Glenda G. Callender

Readmission rates after abdominal surgery: the role of surgeon, primary caregiver, home health, and subacute rehab.

Objective:To prospectively evaluate predictive factors of hospital readmission rates in patients undergoing abdominal surgical procedures. Background:Recommendations from MedPAC that the Centers for Medicare and Medicaid Services (CMS) report upon and determine payments based in part on readmission rates have led to an attendant interest by payers, hospital administrators and far-sighted physicians. Methods:Analysis of 266 prospective treated patients undergoing major abdominal surgical procedures from September 2009 to September 2010. All patients were prospectively evaluated for underlying comorbidities, number of preop meds, surgical procedure, incision type, complications, presence or absence of primary and/or secondary caregiver, their education level, discharge number of medications, and discharge location. Univariate and multivariate analyses were performed. Results:Two hundred twenty-six patients were reviewed with 48 (18%) gastric-esophageal, 39(14%) gastrointestinal, 88 (34%) liver, 58 (22%) pancreas, and 33 (12%) other. Seventy-eight (30%) were readmitted for various diagnoses the most common being dehydration (26%). Certain preoperative and intraoperative factors were not found to be significant for readmission being, comorbidities, diagnosis, number of preoperative medications, patient education level, type of operation, blood loss, and complications. Significant predictive factors for readmission were age (≥69 years), number of discharged (DC) meds (≥9 medications), ⩽50% oral intake (52% vs. 23%), and DC home with a home health agency (62% vs. 11%) Conclusion:Readmission rates for surgeons WILL become a quality indicator of performance. Quality parameters among Home Health agencies are nonexistent, but will reflect on surgeons performance. Greater awareness regarding predictors of readmission rates is necessary to demonstrate improved surgical quality.

Cutting Edge: Identification of Hepatitis C Virus-Specific CD8+ T Cells Restricted by Donor HLA Alleles following Liver Transplantation

By necessity, human liver transplantation is performed across HLA barriers. As a result, intracellular infection of the allograft presents a unique immunologic challenge for the recipient’s immune system. In this study, we describe the presence of HLA-A2-restricted, hepatitis C virus (HCV)-specific CD8+ T cells in liver transplant recipients in whom the allograft is HLA-A2 positive and the recipient is HLA-A2 negative. These memory-effector T cells are recipient derived and recognize HCV peptide uniquely in the context of HLA-A2. Furthermore, these cells were absent before the transplant, suggesting that the allograft is capable of selectively expanding naive CD8+ T cells. The in vitro specificity to donor HLA allele-restricted CD8+ T cells suggests that these cells may function to control HCV spread in the allograft.

Identification of a hepatitis C virus–reactive T cell receptor that does not require CD8 for target cell recognition

Hepatitis C virus (HCV) has been reported to elicit B and T cell immunity in infected patients. Despite the presence of antiviral immunity, many patients develop chronic infections leading to cirrhosis, hepatocellular carcinoma, and liver failure that can require transplantation. We have previously described the presence of HLA‐A2–restricted, HCV NS3–reactive cytotoxic T lymphocytes (CTL) in the blood of HLA‐A2− liver transplantation patients that received an HLA‐A2+ liver allograft. These T cells are analogous to the “allospecific” T cells that have been described in hematopoietic stem cell transplantation patients. It has been speculated that allospecific T cells express high‐affinity T cell receptors (TCRs). To determine if our HCV‐reactive T cells expressed TCRs with relatively high affinity for antigen, we identified and cloned a TCR from an allospecific HLA‐A2–restricted, HCV:NS3:1406‐1415–reactive CD8+ T cell clone and expressed this HCV TCR in Jurkat cells. Tetramer binding to HCV TCR–transduced Jurkat cells required CD8 expression, whereas antigen recognition did not. In conclusion, based on the reactivity of the TCR‐transduced Jurkat cells, we have identified a TCR that transfers anti‐HCV reactivity to alternate effectors. These data suggest this high affinity HCV‐specific TCR might have potential new immunotherapic implications. (HEPATOLOGY 2006;43:973–981.)

Surgery for primary hyperparathyroidism

In the Western world, primary hyperparathyroidism is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women. Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging. Primary hyperparathyroidism is a complex disease process that requires careful diagnosis and thoughtful medical and surgical management. The surgical management of patients with persistent or recurrent disease, inherited primary hyperparathyroidism syndromes, and parathyroid carcinoma is particularly challenging. High‐quality imaging and reliable intraoperative adjuncts are critical to success. Cancer 2014;120:3602–3616.

CD34-based enrichment of genetically engineered human T cells for clinical use results in dramatically enhanced tumor targeting

Objective clinical responses can be achieved in melanoma patients by infusion of T cell receptor (TCR) gene transduced T cells. Although promising, the therapy is still largely ineffective, as most patients did not benefit from treatment. That only a minority of the infused T cells were genetically modified and that these were extensively expanded ex vivo may have prevented their efficacy. We developed novel and generally applicable retroviral vectors that allow rapid and efficient selection of T cells transduced with human TCRs. These vectors encode two TCR chains and a truncated CD34 molecule (CD34t) in a single mRNA transcript. Transduced T cells were characterized and the effects of CD34-based enrichment of redirected T cells were evaluated. Both CD8+ and CD4+ T cells could be transduced and efficiently co-expressed all introduced transgenes on their surface. Importantly, more than fivefold enrichment of both the frequency of transduced cells and the specific anti-tumor reactivity of the effector population could be achieved by magnetic beads-based enrichment procedures readily available for clinical grade hematopoietic stem cell isolation. This CD34-based enrichment technology will improve the feasibility of adoptive transfer of clinically relevant effectors. In addition to their enhanced tumor recognition, the enriched redirected T cells may also show superior reactivity and persistence in vivo due to the high purity of transduced cells and the shortened ex vivo culture.

Real-Time Super Selective Venous Sampling in Remedial Parathyroid Surgery

BACKGROUND Remedial cervical exploration for persistent or recurrent primary hyperparathyroidism can be technically difficult, but is expedited by accurate preoperative localization. We investigated the use of real-time super selective venous sampling (sSVS) in the setting of negative noninvasive imaging modalities. STUDY DESIGN We performed a retrospective analysis of a prospective database incorporating real-time sSVS in a tertiary academic medical center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of primary hyperparathyroidism. Of these, 31 represented remedial patients who had undergone one (n=28) or more (n=3) earlier cervical explorations and had noninformative, noninvasive preoperative localization studies. RESULTS We extended the use of the rapid parathyroid hormone assay in the interventional radiology suite, generating near real-time data facilitating onsite venous localization by a dedicated interventional radiologist. The predictive value of real-time sSVS localization was investigated. Overall, sSVS correctly predicted the localization of the affected gland in 89% of cases. Of 31 patients who underwent sSVS, a significant rapid parathyroid hormone gradient was identified in 28 (90%), localizing specific venous drainage of a culprit gland. All patients underwent subsequent surgery and were biochemically cured, with the exception of one who had metastatic parathyroid carcinoma. Three patients with negative sSVS were also explored and cured. CONCLUSIONS Preoperative parathyroid localization is of paramount importance in remedial cervical explorations. Real-time sSVS is a sensitive localization technique for patients with persistent or recurrent primary hyperparathyroidism, when traditional noninvasive imaging studies fail. These results validate the utility and benefit of real-time sSVS in guiding remedial parathyroid surgery.

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

Abstract The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease are highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high-affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

Modern Experience with Aggressive Parathyroid Tumors in a High-Volume New England Referral Center

BACKGROUND Parathyroid carcinoma (PTCA) is an exceptionally rare malignancy, often with a clinical presentation similar to that of benign atypical parathyroid adenoma. Its low incidence portends unclear guidelines for management. Accordingly, thorough examination of clinical and pathologic variables was undertaken to distinguish between PTCA and atypical adenomas. STUDY DESIGN This was a retrospective analysis of a prospective database at a tertiary academic referral center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of PHPT. Of these, 52 harbored aggressive parathyroid tumors: parathyroid carcinomas (n=18) and atypical adenomas (n=34). We analyzed the surgical and clinicopathologic tumor characteristics, and did a statistical analysis. We measured preoperative and intraoperative variables, and postoperative and pathologic outcomes. RESULTS Parathyroid carcinoma patients present with significantly increased tumor size (3.5 cm vs 2.4 cm, respectively; p=0.002), mean serum calcium (13.0 vs 11.8 mg/dL, respectively; p=0.003) and intact parathyroid hormone (iPTH) levels (489 vs 266 pg/mL, respectively; p=0.04), and a higher incidence of hypercalcemic crisis, compared with patients with atypical adenomas (50% vs 19%, respectively; p=0.072). Parathyroid carcinoma more frequently lacks a distinct capsule (47.1% vs 12.9%, respectively; p=0.03) and adheres to adjacent structures (77.8% vs 20.6%, respectively; p=0.017). Of note, there was no significant difference in loss of parafibromin expression between groups. CONCLUSIONS Clinical distinction between PTCA and atypical adenomas is of critical importance in determining the appropriate extent of resection and follow-up. Loss of parafibromin has not been shown to distinguish between PTCA and atypical adenoma; clearer definition of clinicopathologic criteria for PTCA is warranted and may lead to improved postoperative management.

Retroviral transduction of peptide stimulated t cells can generate dual t cell receptor-expressing (bifunctional) t cells reactive with two defined antigens

BackgroundTumors and viruses have developed many mechanisms to evade the immune system, including down-regulation of target antigens and MHC molecules. These immune escape mechanisms may be able to be circumvented by adoptively transferring T cells engineered to express two different T cell receptors, each specific for a different antigen or MHC restriction molecule.MethodsPBMC from the blood of normal healthy donors were stimulated for three days with an antigenic peptide from cytomegalovirus (CMV) pp65. These CMV reactive cultures were transduced with a encoding the TIL 5 T cell receptor (TCR) that mediates recognition of the dominant epitope of the melanoma antigen MART-1. Following selection for transduced cells, the cultures were evaluated for recognition of CMV pp65 and MART-1 expressing targets.ResultsWe were able to rapidly create bifunctional T cells capable of recognizing both CMV pp65 and MART-1 using a combination of HLA-A2 tetramer staining and intracellular staining for interferon-γ. These bifunctional T cells were sensitive to very low levels of antigen, recognize MART-1+ tumor cells, and maintained their bifunctionality for over 40 days in culture.ConclusionBifunctional T cells can be engineered by transducing short term peptide stimulated T cell cultures. These bifunctional T cells may be more effective in treating patients with cancer or chronic virus infections because they would reduce the possibility of disease progression due to antigen and/or MHC loss variants.

Hepatitis C virus‐cross‐reactive TCR gene‐modified T cells: a model for immunotherapy against diseases with genomic instability

A major obstacle hindering the development of effective immunity against viral infections, their associated disease, and certain cancers is their inherent genomic instability. Accumulation of mutations can alter processing and presentation of antigens recognized by antibodies and T cells that can lead to immune escape variants. Use of an agent that can intrinsically combat rapidly mutating viral or cancer‐associated antigens would be quite advantageous in developing effective immunity against such disease. We propose that T cells harboring cross‐reactive TCRs could serve as a therapeutic agent in these instances. With the use of hepatitis C virus, known for its genomic instability as a model for mutated antigen recognition, we demonstrate cross‐reactivity against immunogenic and mutagenic nonstructural protein 3:1406‐1415 and nonstructural protein 3:1073‐1081 epitopes in PBL‐derived, TCR‐gene‐modified T cells. These single TCR‐engineered T cells can CD8‐independently recognize naturally occurring and epidemiologically relevant mutant variants. TCR‐peptide MHC modeling data allow us to rationalize how TCR structural properties accommodate recognition of certain mutated epitopes and how these substitutions impact the requirement of CD8 affinity enhancement for recognition. A better understanding of such TCRs’ promiscuous behavior may allow for exploitation of these properties to develop novel, adoptive T cell‐based therapies for viral infections and cancers exhibiting similar genomic instability.