Alexander Stojadinovic

Rising Thyroid Cancer Incidence in the United States by Demographic and Tumor Characteristics, 1980-2005

Thyroid cancer incidence has been rising in the United States, and this trend has often been attributed to heightened medical surveillance and the use of improved diagnostics. Thyroid cancer incidence varies by sex and race/ethnicity, and these factors also influence access to and utilization of healthcare. We therefore examined thyroid cancer incidence rates by demographic and tumor characteristics based on 48,403 thyroid cancer patients diagnosed during 1980–2005 from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. The rates varied by histologic type, sex, and race/ethnicity. Papillary carcinoma was the only histologic type for which incidence rates increased consistently among all racial/ethnic groups. Subsequent analyses focused on the 39,706 papillary thyroid cancers diagnosed during this period. Papillary carcinoma rates increased most rapidly among females. Between 1992–1995 and 2003–2005, they increased nearly 100% among White non-Hispanics and Black females but only 20% to 50% among White Hispanics, Asian/Pacific Islanders, and Black males. The increases were most rapid for localized stage and small tumors; however, rates also increased for large tumors and tumors of regional and distant stage. Since 1992–1995, half the overall increase in papillary carcinoma rates was due to increasing rates of very small (≤1.0 cm) cancers, 30% to cancers 1.1 to 2 cm, and 20% to cancers >2 cm. Among White females, the rate of increase for cancers >5 cm almost equaled that for the smallest cancers. Medical surveillance and more sensitive diagnostic procedures cannot completely explain the observed increases in papillary thyroid cancer rates. Thus, other possible explanations should be explored. (Cancer Epidemiol Biomarkers Prev 2009;18(3):784–91)

Analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas.

ObjectiveTo define the significance of positive microscopic resection margins in a large cohort treated for soft tissue sarcoma. MethodsThe authors analyzed 2,084 patients with localized primary soft tissue sarcoma (all anatomic sites) treated from 1982 to 2000. Clinicopathologic variables studied included tumor site, size, depth, histologic type, grade, and resection margin status. Treatment other than resection was not analyzed. Study endpoints included local and distant recurrence-free and disease-specific survival rates, estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and the Cox proportional hazards model. ResultsMedian follow-up was 50 months. After primary resection, 1,624 (78%) patients had negative and 460 (22%) had positive resection margins. Having positive margins nearly doubled the risk of local recurrence and increased the risk of distant recurrence and disease-related death. Seventy-two percent of patients with positive margins had no recurrence. Resection margin did not predict local control for retroperitoneal sarcomas or fibrosarcomas. Resection margin remained significantly associated with distant recurrence-free survival and disease-specific survival across all subsets after adjusting for other prognostic variables. The overall 5-year disease-specific survival rates for negative and positive margins were 83% and 75%. ConclusionsPositive microscopic resection margins significantly decrease the local recurrence-free survival rate for other-than-primary fibrosarcoma and retroperitoneal sarcomas, and independently predict distant recurrence-free survival rates and disease-specific survival rates for all patient subsets. Adjuvant therapy should be considered in the management of soft tissue sarcoma to increase local control. Because 72% of positive margins did not equate with inevitable local recurrence, considerable clinical judgment is required in considering additional treatment. Microscopic resection margins should be considered for inclusion in staging systems and treatment algorithms that address local recurrence.

Validation of Tissue Microarrays for Immunohistochemical Profiling of Cancer Specimens Using the Example of Human Fibroblastic Tumors

Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

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.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Primary Adult Soft Tissue Sarcoma: Time-Dependent Influence of Prognostic Variables

PURPOSE To define prognostic factors for postrelapse survival and their time-dependent influence for adult soft tissue sarcoma (STS). PATIENTS AND METHODS We analyzed 2,123 patients with completely resected localized primary STS treated from 1982 to 1999. Variables studied included tumor site, size, depth, grade, and resection margin but not treatment other than resection. Landmark time frames were used to assess the influence of disease-free interval (DFI) on disease-specific survival (DSS). DSS was estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed using log-rank test and the Cox proportional hazards regression model. Time-dependent stepwise regression analysis evaluated the time-dependent influence of each variable. RESULTS Two thirds of recurrences developed within 2 years of initial resection. Tumor size (P <.001), grade (P <.001), and microscopic resection margin (P <.001) independently predicted DSS for all STS. Size and grade independently predicted early (DFI <or= 3 years) and margin late (DFI > 3 years) DSS. Risk of tumor-related death was the same across all sites 3 years postresection and decreased significantly for extremity/trunk STS when DFI exceeded 3 years (P <.001). Influence of initial high-risk factors for tumor-related mortality in extremity/trunk STS decreased by 40% 3 years postresection, but their influence over DSS for non-extremity/trunk sites remained constant over time. Likelihood of complete resection after recurrence (all sites) increased with DFI (9% and 33% for DFI < 6 and > 36 months, respectively). CONCLUSION Tumor size, grade, and resection margin predict outcome for completely resected STS, and their influence for DSS is time- and site-dependent. The influence of prognostic factors changes over the natural history of extremity/trunk STS. Time to recurrence exerts significant influence over complete resection rates for recurrent disease.

Heterotopic Ossification in High-energy Wartime Extremity Injuries: Prevalence and Risk Factors

BACKGROUND Heterotopic ossification in the extremities remains a common complication in the setting of high-energy wartime trauma, particularly in blast-injured amputees and in those in whom the definitive amputation was performed within the zone of injury. The purposes of this cohort study were to report the experience of one major military medical center with high-energy wartime extremity wounds, to define the prevalence of heterotopic ossification in these patients, and to explore the relationship between heterotopic ossification and other potential independent predictors. METHODS We retrospectively reviewed the records and radiographs of all combat-wounded patients admitted to this institution between March 1, 2003, and December 31, 2006. Patients with a minimum of two months of radiographic follow-up who underwent at least one orthopaedic procedure on an extremity constituted our study group; those who underwent at least one orthopaedic procedure but had not had heterotopic ossification develop constituted the control group. Variables recorded for each study subject included age and sex, location and mechanism of injury, method(s) of fracture fixation, number of débridement procedures, duration of negative pressure therapy, location of heterotopic ossification, presence and severity of traumatic brain injury, and Injury Severity Scores. RESULTS During the study period, 1213 war-wounded patients were admitted. Of those patients, 243 (157 in the heterotopic ossification group and eighty-six controls) met the inclusion criteria. The observed rate of heterotopic ossification was 64.6%. A significant relationship was detected between heterotopic ossification and the presence (p = 0.006) and severity (p = 0.003) of a traumatic brain injury. Risk factors for the development of heterotopic ossification were found to be an age of less than thirty years (p = 0.007, odds ratio = 3.0), an amputation (p = 0.048, odds ratio = 2.9), multiple extremity injuries (p = 0.002, odds ratio = 3.9), and an Injury Severity Score of >or=16 (p = 0.02, odds ratio = 2.2). CONCLUSIONS The prevalence of heterotopic ossification in war-wounded patients is higher than that in civilian trauma. Although trends associated with local wound conditions were identified, the risk factors for the development of heterotopic ossification found in this study suggest that systemic causes predominate.

An evidence-based approach to the surgical management of resectable pancreatic adenocarcinoma.

BACKGROUND Randomized prospective trials have addressed various treatment approaches to pancreatic adenocarcinoma in order to improve on the dismal prognosis associated with this disease. We conducted a comprehensive review of prospective randomized clinical trials and summarized the contemporary treatment of resectable pancreatic carcinoma. STUDY DESIGN A literature search strategy identified prospective randomized clinical trials for pancreatic carcinoma using standard medical subject heading terms. The articles were critically reviewed and ranked according to a standardized three-tiered system (Ia, Ib, Ic) by a panel of experts. RESULTS Surgical studies have demonstrated that morbidity and mortality are similar for pylorus-preserving and classic pancreaticoduodenectomy. Extended retroperitoneal lymphadenectomy can be performed with similar mortality but increased morbidity compared with standard pancreaticoduodenectomy but does not prolong survival. Pancreaticogastrostomy and pancreaticojejunostomy appear to be comparable techniques for pancreatic duct reconstruction. Pancreatic-enteric anastomosis is associated with lower rates of pancreatic fistula and endocrine insufficiency than duct occlusion without anastomosis. Intraperitoneal drainage after pancreatic resection is unwarranted and may contribute to intraabdominal complications. Routine use of prophylactic octreotide does not lower the rate of pancreatic fistula; it should be considered for reoperative pancreatic resection or for a soft gland. Early trials found that adjuvant chemoradiation therapy prolongs survival. But in more recent studies chemoradiation after resection has failed to show a survival advantage over surgery alone. CONCLUSIONS Surgical resection remains the only potentially curative therapy for adenocarcinoma of the pancreas. There is no clear indication as to a single preferable resection approach.