Eran Brauner

Performance of the Afirma Gene Expression Classifier in Hürthle Cell Thyroid Nodules Differs from Other Indeterminate Thyroid Nodules

BACKGROUND The recently introduced Afirma gene expression classifier (AGEC) provides binary results (benign or suspicious) to guide management of cytologically indeterminate thyroid nodules. The AGEC is intended to reduce unnecessary surgeries for benign nodules, and management algorithms favor surgery for suspicious results. Limited data are available on the performance of this test for Hürthle cell nodules (HCNs). This study hypothesized that a predominance of Hürthle cells leads to an increased rate of suspicious AGEC results with a potential for overtreatment, despite a relatively low risk of malignancy. METHODS The pathology databases from three tertiary care facilities were queried from 2010 to 2014 for fine-needle aspirates (FNAs) diagnosed as suspicious for Hürthle cell neoplasm (SHCN) or atypia of undetermined significance/follicular lesion of undetermined significance concerning for Hürthle cell neoplasm (AFHCN). Cytology diagnoses were rendered internally prior to AGEC testing. The patient demographics, FNA diagnosis, AGEC result, surgical procedure, and pathologic outcomes were recorded. RESULTS The cohort consisted of 134 patients with HCNs. Prior to AGEC availability, 62 patients underwent surgery: 81% (50/62) of patients had surgery, and 34% (17/50) of the resected index nodules were malignant. After introduction of the AGEC, 72 patients underwent AGEC testing: 65% (47/72) of patients had surgery, and 13% (6/46) of the resected nodules were malignant. Thirty-two percent (23/72) of patients had a benign AGEC result and did not undergo surgery, and 4% (3/72) had surgery despite a benign AGEC result with benign final pathology, whereas 63% (45/72) of patients had suspicious AGEC results, with 96% of these patients (43/45) undergoing surgery, and 14% (6/43) of these index nodules were malignant. CONCLUSIONS While 32% of tested patients declined surgery based on a benign AGEC, 86% of patients with suspicious AGEC findings had unnecessary surgery, reflecting a substantially lower rate of malignancy from what was previously reported for all indeterminate nodules. Given the approximate pretest malignancy risk of 25-35% for an FNA diagnosis of SHCN or AFHCN, a suspicious AGEC diagnosis does not increase the probability of malignancy in an HCN, and patients should be counseled accordingly.

Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer.

The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53−/− murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3±174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3±60.8, compared to PLX4720 (439.3±188.4 mm3, P=0.023) or PD-L1 antibody (716.7±62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC.

Autoimmune pancreatitis misdiagnosed as a tumor of the head of the pancreas

Autoimmune pancreatitis can mimic pancreatic cancer in its clinical presentation, imaging features and laboratory parameters. Differentiating between those two entities requires implementation of clinical judgment and experience along with objective parameters that may suggest either condition. Few strategies have been proposed for the surgeon to implement when facing borderline cases. The following case is an example of a clinical scenario compatible with an accepted algorithm for diagnosis of pancreatic cancer, which eventually proved wrong. We present a 75-year-old patient who was admitted for obstructive jaundice. Imaging features were highly suggestive for pancreatic cancer as was the carbohydrate antigen 19-9 (CA 19-9) level, leading to a decision for surgery. Pathological examination revealed autoimmune pancreatitis. Though no frank carcinoma was found, premalignant ductal changes of pancreatic intraepithelial neoplasia (PanIN) I and PanIN II were discovered throughout the pancreatic duct. Caution is advised when relying on the combination of highly suggestive radiology features and elevated levels of CA 19-9 in the diagnosis of pancreatic cancer. When the tissue diagnosis is not conclusive, obtaining IgG4 and antinuclear Ab levels is advised, to rule out the rare possibility of autoimmune pancreatitis. Patients with autoimmune pancreatitis should be followed carefully as precancerous lesions may accompany the benign disease and the correlation of these two entities has not been ruled out.

Aberrant right subclavian artery- suggested mechanism for esophageal foreign body impaction: Case report

Aberrant right subclavian artery (ARSA) is asymptomatic in most cases. This variant anatomy can cause dysphagia in elderly patients. Impaction of foreign body in the esophagus is rarely the presenting symptom of ARSA. We present an eighty four years old patient who first presented with esophageal foreign body impaction and was diagnosed with an aberrant right subclavian artery compressing the esophagus just below the site of impaction.We assume that the exact place of impaction was not incidental and that a relative narrowing of the esophagus caused by the vascular anomaly is responsible for this specific presentation.

Clinical presentation predicts the outcome of patients with colon cancer.

AIM To elucidate the relationship between clinical presentation and outcome. METHODS A single institution retrospective chart review of patients admitted with the diagnosis of colon cancer. We used univariate and a multivariate analysis to identify symptoms association with mortality. An odds ratio based clinical score was created to evaluate the contribution of the quality of symptoms to outcome. Primary measure of outcome was survival. RESULTS During the study period, 236 patients met the inclusion criteria. Overall survival was 60.6%, mean follow-up 3.0 years. A bivariate analysis showed that increasing number of symptoms is not associated with mortality. However, a symptom-specific analysis performed using a logistic regression model controlling for age, stage and the duration of complaints revealed that the presence of melena was independently associated with mortality [P = 0.04, odds ratio (OR) 7.4], while rectal bleeding was associated with survival (P = 0.004, OR 3.9). Applying the proposed clinical score to an receiver operating characteristic curve showed that score > 1 had a strong association with mortality. The same logistic regression model was applied. The results showed that a score > 1 was an independent predictor of mortality (P < 0.001) and associated with node-positive disease (P = 0.008). CONCLUSION The quality of symptoms rather than quantity is correlated with outcome among patients with colon cancer. The proposed clinical scoring system may correctly predict the patients outcome.

Genome-wide analysis of differentially expressed miRNA in PLX4720-resistant and parental human thyroid cancer cell lines

BACKGROUND Investigating BRAF((V600E)) inhibitors (BRAFi) as a strategy to treat patients with aggressive thyroid tumors harboring the BRAF((V600E)) mutant currently is in progress, and drug resistance is expected to pose a challenge. MicroRNAs (miRNAs) are involved in development of resistance to a variety of drugs in different malignancies. METHODS miRNA expression profiles in the human anaplastic thyroid cancer cell line (8505c) were compared with its PLX4720-resistant counterpart (8505c-R) by the use of Illumina deep sequencing. We conducted a functional annotation and pathway analysis of the putative and experimentally validated target genes of the significantly altered miRNAs. RESULTS We identified 61 known and 2 novel miRNAs whose expression was altered greatly in 8505c-R. Quantitative reverse-transcription polymerase chain reaction validated altered expression of 7 selected miRNAs in 8505c-R and BCPAP-R (PLX4720-resistant papillary thyroid cancer cell line). We found 14 and 25 miRNAs whose expression levels changed substantially in 8505c and 8505c-R, respectively, after treatment with BRAFi. The mitogen-activated protein kinase and phosphatidylinositol 3-kinase-AKT pathways were among the prominent targets of many of the deregulated miRNAs. CONCLUSION We have identified a number of miRNAs that could be used as biomarkers of resistance to BRAFi in patients with thyroid cancer. In addition, these miRNAs can be explored as potential therapeutic targets in combination with BRAFi to overcome resistance.

Surgical emergencies confounded by H1N1 influenza infection - a plea for concern

The outbreak of the H1N1 influenza pandemic resulted in unprecedented, overwhelming exposure in the medical and lay media, with the obvious focus of healthcare providers being on patients in internal medicine or intensive care settings.Recently, we treated 3 patients with various surgical emergencies who were also diagnosed with active H1N1 influenza. The purpose of this report is to bring the issue of H1N1 flu in association with surgical emergencies to the forefront of the literature, and suggest that surgical diseases might be significantly accentuated in patients with H1N1 influenza.

Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis

Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line. In orthotopic thyroid cancer mouse models of 8505c and BCPAP, treatment with the triple drug combination reduced the size of the tumors and showed significantly higher numbers of cells undergoing apoptosis. This treatment increased the expression of pro-apoptotic protein Bim, while decreasing anti-apoptotic protein Mcl-1. Our results suggest that analyzing the results of BH3-profiling along with the mutational status of tumor can reveal an effective therapy for targeted, personalized treatment of aggressive thyroid cancer.

Gastrostomy tube dislodgment acute pancreatitis

Percutaneous gastrostomy is well established root for long term feeding of patients who cannot be fed orally. The risks of percutanous gastrostomy insertion are low. Tube related complications often resolved by placing a Foley catheter or other balloon gastrostomy tube as a temporary solution. Gastrostomy tube related gastric, duodenal and billiary obstruction were reported. Gastrostomy tube related pancreatitis is scarcely described. We described a patient who suffered a pancreatitis related to Foley catheter gastrostomy dislodgment. Reviewing all reported cases of gastrostomy related pancreatitis revealed higher incidence in patient with Foley catheter used as gastrostomy and revealed questionable trends in conducting tube replacement. We suggest a proper manner for tube replacement and concluded that should a Foley catheter used as a temporary solution a replacement should be schedule in a timely manner to avoid life threatening complications.