Aviram Nissan

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

BackgroundIpilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.MethodsIn this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.ResultsObjective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.ConclusionsBaseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.

Adrenocortical Carcinoma: Clinical, Morphologic, and Molecular Characterization

PURPOSE To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P =.005). The phenotype Ki-67(-)p53(-)mdm-2(+)cyclinD1(-)Bcl-2(-)p21(-)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P =.01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.

Prospective functional voice assessment in patients undergoing thyroid surgery.

ObjectiveTo analyze voice function before and after thyroidectomy for patients with normal preoperative voice using a standardized multidimensional voice assessment protocol. Summary Background DataThe natural history of post-thyroidectomy voice disturbances for patients with preserved laryngeal nerve function has not been systematically studied and characterized with the intent of using the data for postoperative voice rehabilitation. MethodsDuring a prospective single-arm study, patients with normal voice underwent functional voice testing using a standardized voice grading scale and a battery of acoustic, aerodynamic, glottographic, and videostroboscopic tests before, 1 week after, and 3 months after thyroidectomy. Differences in observed sample means were evaluated using analysis of covariance or t test; categorical data was analyzed using the Fisher exact or chi-square test. ResultsFifty-four patients were enrolled; 50 and 46 were evaluable at 1 week and 3 months, respectively. No patient developed recurrent laryngeal nerve injury; one had superior laryngeal nerve injury. Fifteen (30%) patients reported early subjective voice change and seven (14%) reported late (3-month) subjective voice change. Forty-two (84%) patients had significant objective change in at least one voice parameter. Six (12%) had significant alterations in more than three voice measures, of which four (67%) were symptomatic, whereas 25% with three or fewer objective changes had symptoms. Patients with persistent voice change at 3 months had an increased likelihood of multiple (more than three) early objective changes (43% vs. 7%). Early maximum phonational frequency range and vocal jitter changes from baseline were significantly associated with voice symptoms at 3 months. ConclusionsEarly vocal symptoms are common following thyroidectomy and persist in 14% of patients. Multiple (more than three) objective voice changes correlate with early and late postoperative symptoms. Alterations in maximum phonational frequency range and vocal jitter predict late perceived vocal changes. Factors other than laryngeal nerve injury appear to alter post-thyroidectomy voice. The variability of patient symptoms underscores the importance of understanding the physiology of dysphonia.

Colon cancer associated transcript‐1: A novel RNA expressed in malignant and pre‐malignant human tissues

Early detection of colorectal cancer (CRC) is currently based on fecal occult blood testing (FOBT) and colonoscopy, both which can significantly reduce CRC‐related mortality. However, FOBT has low‐sensitivity and specificity, whereas colonoscopy is labor‐ and cost‐intensive. Therefore, the discovery of novel biomarkers that can be used for improved CRC screening, diagnosis, staging and as targets for novel therapies is of utmost importance. To identify novel CRC biomarkers we utilized representational difference analysis (RDA) and characterized a colon cancer associated transcript (CCAT1), demonstrating consistently strong expression in adenocarcinoma of the colon, while being largely undetectable in normal human tissues (p < 000.1). CCAT1 levels in CRC are on average 235‐fold higher than those found in normal mucosa. Importantly, CCAT1 is strongly expressed in tissues representing the early phase of tumorigenesis: in adenomatous polyps and in tumor‐proximal colonic epithelium, as well as in later stages of the disease (liver metastasis, for example). In CRC‐associated lymph nodes, CCAT1 overexpression is detectable in all H&E positive, and 40.0% of H&E and immunohistochemistry negative lymph nodes, suggesting very high sensitivity. CCAT1 is also overexpressed in 40.0% of peripheral blood samples of patients with CRC but not in healthy controls. CCAT1 is therefore a highly specific and readily detectable marker for CRC and tumor‐associated tissues.

Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: A multi‐institutional study

Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate.

Abdominoperineal resection for rectal cancer at a specialty center

PURPOSE: Although sphincter-preservation procedures have replaced abdominoperineal resection as the treatment of choice for rectal cancer, a subset of patients with rectal cancer will still require abdominoperineal resection. The use of adjuvant radiotherapy has been shown to reduce local recurrence, and combined modality therapy (chemoradiation) improves survival. Sharp mesorectal excision compared with the classic teaching of blunt retrorectal dissection is also an important component of local control. The primary aim of the present study was to evaluate the postoperative complications associated with neoadjuvant therapy in patients requiring complete rectal excision. Oncologic outcomes for all patients with abdominoperineal resection are also provided. METHODS: A prospective database of 5,634 patients who underwent surgery for colorectal cancer at Memorial Sloan-Kettering Cancer Center between the years 1987 and 1997 was reviewed. Patients with primary adenocarcinoma of the rectum who underwent abdominoperineal resection were identified. In 1,622 patients who were operated on for primary rectal cancer, 292 patients (18 percent) underwent abdominoperineal resection and the rest had a sphincter-preserving procedure. Ten patients were excluded from the study because of prior pelvic irradiation for other cancer (8 patients) and insufficient radiation dose (<4,000 cGy; 2 patients). Neoadjuvant radiotherapy was given to 123 patients and postoperative adjuvant radiotherapy to 65 patients, whereas 94 did not receive radiotherapy. Intraoperative radiotherapy combined with preoperative radiotherapy was administered to 23 of the 123 patients given neoadjuvant radiotherapy. RESULTS: The duration of the operation was significantly longer in both neoadjuvant radiotherapy and intraoperative radiotherapy groups compared with the nonradiotherapy group (P=0.01 andP<0.0001, respectively). Estimated blood loss, mean number of blood units transfused per patient, and the percentage of patients being transfused were similar among the groups. Early postoperative complications were significantly higher in the neoadjuvant radiotherapy groups compared with the nonradiotherapy group. Late complications, overall survival, disease-free survival, and local recurrence were not significantly different among the groups. CONCLUSIONS: In patients with cancer of the lower one-third of the rectum, sharp pelvic dissection can result in a low rate of local recurrence even without radiotherapy. The role of preoperative radiotherapy, although associated with higher perineal wound complications, is important in increasing resectability and sphincter-preservation rate. Randomized, prospective trials will be needed to establish the role of adjuvant radiotherapy in patients undergoing sharp mesorectal excision for rectal cancer.

Evaluation of a peritoneal surface disease severity score in patients with colon cancer with peritoneal carcinomatosis.

Systemic therapy and cytoreduction (CRS) with hyperthermic intra‐peritoneal chemotherapy (HIPEC) may benefit selected patients with carcinomatosis from colon cancer (PC). This study presents the results of a consecutive series of patients evaluated under a single strategy.

Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the United States Military Cancer Institute Clinical Trials Group Study GI-01.

Background:The principal role of sentinel lymph node (SLN) sampling and ultrastaging in colon cancer is enhanced staging accuracy. The utility of this technique for patients with colon cancer remains controversial. Purpose:This multicenter randomized trial was conducted to determine if focused assessment of the SLN with step sectioning and immunohistochemistry (IHC) enhances the ability to stage the regional nodal basin over conventional histopathology in patients with resectable colon cancer. Patients and Methods:Between August 2002 and April 2006 we randomly assigned 161 patients with stage I–III colon cancer to standard histopathologic evaluation or SLN mapping (ex vivo, subserosal, peritumoral, 1% isosulfan blue dye) and ultrastaging with pan-cytokeratin IHC in conjunction with standard histopathology. SLN-positive disease was defined as individual tumor cells or cell aggregates identified by hematoxylin and eosin (H&E) and/or IHC. Primary end point was the rate of nodal upstaging. Results:Significant nodal upstaging was identified with SLN ultrastaging (Control vs. SLN: 38.7% vs. 57.3%, P = 0.019). When SLNs with cell aggregates ≤0.2 mm in size were excluded, no statistically significant difference in node-positive rate was apparent between the control and SLN arms (38.7% vs. 39.0%, P = 0.97). However, a 10.7% (6/56) nodal upstaging was identified by evaluation of H&E stained step sections of SLNs among study arm patients who would have otherwise been staged node-negative (N0) by conventional pathologic assessment alone. Conclusion:SLN mapping, step sectioning, and immunohistochemistry (IHC) identifies small volume nodal disease and improves staging in patients with resectable colon cancer. A prospective trial is ongoing to determine the clinical significance of colon cancer micrometastasis in sentinel lymph nodes.

Signet-ring cell carcinoma of the colon and rectum: A matched control study

PURPOSE: There is little information comparing signet-ring cell carcinoma to common non-signet-ring cell colon and rectal cancers. The aim of this study was to better define the clinicopathologic differences between these two distinct entities. METHODS: Using a prospective database of 5,350 surgical patients with rectal cancers operated on at Memorial Sloan-Kettering Cancer Center between 1986 and 1997, 46 patients with signet-ring cell carcinoma were identified. Signet-ring cell carcinoma lesions were those in which signet-ring cells constituted more then 50 percent of the tumor. Six patients who presented with recurrent disease were excluded from the study. Control patients were matched for age, gender, TNM stage, primary site, procedure, and adjuvant therapy. Age, primary site of the tumor, stage at presentation, and survival times of patients with signet-ring cell carcinoma were also compared with 3,371 patients with primary non-signet-ring cell rectal cancers. Survival was calculated using Kaplan-Meier survival estimates. RESULTS: Mean age of the signet-ring cell carcinoma group was 59±12 years and median age was 61 (range, 20–91) years. Male-to-female ratio was 1.1:1. Lymphatic and peritoneal spread was more common among the signet-ring cell carcinoma group. Approximately one-third of signetring cell carcinoma patients presented with metastatic disease. Mean survival time of the signet-ring cell carcinoma group was 45.4 months (95 percent confidence interval, 26.9–63.8) compared with 78.5 months (95 percent confidence interval, 62.0–94.9) for the control patients group;P=0.02 by the log-rank test. The cumulative survival curve of patients with signet-ring cell carcinoma resembles that of patients with poorly differentiated rectal cancers. CONCLUSIONS: Patients with signet-ring cell carcinoma of the colon and rectum have a worse prognosis compared with matched controls with the same stage of disease.

Development of a MicroRNA-Based Molecular Assay for the Detection of Papillary Thyroid Carcinoma in Aspiration Biopsy Samples

BACKGROUND Although thyroid nodules are common and diagnosed in over 5% of the adult population, only 5% harbor malignancy. Patients with clinically suspicious thyroid nodules need to undergo fine-needle aspiration biopsy (FNAB). The main limitation of FNAB remains indeterminate cytopathology. Only 20%-30% of the indeterminate nodules harbor malignancy, and therefore up to 80% of patients undergo unnecessary thyroidectomy. The aim of this study was to identify and validate a panel of microRNAs (miRNAs) that could serve as a platform for an FNAB-based diagnostic for thyroid neoplasms. METHODS The study population included 27 consecutive patients undergoing total thyroidectomy for FNAB-based papillary thyroid cancer (n = 20) and benign disorders (n = 7). Aspiration biopsy was performed from the index lesion and from the opposite lobe normal tissue in all study patients at the time of operation. RNA was extracted from all aspiration biopsy samples. Quantitative polymerase chain reaction on a panel of previously selected miRNAs was performed. Polymerase chain reaction results were compared with final histopathology. miRNA from tumor tissues was amplified using the highest value of each miRNA expression in normal tissue as a threshold for malignancy detection. RESULTS Diagnostic characteristics were most favorable for mir-221 in differentiating benign from malignant thyroid pathology. mir-221 was overexpressed in 19 patients (p < 0.0001) with a sensitive yield of 95%. Specificity, negative and positive predictive value, and accuracy of the miRNA panel were 100%, 96%, 100%, and 98%, respectively. CONCLUSIONS miRNA quantification for differential diagnosis of thyroid neoplasms within aspiration biopsy samples is feasible and may improve the accuracy of FNAB cytology.