Recurrence and Complications in Pediatric and Adolescent Papillary Thyroid Cancer in a High-Volume Practice.

BACKGROUND: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms. MATERIALS AND METHODS: A retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence. RESULTS: Seventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non-compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07). CONCLUSIONS: Pediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection. LEVEL OF EVIDENCE: Prognosis study, level IV, retrospective case series.

NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018.

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for BRAF V600E-mutated anaplastic thyroid carcinoma.

DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.

BACKGROUND: Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis. METHODS: MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples. The findings were validated by qRT-PCR, and in follicular thyroid cancers (FTC) and follicular thyroid adenomas (FTA) for comparison. FOXO transcription factor expression was also analyzed. Protein expression was assessed by immunohistochemistry. Genomic integrity was evaluated by whole-exome sequencing-derived read-depth analysis and Mann-Whitney U test. Clinical correlations were assessed using Fisher's exact and t tests. RESULTS: Microarray and qRT-PCR revealed reduced expression of all four MMR genes in PTC compared with PCNT and of PMS2 compared with NT. FTC and FTA showed upregulation in MLH1, MLH3 and PMS2. PMS2 protein expression correlated with the mRNA expression pattern. FOXO1 showed lower expression in PMS2-deficient PTCs (log2-fold change -1.72 vs. -0.55, U = 11, p < 0.05 two-tailed). Rate of LOH, a measure of genomic instability, was higher in PMS2-deficient PTCs (median 3 and 1, respectively; U = 26, p < 0.05 two-tailed). No correlation was noted between MMR deficiency and clinical characteristics. CONCLUSIONS: MMR deficiency, potentially promoted by FOXO1 suppression, may explain the etiology for PTC development in some patients. FTC and FTA retain MMR activity and are likely caused by a different tumorigenic pathway.

Leptin Is Produced by Parathyroid Glands and Stimulates Parathyroid Hormone Secretion.

OBJECTIVE: We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. BACKGROUND: The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. METHODS: From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. RESULTS: Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. CONCLUSIONS: Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

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

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.

Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.

BACKGROUND: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis. METHODS: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples. RESULTS: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden. CONCLUSIONS: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

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.

Financial comparison of laparoscopic versus open hepatic resection using deviation-based cost modeling.

BACKGROUND: There is a growing body of evidence suggesting the equivalence and in some cases superiority of laparoscopic liver resection versus open resection. Fewer data exist regarding the financial impact of laparoscopic liver resection. METHODS: Retrospective review of 98 consecutive patients at a single institution from 2007 through 2011 undergoing first time hepatic resection was performed. Laparoscopic and open cases were compared primarily on OR and hospital charges. Deviation-based cost modeling and weighted average mean cost for the two procedures were used to determine both financial and clinical efficacy on the basis of differences in length of stay, complications, and charges. RESULTS: There were 57 laparoscopic and 41 open cases included in the study. Right hepatectomy was the most common procedure performed in both the laparoscopic (n=23, 40.4%) and open (n=22, 53.7%) groups. Patients in the laparoscopic group were significantly more likely to have an "on course" postoperative hospitalization (73.7 vs. 26.8%; p<0.001), which translated into a WAMC of $58,401 for the laparoscopic cases and $69,728 for the open cases. In the subset of patients undergoing right hepatectomy, patients in the laparoscopic group remained more likely to have an on course hospitalization (61.2 vs. 31.8%; p=0.025). WAMC for the laparoscopic right hepatectomy group, however, was higher than the open group ($69,544 vs. $68,266). CONCLUSIONS: The cost-effectiveness of laparoscopic hepatectomy appears to vary with the complexity of the procedure. Overall, laparoscopy offers a cost advantage; however, with more complex procedures such as right hepatectomy, higher up-front operating room charges offset the financial benefits of less complicated hospitalization.

Diversity of stage III melanoma in the era of sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node (SLN) biopsy for melanoma often detects minimal nodal tumor burden. Although all node-positive patients are considered stage III, there is controversy regarding the necessity of adjuvant therapy for all patients with tumor-positive SLN. METHODS: Post hoc analysis was performed of a prospective multi-institutional study of patients with melanoma ≥ 1.0 mm Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for patients with SLN metastasis. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) was performed. Univariate and multivariate Cox regression analyses were performed. Classification and regression tree (CART) analysis also was performed. RESULTS: A total of 509 patients with tumor-positive SLN were evaluated. Independent risk factors for worse OS included thickness, age, gender, presence of ulceration, and tumor-positive non-SLN (nodal metastasis found on completion lymphadenectomy). As the number of tumor-positive SLN and the total number of tumor-positive nodes (SLN and non-SLN) increased, DFS and OS worsened on Kaplan-Meier analysis. On CART analysis, the 5-year OS rates ranged from 84.9% (women with thickness < 2.1 mm, age < 59 years, no ulceration, and tumor-negative non-SLN) to 14.3% (men with thickness ≥ 2.1 mm, age ≥ 59 years, ulceration present, and tumor-positive non-SLN). Six distinct subgroups were identified with 5-year OS in excess of 70%. CONCLUSIONS: Stage III melanoma in the era of SLN is associated with a very wide range of prognosis. CART analysis of prognostic factors allows discrimination of low-risk subgroups for which adjuvant therapy may not be warranted.

The lymph node ratio has limited prognostic significance in melanoma.

BACKGROUND: The importance of the lymph node ratio (LNR) after regional lymphadenectomy for cutaneous melanoma is unknown. MATERIALS AND METHODS: A post hoc analysis was performed for patients after the completion of lymphadenectomy for cutaneous melanoma. LNR was calculated as the number of tumor-positive nodes divided by the total number of lymph nodes. Comparison of disease-free survival (DFS) and overall survival (OS) and univariate and multivariate analyses with regard to LNR was performed. Comparison of the performance of LNR to other measurements of lymph node disease was performed. RESULTS: A LNR of 0.10 was a significant cutoff point for determining DFS and OS. On multivariate analysis, LNR >0.10 was an independent predictor of DFS and OS without other measures of lymph node disease burden. Patients with LNR >0.10 had worse DFS and OS. Absolute counts of tumor-positive lymph nodes differentiated survival differences better than LNR. LNR was not a significant predictor of survival in patients with neck or axillary dissections but was for inguinal dissections. In multivariate analysis of alternative nodal measures, LNR was an inferior prognostic factor. CONCLUSIONS: A LNR >0.10 has a negative prognostic significance when it is the only measurement of lymph node disease considered but is an inferior prognostic factor to alternative measures of lymph node disease.

recurrence following hepatectomy for metastatic colorectal cancer: development of a model that predicts patterns of recurrence and survival.

BACKGROUND: While several prognostic models have been developed to predict survival of patients who undergo hepatectomy for metastatic colorectal cancer (mCRC), few data exist to predict survival after recurrence. We sought to develop a model that predicts survival for patients who have developed recurrence following hepatectomy for mCRC. METHODS: A retrospective analysis was performed on data from consecutive patients that underwent hepatectomy for mCRC. Clinicopathologic data, recurrence patterns, and outcomes were analyzed. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed. An integer-based model was created to predict the patterns of recurrence and survival after recurrence. RESULTS: This analysis included 280 patients with a median follow-up of 50.1 months. Of these, 53% underwent major hepatectomy and 87% had negative margins. Recurrent disease developed in 63% of patients. After hepatectomy, factors associated with short disease-free interval (DFI) and overall survival (OS) included CEA > 200 ng/ml (P < 0.0005), >1 metastasis (P < 0.0005), and a high Fong score (P < 0.0005). After recurrence, the pattern of recurrence was a strong predictor of OS (P < 0.0005). Independent predictors of the pattern of recurrence on multivariate analysis include CEA > 200 ng/ml, tumor size >5 cm, and >1 liver metastasis. A simple predictive scoring system was developed from the beta coefficients of this analysis that correlated with recurrence pattern (P < 0.0005). CONCLUSIONS: After hepatectomy, survival of patients with recurrent mCRC is strongly predicted by the patterns of recurrence, and the recurrence pattern can be predicted with a simple model. This can also be extended to create a scoring system that estimates expected survival.

Preoperative serum osteocalcin may predict postoperative elevated parathyroid hormone in patients with primary hyperparathyroidism.

BACKGROUND: Persistent postoperative elevation of parathyroid hormone (POePTH) following successful parathyroidectomy for primary hyperparathyroidism (PHPT) is presumed to result from bone remineralization. Predicting which patients may need treatment is difficult. This study investigated whether preoperative serum osteocalcin (OC), a bone turnover marker involved in mineralization, can predict POePTH. METHODS: A total of 198 patients (155 women and 43 men) with parathyroidectomy from November 2007 to October 2009 in MD Anderson Cancer Center, Houston, TX, USA, were included in our analysis. Separate multivariate regression models determined associations between preoperative OC and POePTH at 6 and 12 months postoperatively. Regression models were adjusted for demographics (age, gender, race, height, weight, BMI), preoperative BMD and bisphosphonate use, adenoma weight, serum levels of PTH, calcium, vitamin D, creatinine, and phosphate. Patients with baseline GFR <60 ml/min/1.73 m(2) and postoperative serum calcium >10.14 mg/dl at 6 and 12 months were excluded. RESULTS: Patients' mean age (±SD) was 60 (±14) years. POePTH (>80 pg/ml) occurred in 13 and 12% patients at 6 and 12 months, respectively. Preoperative serum creatinine and bisphosphonate use were positively associated with POePTH (p < 0.05) both at 6 and 12 months. Preoperative OC was predictive of POePTH (p < 0.05) at 6 months (ß 0.35; 95% confidence interval (CI), 0.11-0.58) and at 12 months (ß 0.79; 95% CI, 0.27-1.31). CONCLUSIONS: Preoperative OC may help to predict risk of POePTH in patients with PHPT. Research with longer follow-up in patients with no known baseline chronic kidney disease stratified by high versus normal preoperative serum creatinine is recommended.

Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection.

BACKGROUND: The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival. METHODS: A retrospective review from seven centres was performed. Metabolic factors, tumour characteristics and outcomes of patients undergoing resection for PDAC were collected. Univariate and multivariable analyses were performed to determine factors associated with disease-free (DFS) and overall survival (OS). RESULTS: Of the 509 patients in the present study, 31.2% had diabetes. Scoring systems were devised to predict OS and DFS based on a training set (n= 245) and were subsequently tested on an independent set (n= 264). Pre-operative diabetes (P < 0.001), tumour size >2 cm (P= 0.001), metastatic nodal ratio >0.1 (P < 0.001) and R1 margin (P < 0.001) all correlated with DFS and OS on univariate analysis. Scoring systems were devised based on multivariable analysis of the above factors. Diabetes and the metastatic nodal ratio were the most important factors in each system, earning two points for OS and four points for DFS. These scoring systems significantly correlated with both DFS (P < 0.001) and OS (P < 0.001). CONCLUSION: Pre-operative diabetes status provides useful information that can help to stratify patients in terms of predicted post-operative OS and DFS.

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 surgeon's performance. Greater awareness regarding predictors of readmission rates is necessary to demonstrate improved surgical quality.

Common locations of parathyroid adenomas.

BACKGROUND: We have developed a nomenclature system that succinctly specifies the locations of parathyroid adenomas in the neck. We report our experience using the system in a large, contemporary cohort of patients. METHODS: A prospective, endocrine surgery database at a single, tertiary care center was retrospectively analyzed. We reviewed the records of 271 patients operated on for sporadic primary hyperparathyroidism between January 2006 and May 2008 and analyzed the effect of adenoma location at operative intervention and outcome. RESULTS: Adenomatous gland locations were classified intraoperatively as: A (adherent to posterior thyroid capsule) in 12.5% of cases; B (tracheoesophageal groove) in 17.3%; C TE groove but (close to clavicle) in 13.7%; D (directly over the recurrent laryngeal nerve) in 12.2%; E (easy to identify, inferior thyroid pole) in 25.8%; F (fallen into thymus) in 7.4%; and G gauge (within thyroid gland) in 0.4%. More than one enlarged gland was present in 10.7% of patients and usually involved coexistence of enlarged types A and E glands. Type F glands were associated with a longer mean operative time (p = 0.0487) and type E glands with a higher rate of outpatient surgery (p = 0.0195). At 6 months from the surgery, 94.5% of the patients were normocalcemic. CONCLUSIONS: Our nomenclature system provides a simple way to describe the locations of parathyroid adenomas. Type E adenomas were associated with a higher rate of outpatient surgery and type F adenomas with a longer operative time. Biochemical cure rates were comparable for all locations of single adenomas.

Safety and efficacy of hepatectomy for colorectal metastases in the elderly.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the safety and efficacy of hepatic metastasectomy in elderly patients with colorectal liver metastases (CLM). METHODS: A retrospective review of a hepatobiliary database was performed on consecutive patients treated with metastasectomy for CLM. Patients were stratified by age (<70 years old vs. ≥70). Patient and tumor characteristics as well as operative factors were compared, as were morbidity, mortality, and length of stay. Logistic regression and Cox proportional hazards were used to evaluate the association of age and postoperative outcomes. RESULTS: There were 59 elderly (median age 75) and 220 non-elderly (median age 58) patients analyzed over a 13 year period. The Charlson comorbidity index was higher in the elderly group (mean 4.7 vs. 4.4 P = 0.005). Postoperative morbidity and mortality were 52.5 and 0% vs. 48.2 and 4.1% in the elderly and non-elderly groups, respectively (P = 0.56 and P = 0.21). There were no differences in median DFS (21.8 months vs. 28.9 months; P = 0.157) or OS (36 months vs. 47.7 months; P = 0.070) between the elderly and non-elderly groups, respectively. CONCLUSIONS: Age itself does not appear to be a significant contraindication to liver resection, including major hepatectomy, when patients are appropriately selected.

What does ulceration of a melanoma mean for prognosis?

Ulceration of a primary cutaneous melanoma is clearly associated with worse prognosis, although the underlying mechanisms are not well understood. Recent studies have shown that the presence of ulceration may predict response to adjuvant IFN in high-risk patients. As molecular pathways continue to be elucidated, it is possible that continued study of ulceration will provide insight into potential therapeutic strategies, or will predict response to novel targeted therapies. Future investigation into melanoma ulceration is warranted.

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.

Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane.

BACKGROUND: A recent nonrandomized interinstitutional study reported that adjuvant mitotane following surgery for adrenocortical carcinoma (ACC) was associated with decreased recurrence. Because of the limitations of this study, we investigated the influences of surgery and adjuvant mitotane in a large series of ACC patients evaluated and treated at a single referral center. STUDY DESIGN: Retrospective evaluation of patients followed at a single institution after surgery for ACC. RESULTS: 218 patients with ACC underwent primary resection either at the index institution [surgery index (SI), n = 28] or an outside institution [surgery outside (SO), n = 190] and had a median follow-up of 88 months. SI patients had a superior disease-free survival compared with SO patients (median 25 versus 12 months, P = 0.003), and SI patients also had a superior overall survival compared with SO patients (median not reached versus 44 months, P = 0.02). Factors predicting increased risk of recurrence on multivariate analysis were surgery at an outside institution [hazard ratio (HR) 2.56, 95% confidence interval (CI) 1.44-4.53, P = 0.001] and no treatment with adjuvant mitotane (HR 1.95, 95% CI 1.06-3.59, P = 0.03), and those predicting a poorer survival were advanced stage at presentation (P = 0.01) and surgery at an outside institution (HR 2.62, 95% CI 1.31-5.25, P = 0.007). CONCLUSIONS: The recurrence rate of the index group (50%) in the current series, the overwhelming majority of whom did not receive adjuvant mitotane, is indistinguishable from that reported for those who received adjuvant mitotane (49%) in the recent interinstitutional report, emphasizing the importance of completeness of initial surgery in the management of patients with ACC.