John S. Young

Effect of PD-1: PD-L1 in Invariant Natural Killer T-Cell Emigration and Chemotaxis Following Sepsis.

ABSTRACT Invariant natural killer T-cells (iNKT) are a subset of T-cells that play a regulatory role in sepsis. Following cecal ligation and puncture (CLP), iNKT cells emigrate from the liver and into the circulation and peritoneum in a manner dependent upon coinhibitory molecule Programmed Cell Death Receptor 1 (PD-1). We hypothesized that the effect of PD-1 on iNKT-cell emigration was dependent upon the direct PD-1:PD-L1 interaction, and that PD-1 and PD-L1 would play a role in chemotaxis and chemokine receptor expression. Adoptive transfer of Vybrant-labeled wild-type (WT) cells showed the donor iNKT cells migrated from the liver to the peritoneum following CLP, but PD-L1 deficient donor iNKT cells did not. In a chemotaxis assay, WT-iNKT cells chemotaxed to CXCL12, but PD-1 and PD-L1 deficient iNKT cells did not. Using flow cytometry to evaluate chemokine receptor expression, peritoneal iNKT expression of CXCR4 increased following CLP in the WT, PD-1, and PD-L1 deficient animals, and CXCR6 increased in the WT and PD-1 deficient animals. In conclusion here we document that the hepatic emigration of iNKT cells following CLP to the peritoneum appears dependent upon the direct PD-1:PD-L1 interaction; however, although PD-1 and PD-L1 appear to play a role in chemotaxis, this is unlikely a reflection of iNKT-cell chemokine receptor expression changes.

Adenocarcinoma arising from cervical esophageal gastric inlet patch

FIGURE 2. Positron emission tomography shows the cervical esophageal mass to be intensely avid but without nodal or distal metastasis. A 57-year-old man with symptoms of reflux underwent upper endoscopy, with the finding of a 3-cm polypoid mass at 19 to 22 cm measured from the incisors occupying close to one third of the esophageal circumference (Figure 1). It was estimated that there was a distance of 3.5 to 4 cm from the upper esophageal sphincter to the top of the mass. The mass was associated with a patch of what appeared to be ectopic gastric-type mucosa in the cervical esophagus. Biopsy of this patch at 18 cm showed oxyntic type gastric mucosa with focal dilated glands, consistent with an inlet patch. Biopsy of the mass showed adenocarcinoma, which was at least intramucosal because deeper invasion could not be excluded. On endoscopic ultrasonography, the mass was staged at T2N0 with involvement of the muscularis propria. Positron emission tomographic scan showed the mass to be intensely avid, but without nodal or distal metastasis (Figure 2). The patient underwent curative resection by 3-incision esophagectomy, with reconstruction by colon interposition. Pathology revealed moderately differentiated

Divergent Invariant Natural Killer T-Cell Response to Sepsis of Abdominal vs. Non-Abdominal Origin in Human Beings

BACKGROUND The etiology of sepsis is broad. The peritoneal cavity displays compartmentalization with respect to inflammatory responses, so peripheral blood responses to sepsis of abdominal vs. non-abdominal origin are expected to be divergent. Lymphocytes and invariant natural killer T (iNKT) cells play important roles in survival from sepsis, as they dampen the neutrophil and macrophage responses. We assessed whether circulating iNKT cells display distinct phenotypic profiles depending on the presence of abdominal vs. non-abdominal infection with sepsis. METHODS Patients with sepsis, defined as infection confirmed microbiologically with a systemic inflammatory response syndrome (SIRS), were enrolled prospectively. They were categorized as having either exclusively sepsis of abdominal or exclusively non-abdominal origin. The white blood cell (WBC) count was recorded. Whole-blood staining with monoclonal antibodies to CD3, V-alpha-24 (to identify iNKT cells), and CD69 (marker of early activation) was applied. RESULTS Of the 53 enrolled patients, 18 had abdominal infection. Pneumonia was the most common non-abdominal type. There was no difference in gender, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, WBC count, or CD3(+) T cells (7.1%±1.6% vs. 6.5%±0.9%; p=0.75) in the two groups. Patients with abdominal infection had a higher proportion of iNKT cells (2.7%±1.1% vs. 0.89%±0.14%; p=0.032). Correcting for WBC count, this translated into a higher absolute number of iNKT cells (3.4±1.8×10(7)/L vs. 0.74±0.15×10(7)/L; p=0.03). Patients with sepsis of abdominal origin had a lower percentage of CD69(+) iNKT cells (9.1%±3.1% vs. 27.2%±5.8%; p=0.028). In patients in shock vs. those who were not, patients with non-abdominal infection exhibited a greater number of iNKT cells (1.47±0.3 v. 0.62±0.1×10(7)/L; p=0.022) and percentage of activated iNKT cells (53±14.5% vs. 17.9±4.8%; p=0.04). Patients with non-abdominal infection who died had a lower absolute number of activated iNKT cells (0.8±1.2×10(7)/L vs. 0.34±0.1×10(7)/L; p=0.023); however, no such shock or death correlation was noted in patients with sepsis of abdominal origin. CONCLUSIONS Divergent sepsis etiologies display distinct blood iNKT cell population changes. In non-abdominal infection, this difference was associated with septic shock and death. Elucidating the importance and basis for these changes relative to the response to sources of infection will help clarify appropriate diagnosis and management of the patient with sepsis.

Risk factors for reinsertion of urinary catheter after early removal in thoracic surgical patients

Objectives: To reduce the incidence of urinary tract infection, Surgical Care Improvement Project 9 mandates the removal of urinary catheters within 48 hours postoperatively. In patients with thoracic epidural anesthesia, we sought to determine the rate of catheter reinsertion, the complications of reinsertion, and the factors associated with reinsertion. Methods: We conducted a prospective observational study of consecutive patients undergoing major pulmonary or esophageal resection with thoracic epidural analgesia over a 2‐year period. As per Surgical Care Improvement Project 9, all urinary catheters were removed within 48 hours postoperatively. Excluded were patients with chronic indwelling catheter, patients with urostomy, and patients requiring continued strict urine output monitoring. Multivariable logistic regression analysis was used to identify independent risk factors for urinary catheter reinsertion. Results: Thirteen patients met exclusion criteria. Of the 275 patients evaluated, 60 (21.8%) required reinsertion of urinary catheter. There was no difference in the urinary tract infection rate between patients requiring reinsertion (1/60 [1.7%]) versus patients not requiring reinsertion (1/215 [0.5%], P = .389). Urethral trauma during reinsertion was seen in 1 of 60 patients (1.7%). After reinsertion, discharge with urinary catheter was required in 4 of 60 patients (6.7%). Multivariable logistic regression analysis found esophagectomy, lower body mass index, and benign prostatic hypertrophy to be independent risk factors associated with catheter reinsertion after early removal in the presence of thoracic epidural analgesia. Conclusions: When applying Surgical Care Improvement Project 9 to patients undergoing thoracic procedures with thoracic epidural analgesia, consideration to delayed removal of urinary catheter may be warranted in patients with multiple risk factors for reinsertion.

Late gastric conduit ischemia from celiac artery stenosis salvaged by stent therapy

Gastric conduit necrosis after esophagectomy usually presents early in the postoperative phase. The etiology of this ischemia most often lies in the inability of the isolated right gastroepiploic artery to provide adequate blood supply to the entire conduit. Here we describe an unusual presentation of late gastric conduit ischemia, occurring many years after surgery as a result of atherosclerosis and stenosis of the celiac artery. Successful salvage of the gastric conduit was achieved with stenting of the celiac artery.