Surgical versus non-surgical management for patients with malignant bowel obstruction (S1316): a pragmatic comparative effectiveness trial.

BACKGROUND: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction. METHODS: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450. FINDINGS: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group). INTERPRETATION: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction. FUNDING: Agency for Healthcare Research and Quality and the National Cancer Institute. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Gender Discrepancies in Middle Author Publications in US Academic General Surgery.

INTRODUCTION: To explore gender discrepancies in publications at general surgery departments, we performed a cross-sectional comparing the number of women and men at each academic rank and their number of first author (FA), middle author (MA), last author (LA), and total publications. METHODS: Thirty academic general surgery departments were randomly selected. For each faculty, we tabulated: first, middle, last names, gender, academic rank, educational leadership, year of medical school graduation, and additional graduate degrees. Bibliography, H-index, and citations were downloaded from the Scopus database. RESULTS: One thousand three hundred twenty-six faculty sampled, 881 (66.4%) men and 445 (33.5%) women. Men outnumbered women at all ranks, with increasing disparity at higher ranks. Men outnumbered women in all subspecialties-largest difference in transplant surgery (84.4% versus 15.6%, P < 0.001). Men at all ranks had more MA publications: assistant professor (rate ratio 1.20; 95% confidence interval, 1.01-1.43, P = 0.024), associate professor (1.65; 1.31-2.06, P < 0.001), and professor (1.50; 1.20-1.91, P = 0.008). Men associate professors had more LA publications (1.74; 1.34-2.37, P < 0.001). No differences found in FA publications at any rank, nor LA publications at assistant professor and professor ranks. At subspecialty level, men in surgical oncology (1.95; 1.55-2.45, P < 0.001) and transplant surgery (1.70; 1.09-2.66, P = 0.02) had more MA publications. CONCLUSIONS: While FA and LA publications did not differ significantly across genders, the largest difference lies in MA publications, beginning at junior ranks and persisting with seniority. Discrepancies in MA publications may reflect gender discrepancies in collaborative opportunities, hence total publications should be used cautiously when determining academic productivity.

Thyroid nodules of indeterminate cytology in Hispanic/Latinx patients.

BACKGROUND: Behavior of differentiated thyroid cancer (DTC) varies among ethnic groups. Recommended management of thyroid nodules with indeterminate cytology (TN-IC) is based on molecular analysis from predominantly non-Hispanic white patients. We hypothesized that TN-IC in Hispanic/Latinx patients would have different features, management, and outcomes and that molecular testing might perform differently in Hispanic/Latinx patients. METHODS: Retrospective chart review was performed on 127 TN-IC analyzed with Afirma. Patient characteristics were compared using linear model ANOVA and Fisher's exact test. RESULTS: Out of 127 TN-IC, 71 (56%) were Hispanic/Latinx. Hispanic/Latinx had a greater prevalence of diabetes, but Afirma results (benign or suspicious) were similar between ethnic groups. Fourteen patients had malignant pathology. Their management and outcomes were similar across groups. The negative predictive value for our cohort (97.9%) was similar to published data. CONCLUSIONS: Data from our predominantly-Hispanic/Latinx cohort suggest that Afirma performs similarly in Hispanic/Latinx and non-Hispanic white patients with TN-IC.

How to Optimize Your Research During a Pandemic - A Summary of Discussions From the Association for Academic Surgery Town Hall and Lessons Learned From 2020.

The year 2020 was an unprecedented year for all of us, including for the academic surgery research community. Both stay-at-home and social distancing restrictions posed challenges to our personal and professional lives. The Association for Academic Surgery held its inaugural webinar-based panel discussion titled Association for Academic Surgery Town Hall with its topic on how to optimize research during a pandemic. This article summarizes the highlights from that discussion and lessons learned from the academic surgery research community in 2020.

Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update.

PURPOSE: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). DESIGN: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. MAIN OUTCOME ANALYSIS: Clinical, genetic, and functional associations were determined. RESULTS: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. CONCLUSIONS: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

A case of adrenocortical oncocytic carcinoma arising in ectopic adrenal tissue: a multidisciplinary diagnostic challenge.

Adrenocortical oncocytic neoplasm arising in ectopic adrenal tissue is a rare finding and presents as a unique diagnostic challenge. We report a case of a 26-year-old female who presented with vague left-sided abdominal pain and a large left retroperitoneal mass. She underwent exploratory laparotomy and resection of the mass and was diagnosed with extra-adrenal adrenocortical oncocytic carcinoma.

Transarterial Chemoembolization for Metastatic Neuroendocrine Tumors With Massive Hepatic Tumor Burden: Is the Benefit Worth the Risk?

BACKGROUND: Neuroendocrine tumors (NETs) have a propensity to metastasize to the liver, often resulting in massive tumor burden and hepatic dysfunction. While transarterial chemoembolization (TACE) is effective in treating patients with NET metastatic to the liver, there are limited data on its utility and benefit in patients with large hepatic involvement. The aim of our study was to determine the clinical benefit and complication rate of TACE in patients with massive hepatic tumor burden. METHODS: Medical records were reviewed in patients with grade 1 or 2 NETs with hepatic metastasis at our institution from January 2000 to September 2014 who underwent TACE. Of 201 total patients, 68 had massive hepatic tumor burden involving >75 % of liver parenchyma. RESULTS: Carcinoid syndrome was present in 40 (59 %) patients, and 57 (84 %) of the 68 patients were symptomatic from their disease. Complications beyond post-TACE syndrome occurred in 21.7 % of patients, with the most common complication being cardiac arrhythmias. The 30-day mortality rate was 7 %. Biochemical response was observed in 78 % of patients, while symptomatic relief and radiographic response was achieved in 85 and 82 % of patients, respectively. Median overall survival following TACE was 28 months, with 1-, 2-, and 5-year overall survival of 76, 54, and 26 %, respectively. CONCLUSIONS: In spite of massive tumor burden, clinical and biochemical improvements were seen in the majority of patients. Morbidity was acceptable and reversible but with a fairly high mortality rate of 7 %. TACE should still be considered in selective patients with massive hepatic tumor burden from metastatic NET for symptom control and palliation.

Hepatic Stellate Cells and microRNAs in Pathogenesis of Liver Fibrosis.

microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either blocking translation or inducing degradation of target mRNA. miRNAs play essential roles in diverse biological and pathological processes, including development of hepatic fibrosis. Hepatic stellate cells (HSCs) play a central role in development of hepatic fibrosis and there are intricate regulatory effects of miRNAs on their activation, proliferation, collagen production, migration, and apoptosis. There are multiple differentially expressed miRNAs in activated HSCs, and in this review we aim to summarize current data on miRNAs that participate in the development of hepatic fibrosis. Based on this review, miRNAs may serve as biomarkers for diagnosis of liver disease, as well as markers of disease progression. Most importantly, dysregulated miRNAs may potentially be targeted by novel therapies to treat and reverse progression of hepatic fibrosis.

Appendicitis secondary to metastatic melanoma: review of the National Institutes of Health experience.

IMPORTANCE: Malignant melanoma has an unusual propensity to metastasize to the small bowel; however, malignant melanoma with metastatic spread to the appendix presenting as acute appendicitis has rarely been reported. We describe cases of melanoma of the appendix presenting with appendicitis and review our institutional experience with this entity. OBSERVATIONS: Medical records were reviewed in patients with melanoma at the National Cancer Institute between January 1, 1953, and December 31, 2010, who underwent appendectomy. Of 5822 cases of melanoma treated at the National Institutes of Health, appendectomies were performed on 31 patients, 2 of whom had acute appendicitis secondary to malignant obstruction and presented with symptoms of vague abdominal pain. Both patients had been heavily pretreated for metastatic melanoma and had multiple sites of intraperitoneal and extraperitoneal disease. On exploratory laparotomy, both patients showed clinical evidence of acute appendicitis, and an appendectomy was performed. Both patients recovered fully from the operation and proceeded to further systemic therapy. CONCLUSIONS AND RELEVANCE: Although rare, the diagnosis of appendicitis should be considered in patients with melanoma and acute abdominal pain. Timely surgical intervention may allow palliation and the ability to pursue subsequent systemic treatment.

Assessment of tumor growth in pancreatic neuroendocrine tumors in von Hippel Lindau syndrome.

BACKGROUND: The incidence of pancreatic neuroendocrine tumors (PNETs) is increasing, but only a subset of these heterogeneous tumors will progress to malignant disease, which is associated with a poor prognosis. Currently, there are limited data on the natural history of these tumors and it is difficult to determine which patients require surgical intervention because the risk of metastatic disease cannot be accurately determined. STUDY DESIGN: We conducted a prospective study of 87 patients with von Hippel Lindau syndrome-associated solid pancreatic lesions to determine the natural history of these tumors with biochemical testing, follow-up anatomic and functional imaging, and advanced imaging analysis, with a median follow-up of 4 years. RESULTS: Approximately 20% of consecutive tumor measurements during follow-up were decreased in size and 20% showed no change. This included 2 of 4 surgically proven malignant tumors, which had a net decrease in tumor size over time. Tumor volume, as derived from greatest diameter and volumetric measurements, showed good correlation to pathology tumor measurement of surgically resected tumors (Spearman rank correlation ρ = 0.72, p = 0.0011, and ρ = 0.83, p < 0.0001, respectively). Tumor density measurement had an inverse relationship with tumor size (Spearman rank correlation -0.22, p = 0.0047). A tumor density cutoff of 200 was 75% specific for malignant tumors. CONCLUSIONS: Pancreatic neuroendocrine tumors demonstrate a nonlinear growth pattern, which includes periods of no growth and apparent decrease in size by imaging. These growth patterns are variable and are not associated with tumor grade and malignancy. Tumor density, as measured in this cohort, may offer a specific diagnostic tool for malignant disease.

RTN4IP1 is down-regulated in thyroid cancer and has tumor-suppressive function.

CONTEXT: Previously we identified RTN4IP1 to be differentially expressed in thyroid cancer by sex and the gene is located on chromosome 6q21, a chromosomal region frequently deleted or with loss of heterozygosity in a variety of human malignancies including thyroid cancer. OBJECTIVE: Because the expression and function of this gene is unknown, we sought to characterize its expression in normal, hyperplastic, and benign and malignant thyroid tissue samples and to evaluate its function in cancer cells. DESIGN: RTN4IP1 expression was analyzed in normal and hyperplastic thyroid tissue and benign and malignant thyroid tissue samples. In 3 thyroid cancer cell lines (TPC1 from a papillary thyroid cancer, FTC133 from a follicular thyroid cancer, XTC1 from a Hürthle cell carcinoma), small interfering RNA knockdown of RTN4IP1 was used to determine its role in regulating the hallmarks of malignant cell phenotype (cellular proliferation, migration, apoptosis, invasion, tumor spheroid formation, anchorage independent growth). RESULTS: We found RTN4IP1 mRNA expression was significantly down-regulated in follicular and papillary thyroid cancer as compared with normal, hyperplastic, and benign thyroid neoplasms (P < .05). Moreover, RTN4IP1 mRNA expression was significantly lower in larger papillary thyroid cancers (P < .05). Small interfering RNA knockdown of RTN4IP1 expression increased cellular proliferation (2- to 4-fold) in all 3 of the cell lines tested and increased cellular invasion (1.5- to 3-fold) and migration (2- to 7.5-fold), colony formation (3- to 6-fold), and tumor spheroid formation (P < .05) in 2 of the 3 cell lines tested (FTC-133 and XTC1). CONCLUSIONS: This is the first study to characterize the expression and function of RTN4IP1 in cancer. Our results demonstrate RTN4IP1 is down-regulated in thyroid cancer and is associated with larger papillary thyroid cancer and that it regulates malignant cell phenotype. These findings, taken together, suggest that RTN4IP1 has a tumor-suppressive function and may regulate thyroid cancer progression.

Evaluation of candidate diagnostic microRNAs in thyroid fine-needle aspiration biopsy samples.

BACKGROUND: Thyroid cancer diagnosis in the United States has increased by 2.3-folds in the last three decades. Up to 30% of thyroid fine-needle aspiration biopsy (FNAB) results are inconclusive. Several differentially expressed microRNAs (miRNAs) have been identified as candidate diagnostic markers for thyroid nodules. We hypothesized that these differentially expressed miRNAs may improve the accuracy of FNAB in difficult to diagnose thyroid nodules. METHODS: Expression levels of four miRNAs (miR-7, -126, -374a, and let-7g) were analyzed using quantitative real-time reverse transcription-polymerase chain reaction in 95 FNAB samples as the training set. A predictor model was formulated based on the most differentially expressed miRNA (miR-7) ΔCt value and the model was applied on a separate cohort of 59 FNAB samples as the validation set. RESULTS: miR-7 was the best predictor to distinguish benign from malignant thyroid FNAB samples. The other three miRNAs were co-expressed and did not significantly contribute to the predictor model. miR-7 had a sensitivity of 100%, specificity of 29%, positive predictive value (PPV) of 36%, negative predictive value (NPV) of 100%, and overall accuracy of 76% when applied to the validation set. In subgroup analysis of preoperative nondiagnostic, indeterminate, or suspicious FNAB samples, the predictor model had an overall accuracy of 37% with sensitivity of 100%, specificity of 20%, PPV of 25%, and NPV of 100%. CONCLUSIONS: miR-7 may be a helpful adjunct marker to thyroid FNAB in tumor types which are inconclusive. Given the high NPV of miR-7, a patient with a benign result based on the predictor model may be followed as opposed to performing an immediate diagnostic thyroidectomy. Future prospective clinical trials evaluating its accuracy in a larger cohort are warranted to determine its clinical utility.

Clinical utility of functional imaging with ¹8F-FDOPA in Von Hippel-Lindau syndrome.

CONTEXT: Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which patients are at risk of developing multiple tumors in different organs. 6-L-¹8F-fluorodihydroxyphenylalanine (¹8F-FDOPA) positron emission tomography (PET) is a relatively new metabolic imaging tracer proposed for the use of localizing sites of neuroendocrine tumors. There are limited data on the clinical utility of using ¹8F-FDOPA PET for identifying neuroendocrine tumors in a high-risk population such as VHL. OBJECTIVE: The aim of this prospective study was to evaluate the clinical utility of ¹8F-FDOPA PET in patients with VHL-related tumors. DESIGN: Radiological findings were prospectively collected from four imaging modalities: computed tomography, magnetic resonance imaging (MRI), ¹8F-fluorodeoxyglucose PET, and ¹8F-FDOPA PET. ¹8F-FDOPA PET findings were compared with those from other imaging modalities, as well as with clinical and laboratory data, and pathology findings if patients underwent an operation. RESULTS: In 52 patients with VHL, 390 lesions were identified by computed tomography (n = 139), MRI (n = 117), ¹8F-fluorodeoxyglucose PET (n = 94), and ¹8F-FDOPA PET (n = 40). ¹8F-FDOPA PET identified 20 pancreatic and 20 extrapancreatic tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4), lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen by conventional imaging studies in 9.6% of patients and 4.4% of lesions. Seven of eight patients who had an ¹8F-FDOPA PET-positive lesion underwent resection, and pathology showed a neuroendocrine tumor. Four of 10 patients with positive adrenal uptake had elevated catecholamine levels, and six of 10 patients had a discrete mass on axial imaging. CONCLUSIONS: ¹8F-FDOPA PET is a useful complementary imaging study to detect neuroendocrine tumors in patients with VHL undergoing surveillance, especially in those suspected to have adrenal pheochromocytoma or unusual ectopic locations.

Comparison of 6-18F-fluoro-L-DOPA, 18F-2-deoxy-D-glucose, CT, and MRI in patients with pancreatic neuroendocrine neoplasms with von Hippel-Lindau disease.

INTRODUCTION: There are limited data on the utility of 6-(18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-DOPA) and (18)F-2-deoxy-d-glucose ((18)F-FDG) in the workup of patients with pancreatic neuroendocrine tumors (PNETs). The aim of our study was to determine the accuracy of (18)F-DOPA and (18)F-FDG to detect PNETs in patients with von Hippel-Lindau disease (vHL). METHODS: We studied prospectively 69 patients with a diagnosis of vHL and pancreatic lesion(s) using computed tomography (CT), magnetic resonance imaging (MRI), (18)F-FDG, and (18)F-DOPA. Clinical, genetic, and laboratory characteristics were analyzed to determine association with imaging study results. RESULTS: In sum, 40 patients underwent evaluation by all 4 modalities; 98 PNETs and 55 PNETs were identified on CT and MRI, respectively. Only 11 of the 98 lesions (11%) were positive on (18)F-DOPA and 45 of the 98 (46%) lesions were positive on (18)F-FDG. There were 13 (18)F-DOPA and 26 (18)F-FDG avid extrapancreatic lesions. One patient underwent resection of an (18)F-DOPA avid extrapancreatic lesion in the lung, with pathology demonstrating a NET. There was no association between (18)F-DOPA and (18)F-FDG avidity and tumor size, age, gender, vHL mutation, or serum chromogranin A level. CONCLUSION: (18)F-FDG and MRI may be adjuncts to CT in identifying PNETs and metastatic disease. (18)F-DOPA has limited value in identifying PNETs in patients with vHL, but may be useful for identifying extrapancreatic NET lesions.

Expression profiling of difficult-to-diagnose thyroid histologic subtypes shows distinct expression profiles and identify candidate diagnostic microRNAs.

BACKGROUND: The incidence of thyroid cancer is increasing worldwide. The findings of up to 30% of thyroid fine-needle aspiration biopsies (FNAB) are inconclusive, primarily as a result of several thyroid histologic subtypes with overlapping cytologic features. MicroRNAs (miRNAs) are small noncoding RNAs and have been implicated in carcinogenesis. We hypothesized that there are miRNAs that are differentially expressed between benign and malignant thyroid tumors that are difficult to distinguish by FNAB. METHODS: The expression of 1263 human miRNAs was profiled in 47 tumor samples representing difficult to diagnose histologic subtypes of thyroid neoplasm (21 benign, 26 malignant). Differentially expressed miRNAs were validated by quantitative real-time reverse transcriptase-polymerase chain reaction. The area under the receiver operating characteristic curve (AUC) was used to determine the diagnostic accuracy of differentially expressed miRNAs. RESULTS: Supervised hierarchical cluster analysis demonstrated grouping of 2 histologies (papillary and follicular thyroid carcinoma). A total of 34 miRNAs were differentially expressed in malignant compared to benign thyroid neoplasms (P<0.05). A total of 25 of the 34 nonproprietary miRNAs were selected for validation, and 15 of the 25 miRNAs were differentially expressed between benign and malignant samples with P-value<0.05. Seven miRNAs had AUC values of >0.7. miR-7 and miR-126 had the highest diagnostic accuracy with AUCs values of 0.81 and 0.77, respectively. CONCLUSION: To our knowledge, this is the first study to evaluate the diagnostic accuracy of miRNAs in thyroid histologies that are difficult to distinguish as benign or malignant by FNAB. miR-126 and miR-7 had high diagnostic accuracy and could be helpful adjuncts to thyroid FNAB.

Prospective randomized trial of ligasure versus harmonic hemostasis technique in thyroidectomy.

BACKGROUND: Two surgical devices have become popular in thyroid surgery: a bipolar energy sealing system (B) and ultrasonic coagulation (UC). Retrospective and prospective studies have demonstrated that the use of these surgical devices for thyroidectomy compared with conventional thyroidectomy (clamp-and-tie) techniques reduces operative time and cost. We conducted a prospective randomized clinical trial to determine if there is any difference in operative time and cost between B and UC. MATERIALS AND METHODS: A single-blinded prospective randomized controlled trial was conducted at a tertiary referral center. A total of 90 patients who required a thyroidectomy for thyroid cancer, thyroid nodules, or hyperthyroidism were randomized to either B or UC during thyroidectomy. The operative time and cost of thyroidectomy were compared between the two groups. RESULTS: There was no statistically significant difference in patient age, gender, body mass index, indication for thyroidectomy and thyroid gland weight between the two groups. There was no statistically significant difference in operating room cost or total cost for thyroidectomy between the B and UC groups. There was also no statistically significant difference in the operative time between the B and UC groups (187.6 vs. 184.2 min, P = 0.48) or in postoperative complication rates. The only statistically significant difference in total cost was between surgeons independent of the device used (P < 0.01). CONCLUSIONS: In thyroid surgery, total cost and operative time were similar between the two surgical devices used.

A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy.

BACKGROUND: Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy. METHODS: Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived. RESULTS: By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups. CONCLUSION: Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.

Pulmonary resection for metastatic gastric cancer.

INTRODUCTION: Sixteen percent of patients with gastric cancer will develop pulmonary metastases. Standard of care for these patients is systemic chemotherapy with a median survival of 6 months and a 5-year survival of only 2%. Our aim was to critically evaluate the published data on pulmonary resection for metastatic gastric cancer (MGC) and to analyze the potential rationale for surgical management to determine which patients may benefit from this approach. METHODS: The Pubmed and SCOPUS databases were queried for all studies reporting on pulmonary resections for MGC. All available clinicopathologic data were analyzed. RESULTS: Twenty-one studies from 1975 to 2008 reported 48 pulmonary resections in 43 patients including five repeat resections and four extrapulmonary metastasectomies. Eighty-two percent (34/43) of patients had solitary lesions with a median size of 24 mm (4-90 mm). Median time from gastrectomy to pulmonary resection was 35 months (0-120 months). At a median follow-up of 23 months, 15 of 43 (35%) patients were alive without disease, and two patients died without disease. Median survival was 29 months (3-84 months) after pulmonary metastasectomy and 65 months (5-180 months) after gastrectomy. Fifty-six percent (24/43) of patients had another recurrence at a median of 12 months (range: 6-48 months) after resection including 30% (13/43) of patients with pulmonary recurrences. Overall 5-year survival was 33%. CONCLUSIONS: Pulmonary metastasectomy for MGC can potentially result in long-term survival in a highly selected group of patients and should be considered for those who present with small, isolated lesions after a prolonged disease-free interval.

Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.

In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard treatments. The gene transfer efficiency into autologous T cells was 79% CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays. Following completion of nonmyeloablative conditioning, the patient received 10(10) cells intravenously. Within 15 minutes after cell infusion the patient experienced respiratory distress, and displayed a dramatic pulmonary infiltrate on chest X-ray. She was intubated and despite intensive medical intervention the patient died 5 days after treatment. Serum samples after cell infusion showed marked increases in interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10, consistent with a cytokine storm. We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells.