Correlation Between Standardized Uptake Value in Preneoadjuvant and Postneoadjuvant Chemoradiotherapy and Tumor Regression Grade in Patients With Locally Advanced Esophageal Cancer.

PURPOSE: To investigate whether positron emission tomography/computed tomography (PET/CT) initial and restaging imaging predicts for pathologic response measured by tumor regression grade (TRG) after preoperative chemoradiotherapy (CRT) in patients with locally advanced esophageal cancer. METHODS: A retrospective review of 220 patients with stage II-III esophageal cancer treated with neoadjuvant CRT followed by surgery was performed. In total, 187 patients were eligible for statistical analysis. Pretreatment and posttreatment PET/CT scans were reviewed. Maximum standard uptake value (SUV) at the site of the primary tumor was recorded before and 6 weeks after neoadjuvant therapy. Upon completion of surgery, TRG was determined by a specialized site-specific gastrointestinal pathologist. Spearman correlation was used to compare pre, post, and change in maximum SUV, TRG, and overall survival. RESULTS: The median follow-up was 24 months. Although no significant correlation was found between pretreatment SUV and TRG (r=0.073, P=0.32), post-CRT SUV, however, showed a significant positive correlation with TRG (r=0.374, P<0.01). There was no significant correlation between the absolute change in fluorodeoxyglucose uptake after CRT and TRG (r=0.057, P=0.44); however, the rate of SUV change showed a significant correlation with TRG (r=0.178, P=0.017). Similar to previous studies, our study showed a significant difference in overall survival between TRG groups (log-rank test, P=0.019). Patients with TRG 3 showed prominently worse survival with median survival of 27.4 months. Patients with favorable pathologic responses were those whose scans demonstrated a metabolic response defined as a decrease in SUV≥70%. CONCLUSIONS: Changes in SUV uptake on PET/CT scans after CRT have prognostic value in predicting pathologic response of esophageal cancer after neoadjuvant therapy. Further studies are needed to validate the integration of PET/CT as a decision-making tool.

Immune checkpoint protein inhibition for cancer: preclinical justification for CTLA-4 and PD-1 blockade and new combinations.

Over the last two decades, our understanding of the molecular basis of immunity has revealed the complexity of regulatory pathways involved in immune responses to cancer. A significant body of data support the critical importance of immune checkpoints in the control of the adaptive immune response to malignancy, and suggest that inhibitors of those checkpoints might have significant utility in treating cancer. This has been borne out by the recent US Food and Drug Administration (FDA) approvals of two different antibodies, one against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and one against programmed death-1 (PD-1). Here, we provide a comprehensive review of the literature regarding the preclinical justification for the use of CTLA-4 and PD-1 blockade as monotherapy, and as combination therapy in the treatment of cancer. The animal data strongly supported the use of these drugs in patients, and in many cases suggested strategies that directly led to successful registration trials. In contrast, many of the toxicities, and some of the unusual response patterns seen in patients with these drugs, were not predicted by the preclinical work that we cite, highlighting the importance of early-phase trials with patients to inform future drug development. In addition, we review herein the preclinical data surrounding emerging immune checkpoint proteins, including BTLA, VISTA, CD160, LAG3, TIM3, and CD244 as potential targets for inhibition. The current comprehensive review of the literature regarding CTLA-4 and PD-1, as well as a number of novel checkpoint proteins demonstrates a strong preclinical basis for the use of these antibodies singly and in combination to overcome checkpoint inhibition in the treatment of cancer. We also suggest that the use of these antibodies may augment the efficacy of other activating immune antibodies, cytokines, radiation, and adoptive cell therapy in human cancer.

Trends in adrenalectomy rates, indications, and physician volume: A statewide analysis of 1816 adrenalectomies.

BACKGROUND: Adrenalectomy rates seem to be increasing in Florida, possibly due to increased availability of laparoscopic adrenalectomy, identification of incidentalomas, and access to care for minorities. We hypothesized that the rate of adrenalectomies in Florida increased from 1998-2005 while characteristics of patients, diagnoses, operations, and operating physicians changed over this period. METHODS: Prospectively-collected, mandatory-reported, hospital discharge data for all inpatient adrenalectomies undertaken in Florida from 1998-2005 were obtained along with Florida census and physician certification and education data. Characteristics of adrenalectomy patients, diagnoses, operations, and physicians were analyzed. RESULTS: 1816 adrenalectomies were available for analysis. Yearly rates of adrenalectomy nearly doubled from 1.20 to 2.26 per 100,000 Florida residents (P = .0024). Overall, patient characteristics such as demographics, indications and comorbidities did not change, whereas hospital charges increased and length-of-stay (LOS) significantly decreased (P = .0031 and P < .0001, respectively). There was a non-significant trend toward a yearly increase in physician volume and an inverse relationship between physician volume categories and mean LOS (P < .0001). CONCLUSIONS: The rate of adrenalectomies is increasing in Florida. This increase was not associated with distinct trends in patient characteristics, although a significant decrease in LOS was identified. As these trends continue and adrenalectomy is applied more liberally, indications for adrenalectomy may need to be re-evaluated.

Nuclear factor-kappaB mediates Kupffer cell apoptosis through transcriptional activation of Fas/FasL.

INTRODUCTION: Nuclear factor (NF)-kappaB is a key transcriptional factor for cell survival, inflammation, and stress response. We demonstrated that Kupffer cell-derived FasL plays a central role in pancreatitis-induced hepatocyte injury. The aim of this study was to determine the role of NF-kappaB in regulating death ligand/receptor pathway in Kupffer cells during conditions that mimic acute pancreatitis. MATERIALS AND METHODS: Tissue cultures of rat Kupffer cells were treated with elastase (1 U/L) to mimic pancreatitis before and after infection with AdIkappaB to block activation of NF-kappaB. Tumor necrosis factor (enzyme-linked immunoassay), Fas/FasL, and caspase-3 (Western), tumor necrosis factor and Fas/FasL mRNA (reverse-transcription polymerase chain reaction), and NF-kappaB DNA binding (electrophoretic mobility shift assay) were determined. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and DNA fragmentation. Gels were quantified by densitometry. Data (n=3) are mean+/-SEM; student's t test was used for statistical analysis. RESULTS: AdIkappaB infection up-regulated mutated IkappaBalpha that maintained its binding properties to NF-kappaB. Promoter-reporter assay demonstrated that FasL gene promoter was regulated by NF-kappaB. Infection with AdIkappaB attenuated the elastase-induced up-regulation of Fas/FasL (all P<0.01 versus elastase) and NF-kappaB DNA binding but did not affect elastase-induced up-regulation of TNF. AdIkappaB attenuated elastase-induced cleavage of caspase-3, DNA fragmentation and TUNEL staining (all P<0.01 versus elastase). CONCLUSIONS: Inhibition of NF-kappaB DNA binding down-regulates Fas/FasL and attenuates elastase-induced apoptosis; however, it has no effect on TNF production, suggesting that regulation of Fas/FasL and TNF may occur via different pathways. The ability of Kupffer cells to autoregulate their stress response by up-regulating their death ligand/receptor and apoptosis warrants further investigation.

Fas/FasL play a central role in pancreatitis-induced hepatocyte apoptosis.

Liver injury is a clinical prognostic indicator in acute pancreatitis (AP). We have demonstrated that Kupffer cell-derived FasL mediates liver injury during AP and sought to determine its role in AP-induced hepatocyte apoptosis. AP was induced in National Institutes of Health (NIH) Swiss mice, C57/C57, and Fas-/-, FasL-/- mice by a choline-deficient ethionine-supplement diet. Liver Fas, FasL, p38-mitogen activated phosphokinase (p38-MAPK), poly-ADP ribose polymerase (PARP), and cytochrome C were measured by immunoblotting. Apoptosis was assessed by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and DNA fragmentation (ELISA). AP upregulated liver FasL (4280 +/- 580 vs. 733 +/- 336), Fas (2866 +/- 595 vs. 649 +/- 111), cytochrome C (6980 +/- 237 vs. 903 +/- 156), and PARP (6393 +/- 591 vs. 466 +/- 261) as well as increased TUNEL staining (40 +/- 2 vs. 14 +/- 1) and DNA fragmentation (all P < 0.03 vs. control). In FasL-/- and Fas-/- mice, AP-induced upregulation of p38-MAPK, PARP, and cytochrome C was significantly attenuated (all P < 0.01 compared to C57/C57 control). In addition, AP-induced DNA fragmentation was reduced 60% in Fas-/- and FasL-/- mice (P < 0.01 vs. C57/C57). AP induces apoptosis by transcriptional activation of Fas/FasL. AP-induced apoptosis was significantly reduced in Fas and FasL knockout mice along with downregulation of p38-MAPK, PARP, and cytochrome C, thereby suggesting a central role for Fas/FasL in hepatocyte apoptosis. The manipulation of interactions between Kupffer cell-derived FasL and hepatocytes may have important therapeutic implications.

Acute pancreatitis induces FasL gene expression and apoptosis in the liver.

BACKGROUND: Liver injury is an important prognostic indicator in acute pancreatitis. We previously demonstrated that Kupffer cell-derived cytokines mediate liver injury. In this work, we sought to characterize the role of Fas Ligand (FasL) in liver injury during acute pancreatitis. METHODS: Acute pancreatitis was induced in mice using cerulein; serum FasL, AST, ALT, liver FasL, p38-MAPK, and caspase-3 were measured. FasL mRNA and protein and its receptor (Fas) were determined in rat Kupffer cells treated with elastase (1 U/ml) to mimic acute pancreatitis. Apoptosis was measured by flow cytometry. RESULTS: Cerulein-induced pancreatitis increased serum AST, ALT, and FasL and up-regulated liver FasL (1315 +/- 111 versus 310 +/- 164 pg/ml, P = 0.002 versus sham), while inducing p38-MAPK phosphorylation (P < 0.01 versus sham) and cleavage of caspase-3 (P < 0.04 versus sham); all were attenuated by pretreatment with the Kupffer cell inhibitor, gadolinium (all P < 0.003). In vitro, elastase induced a time-dependent increase in Kupffer cell FasL protein (FasL = 404 +/- 94 versus 170 +/- 40, P = 0.02, versus control), a 100-fold increase in FasL mRNA, and up-regulated Fas (FasL receptor). Gadolinium significantly attenuated the elastase-induced increase in FasL and FasL mRNA (FasL = 230 +/- 20 versus 404 +/- 94, P = 0.01, versus elastase) but had little effect on Fas. Additionally, elastase-primed Kupffer cell media induced apoptosis in hepatocytes (29 +/- 1 versus 16% +/- 1%; versus control, P < 0.001). CONCLUSIONS: Acute pancreatitis induces liver injury and hepatocyte death while up-regulating FasL, p38-MAPK, and caspase-3. Fas is up-regulated within Kupffer cells, suggesting that FasL may autoregulate its production by inducing its originator-cell death. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications.