Citations

Purpose The sixth edition of the American Joint Committee on Cancer (AJCC) rectal cancer staging subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III as a result of improved survival with T1-2N2 versus T3-4N2 and survival of T4N1 more similar to T3-4N2 than T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion interacts with nodal status to affect survival. Methods Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 35,829 patients with rectal cancer were compared with rectal pooled analysis data (3,791 patients). T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of positive nodes as follows: N1a/N1b (one v two to three nodes) and N2a/N2b (four to six v ≥ seven nodes). Five-year observed and relative survival rates were obtained for each TN category. Results SEER rectal cancer analyses confirm that T1-2N2 cancers have better prognosis than T3-4N2, T4bN1 have similar prognosis to T4N2, T1-2N1 have similar prognosis to T2N0/T3N0, and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a). Prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects prognosis. Conclusion This SEER population-based rectal cancer analysis validates the rectal pooled analyses and supports the shift of T1-2N2 lesions from IIIC to IIIA or IIIB and T4bN1 from IIIB to IIIC. SEER outcomes support subdividing T4, N1, and N2 and revised substaging of stages II and III. Survival by TN category suggests a complex biologic interaction between depth of invasion and nodal status.

PurposeRecent research on head shake posturography has demonstrated a modest increase in sensitivity to identifying peripheral vestibular system asymmetry when horizontal head movements were added to portions of the standard Sensory Organization Test (SOT) battery. However, limitations with respect to the head shake protocol were outlined, and usable data for assessing performance could not be established. The purpose of this study was to test a change in protocol for use of head shake SOT to address the noted limitations.MethodForty participants ranging in age from 20 to 79 years with no history of dizziness completed Conditions 2 and 5 of the SOT portion of computerized dynamic posturography on EquiTest equipment, while maintaining head still as well as 4 horizontal head movement velocity tasks.ResultsSlope of a linear regression fit to 6 performance points was used to characterize each participant. Spearman’s ranked correlation (r) indicated a significant relationship between the slope of the line representing a decline in performance with age (r= −.52,p= .0006).ConclusionsThe head shake modification showed a trend in increasing the separation of normal individuals across age and eliminated the limitations addressed in earlier research. Future research will investigate the head shake modification for identifying vestibular peripheral system asymmetries.

Abstract Multiple myeloma (MM) is a plasma cell neoplasm that proceeds through a premalignant state of monoclonal gammopathy of unknown significance; however, the molecular events responsible for myelomagenesis remain uncharacterized. To identify cellular pathways deregulated in MM, we addressed that sumoylation is homologous to ubiquitination and results in the attachment of the ubiquitin-like protein Sumo onto target proteins. Sumoylation was markedly enhanced in MM patient lysates compared with normal plasma cells and expression profiling indicated a relative induction of sumoylation pathway genes. The Sumo-conjugating enzyme Ube2I, the Sumo-ligase PIAS1, and the Sumo-inducer ARF were elevated in MM patient samples and cell lines. Survival correlated with expression because 80% of patients with low UBE2I and PIAS1 were living 6 years after transplantation, whereas only 45% of patients with high expression survived 6 years. UBE2I encodes the sole Sumo-conjugating enzyme in mammalian cells and cells transfected with a dominant-negative sumoylation-deficient UBE2I mutant exhibited decreased survival after radiation exposure, impaired adhesion to bone marrow stroma cell and decreased bone marrow stroma cell–induced proliferation. UBE2I confers cells with multiple advantages to promote tumorigenesis and predicts decreased survival when combined with PIAS1. The sumoylation pathway is a novel therapeutic target with implications for existing proteasomal-based treatment strategies.

Purpose The sixth edition of American Joint Committee on Cancer (AJCC) Cancer Staging Manual for colon cancer subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III because of improved survival for T1-2N2 versus T3-4N2 and T4N1 survival was more similar to T3-4N2 than to T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion and nodal status interact to affect survival. Patients and Methods Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 109,953 colon cancer patients were compared with National Cancer Data Base (NCDB) data on 134,206 patients. T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of involved positive lymph nodes (N+): N1a/N1b (1 v 2-3), N2a/N2b (4 to 6 v ≥ 7). Five-year observed and relative survival data were obtained for each TN category. Results SEER colon cancer analyses confirm that patients with T1-2N0 cancers have better survival than T3N0, T3N0 better than T4N0, T1-2N2 better than T3-4N2, and T4bN1 similar to T4N2. Patients with T4a lesions have better survival than T4b by N category. The number of positive nodes affects survival for each T category. Conclusion This SEER population-based colon cancer analysis is highly consistent with rectal cancer pooled analysis and SEER rectal cancer analyses, supporting the shift of T1-2N2 lesions from IIIC to IIIA/IIIB, shifting T4bN1 from IIIB to IIIC, subdividing T4/N1/N2, and revising substaging of stages II/III. Survival outcomes by TN category for colon and rectal cancer are strikingly similar.

Background Hepatitis B virus (HBV) genotype B and C seem not to affect the therapeutic response to lamivudine (3TC). Whether a given genotype has an earlier emergence of 3TC resistance remains unclear. We thus conducted this study to elucidate the association of HBV genotype with the emergence of 3TC-resistant strains in Taiwanese patients. Methods Forty chronic hepatitis B patients who developed resistance after 3TC therapy were retrospectively enrolled. HBV genotype, serum alanine aminotransferase (ALT) and HBV DNA levels were determined at baseline. The presence of 3TC-resistant mutations was confirmed by direct sequencing whenever biochemical breakthrough developed. Results The distribution of HBV genotype B and C in 40 patients receiving 3TC therapy were 60% and 40%, respectively. The mean interval to detect 3TC- resistant strain was 19.6 ±1.7 months. By using multivariate analysis, HBV genotype B and higher pre-treatment HBV DNA level were independently associated with earlier detection of 3TC-resistant strains. In addition, genotype B was significantly associated with development of 3TC resistance within the first 12 months of 3TC therapy compared with genotype C (odds ratio 8.27; P=0.004). Conclusions Compared with HBV genotype C, genotype B appears to have an earlier biochemical resistance to 3TC than genotype C. Therefore, more frequent monitoring of viral load or genotypical resistance might be needed for patients with HBV genotype B infection receiving 3TC therapy, especially during the first year.

Abstract Purpose: Preexisting antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its antitumor potency. In contrast to “naked” viruses, cell-associated viruses are protected from antibody neutralization. Hence, we hypothesized that measles virotherapy of ovarian cancer in measles-immune mice might be superior if MV-infected mesenchymal stem cell (MSC) carriers are used. Experimental Design: Antimeasles antibodies titers in ovarian cancer patients were determined. The protection of MV by MSC from antimeasles antibodies, the in vivo biodistribution profiles, and tumor infiltration capability of MSC were determined. Measles-naïve or immune tumor–bearing mice were treated with naked virus or MSC-associated virus and mice survivals were compared. Results: MSC transferred MV infection to target cells via cell-to-cell heterofusion and induced syncytia formation in the presence of high titers of antimeasles antibody, at levels that completely inactivated naked virus. Athymic mice bearing i.p. human SKOV3ip.1 ovarian tumor xenografts passively immunized with measles-immune human serum were treated with saline, naked MV, or MV-infected MSC. Bioluminescent and fluorescent imaging data indicated that i.p. administered MSC localized to peritoneal tumors, infiltrated into the tumor parenchyma, and transferred virus infection to tumors in measles naïve and passively immunized mice. Survival of the measles-immune mice was significantly enhanced by treatment with MV-infected MSC. In contrast, survivals of passively immunized mice were not prolonged by treatment with naked virus or uninfected MSC. Conclusions: MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients. (Clin Cancer Res 2009;15(23):7246–55)

Abstract By using LNCaP and its derivative cell lines, we first observed an association between tumor necrosis factor-α (TNF-α) resistance and hormone independence. Moreover, we found that the expression of tumor necrosis factor receptor–associated death domain (TRADD) was reduced in androgen deprivation–independent cells compared with that in androgen deprivation–dependent cells. TRADD is a crucial transducer for TNF-α–induced nuclear factor-κB (NF-κB) activation. Knocking down TRADD expression in LNCaP cells impaired TNF-α–induced NF-κB activation and androgen receptor repression, whereas overexpression of TRADD in C4-2B cells restored their sensitivity to TNF-α. Finally, we found that androgen deprivation reduces TRADD expression in vitro and in vivo, suggesting that androgen deprivation therapy may promote the development of TNF-α resistance by reducing TRADD expression during prostate cancer progression. [Cancer Res 2009;69(24):9448–56]

Objective Minimally invasive esophagectomy (MIE) can be performed a variety of ways using different techniques for the anastomosis. End-to-end anastomosis (EEA) transoral circular staplers have traditionally been used in gastric bypass surgery with good success. An evaluation of the safety and utility of the EEA transoral circular stapler for esophageal anastomoses in MIE is reviewed. Methods A retrospective chart review of all patients who underwent transthoracic MIE with EEA-stapled transoral anastomoses between January 2008 and May 2009 was performed. Patient demographics, indication for esophagectomy, perioperative treatments, intraoperative data, postoperative complications, hospital length of stay, and in-hospital mortality were evaluated. Results Twenty-six consecutive patients underwent MIE with EEA circular-stapled transthoracic anastomoses. Twenty-three were male with a mean age of 64 years (32–88). Indications for esophagectomy included esophageal cancer (24), high-grade dysplasia (1), and refractory stricture (1). Fifteen patients (63%) had neoadjuvant chemotherapy and radiation. There were no conversions to open thoracotomy or laparotomy. Mean operative time was 6.0 hours. Eight patients (31%) suffered postoperative complications; including leak from the gastric conduit staple line requiring operative intervention (1), postoperative bleeding requiring multiple transfusions (1), aspiration pneumonia (1), acute respiratory distress syndrome (1), myocardial infarction (1), chylothorax (1), and anastomotic stricture (2). Median hospital length of stay was 9 days (range 6–43). There were no in-hospital mortalities. Conclusions In our series, the EEA circular stapler seems technically feasible and relatively safe for an intrathoracic anastomosis in MIE.

Purpose No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. Patients and Methods This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. Conclusion Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.