%, 73±6% and 9±3% specific lysis, respectively, 10:1 E:T, n=3). Although these CAR-T cells had potent anti-tumor activity in vitro and in vivo, pancreatic tumors employ immune evasion mechanisms, such as the production of inhibitory cytokines, which limit in vivo CAR-T cell persistence and effector function. Indeed, when the serum of patients with pancreatic cancer (n=8) was examined, we found the levels of the immunosuppressive cytokine IL4 to be elevated relative to patients with benign pancreatic disorders or normal healthy controls (14.25±19.48 pg/mL vs 7.28±9.03 vs 1.13±1.42 pg/mL). Thus, to protect the CAR-PSCA T cells from the negative influences of IL-4, we generated a chimeric cytokine receptor in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (IL4/7 ChR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL4 and instead promote the proliferation of the effector CAR T cells. In preliminary experiments we successfully co-expressed both CAR-PSCA and IL4/7 ChR (47.5±12.3% double-positive cells, n=4) on primary T cells. These T cells retained their tumor-specific activity (80±8% specific lysis against CAPAN1, 10:1 E:T, n=3) and when cultured in conditions that mimic the tumor milieu (IL4 12.5 ng/ml), CAR-PSCA 4/7R ChR-modified T cells continued to expand unlike unmodified CAR-PSCA T cells (from 2x106 cells on day 0 to 5.53x1010±8.46x1010 cells (CAR-PSCA 4/7R ChR) on day 28, in comparison to CAR-PSCA T cells that reached only 3.84x108±5.43x108 cells, n=4). Indeed, in the presence of IL4, transgenic cells had a selective advantage (comprising 44.8±11.0% of the population on day 0 and 87.6±10.0% on day 28, n=4), but even after prolonged cytokine exposure these T cells remained both antigen- and cytokine-dependent. Conclusions: CAR-PSCA 4/7 ChR-modified tumor-specific T cells can effectively target pancreatic cancer cells and should be equipped to expand, persist, and retain their cytotoxic function even in the presence of high levels of IL4 in the tumor microenvironment. Citation Format: Somala Mohammed, Sujita Sukumaran, Usanarat Anurathapan, Pradip Bajgain, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera. Improving CAR T cell function by reversing the immunosuppressive tumor environment of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B63.

Objective Local vancomycin treatment has been shown to decrease sternal wound complication rates. Whether a similar effect can be achieved at other surgical sites is unknown. This study investigates the effect of local vancomycin on inguinal wound complication rates after vascular procedures. Methods Retrospective analysis was performed on 454 patients who underwent open aortofemoral or infrainguinal vascular procedures between 2006 and 2011. Patients received preoperative systemic antibiotics either alone (group A) or in conjunction with intraoperative wound application of vancomycin powder and irrigation (group B). Inguinal wound infection and dehiscence over a 30-day period were recorded. Fisher exact test and multivariate regression analyses were performed. Results There were 211 patients in group A and 243 patients in group B. Both groups had similar demographics and operative characteristics. There was a small but statistically significant decrease in the 30-day incidence of overall wound infections (25.1% vs 17.2%; P = .049) for group B patients. This was primarily due to a decreased rate in superficial infections (18.9% vs 11.5%; P = .033). No significant difference in the incidence of deep wound infections (6.1% vs 5.7%; P = .692) or overall dehiscence rates (22.2% vs 17.7%; P = .239) was detected. On multivariate analysis, history of chronic obstructive pulmonary disease and increased body mass index significantly increased risk of both infection and dehiscence. Medically optimized coronary artery disease was associated with less risk for dehiscence. Conclusions Addition of intraoperative local vancomycin did not improve the rates of inguinal wound dehiscence or deep infections but had a positive impact on superficial wound infections.