The Role of Central Neck Lymph Node Dissection in the Management of Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is the most common thyroid malignancy, and cervical nodal metastases are frequent at presentation. The most common site for nodal metastases from PTC is the central compartment of the ipsilateral neck in the paratracheal and pretracheal regions. The decision to resect these lymph nodes at the time of thyroidectomy often depends on if nodes with suspected malignancy can be identified preoperatively. If nodal spread to the central neck nodes is known, then the consensus is to remove all nodes in this area. However, there remains significant controversy regarding the utility of removing central neck lymph nodes for prophylactic reasons. Herein, we review the potential utility of central neck lymph node dissection as well as the risks of performing this procedure. As well, we review the potential of molecular testing to stratify patients who would most benefit from this procedure. We advocate a selective approach in which patients undergo clinical neck examination coupled with ultrasound to detect any concerning lymph nodes that warrant additional evaluation with either fine needle aspiration or excisional biopsy in the operating room. In lieu of clinical lymphadenopathy, we suggest the use of patient and disease characteristics as identified by multiple groups, such as the American Thyroid Association and European Society of Endocrine Surgeons, which include extremes of ages, large primary tumor size, and male gender, when deciding to perform central neck lymph node dissection. Patients should be educated on the potential long-terms risks versus the lack of known long-term benefits.

NK Cell-Mediated Antitumor Effects of a Folate-Conjugated Immunoglobulin Are Enhanced by Cytokines.

Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor-expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P< 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNγ, MIP-1α, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P< 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P =0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.

Liver-directed therapies in patients with advanced neuroendocrine tumors.

Neuroendocrine tumors (NETs) are increasing in incidence. Incidental NETs that may have little clinical significance, such as gastric and rectal primaries, are often identified because of increased screening efforts and advanced imaging modalities. Although NETs are biologically indolent cancers, many patients present with incurable metastatic disease to the liver at initial diagnosis. Some literature suggests a delay averaging almost 5 years in making the correct diagnosis based on clinical symptoms. Although surgical resection offers the only potentially curative therapy, liver-directed therapies, such as embolization and ablation, offer effective alternatives to control symptoms and potentially impact overall survival. This article reviews the latest liver-directed approaches to the management of advanced NETs.

Cytopathologic evaluation of the in situ margin in patients undergoing hepatectomy.

BACKGROUND: Margin status is a predictor of outcome for patients with liver malignancies, although what constitutes a negative margin is controversial. Traditionally, the completeness of resection is estimated by surgical histopathology of the resected specimen margin, despite the in situ margin being potentially more important. The true margin is often altered by parenchymal transection techniques. The authors propose that cytologic assessment of the in situ margin is more specific for determining the true margin. METHODS: A total of 84 patients with primary or metastatic liver tumors who were undergoing surgical resection were enrolled in this prospective Institutional Review Board-approved study. Specimen and in situ (patient) margins were assessed using a "scrape preparation" cytologic technique and compared with traditional surgical histopathology. Patients were followed for assessment of local disease recurrence. RESULTS: Follow-up data were complete for 64 patients for a median of 37 months (range, 12 months-56 months). Twenty patients were excluded because of perioperative death (6 patients; 7%) or a follow-up of < 12 months. Seven patients (12.2%) had positive histopathologic specimen margins, but only 1 was found to be positive by cytology (1.8%). No in situ cytologically positive margins were identified along the cut edge of the liver remnant. The rate of intra- or extrahepatic recurrences was 56.7%, whereas the local recurrence rate was 1.8%. One patient with local recurrence demonstrated simultaneous intra- and extrahepatic disease recurrences and had negative margins by all methods of evaluation. CONCLUSIONS: To the authors' knowledge, the current study is the first to demonstrate that in situ margins can be assessed using cytopathology. This method is quick and can be universally applied. Given the difficulty of accurately assessing margins after hepatectomy, cytopathologic evaluation may be more reflective of the true margin. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.

Prognostic factors and staging for soft tissue sarcomas: an update.

Soft tissue sarcoma (STS) staging is a constantly evolving process. Grading is still of utmost importance and has been adapted into a three-tier system. The STS most difficult to categorize are those with uncertain malignant potential, such as solitary fibrous tumors, gastrointestinal stromal tumors, and glomus tumors, some of which have developed completely separate staging systems and may not even be considered sarcomas. Beyond the current TNM staging system, a multitude of prognostic factors for STS will continue to be discovered and ultimately incorporated into future revisions of the staging system.

Repeat hepatectomy for metastatic colorectal cancer is safe but marginally effective.

BACKGROUND: Although hepatectomy for metastatic colorectal cancer (mCRC) offers prolonged survival in up to 40% of people, recurrence rates are high, approaching 70%. Many patients experience recurrent disease in the liver after initial hepatectomy. We examined our experience with repeat hepatectomy for mCRC. METHODS: After Institutional Review Board approval, we reviewed the records of all patients at a single institution who underwent hepatectomy for mCRC. Repeat hepatectomy was defined as partial liver resection any time after the initial hepatectomy for recurrent mCRC. We estimated time to recurrence and survival by using the Kaplan-Meier method and compared outcomes between groups by using the log-rank test. RESULTS: From 1998 to 2008, 405 patients underwent hepatectomy for mCRC, and 215 (53%) experienced disease recurrence at a median of 13 months. Of 150 patients with liver-only or liver-predominant recurrence, 52 (35%) underwent repeat hepatectomy. The median time to recurrence after repeat hepatectomy was 10 months, and median overall survival was 19 months. There was one (1.9%) perioperative death, and there were 14 (27%) major complications. The median overall survival in the repeat hepatectomy group from the time of recurrence after initial hepatectomy was 22 months, compared with 15 months in the 98 patients with liver recurrence who were not selected for repeat hepatectomy (P=0.02). CONCLUSIONS: Repeat hepatectomy for mCRC is feasible in highly selected patients, with acceptable perioperative morbidity and mortality. Although repeat hepatectomy should be considered, recurrence rates are high. Although the initial hepatectomy for mCRC is potentially curative, recurrence of metastatic disease in the liver is unlikely to be cured.

Use of a nanoporous biodegradable miniature device to regulate cytokine release for cancer treatment.

The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-α), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-α and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-α from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-α was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform.

IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production.

The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 µg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26(HER2/neu)) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ-deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4(+) or CD8(+) T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26(HER2/neu) tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs.

Contralateral prophylactic mastectomy for unilateral breast cancer: an increasing trend at a single institution.

BACKGROUND: An increasing trend in the use of contralateral prophylactic mastectomy (CPM) for the treatment of unilateral breast cancer has been observed nationally. The purpose of this study was to confirm this trend and to identify differences between the groups that chose unilateral mastectomy alone or with CPM. METHODS: A prospectively maintained breast cancer database was retrospectively reviewed. Age, histologic grade, stage, education, family history, tumor receptor status, and use of immediate reconstruction were evaluated. Statistical analysis was performed by Fisher's exact test, chi(2) test, and Student's t-test. RESULTS: Between 1998 and 2007, a total of 1639 women who selected UM and 201 who had UM and CPM for unilateral breast cancer were identified. An increasing trend in CPM was observed (6.5% in 1999 vs. 16.1% in 2007). The CPM group was significantly younger (mean age 47.8 vs. 55.1 years, P < .001). No difference in histologic grade was noted between the two groups; however, an increasing trend toward CPM was observed with lower-stage disease. Women with a higher educational level were more likely to have CPM (P < .001). Women with a family history of cancer were also more likely to have CPM (57% vs. 41%, P < .001). Use of reconstruction was similar between the groups (6.0% for CPM vs. 6.7% for UM, P = NS). CONCLUSIONS: Our experience parallels the national trend of increasing use of CPM in women diagnosed with unilateral breast cancer. Women who chose to have CPM were younger, more highly educated, and more likely to have a family history of cancer.

Clinical factors predictive of malignant and premalignant cystic neoplasms of the pancreas: a single institution experience.

BACKGROUND: As cystic neoplasms of the pancreas are discovered with advanced imaging techniques, pancreatic surgeons often struggle with identifying who is at risk of having or developing pancreatic cancer. We sought to review our experience with the surgical management of cystic neoplasms of the pancreas to determine pre-operative clinical indicators of malignancy or premalignant (i.e. mucinous) lesions. METHODS: Between 1996 and 2007, 114 consecutive patients with cystic neoplasms of the pancreas underwent a pancreatectomy. Invasive adenocarcinoma was identified in 35 whereas 79 had benign lesions. Mucinous lesions were considered premalignant and consisted of 29 intraductal papillary mucinous neoplasms (IPMN) and 17 mucinous cystic neoplasms (MCN). The remaining 33 benign lesions were serous microcystic adenomas. Descriptive statistics were calculated and multivariate logistic regression was performed. Receiver-operating characteristic (ROC) curves were constructed for continuous variables and the area under the curves compared. Likelihood ratios were calculated from the combinations of predictors. RESULTS: Patients with pancreatic cancer arising from a cystic neoplasm were older than those with benign cysts. Mucinous lesions with or without associated cancer were more likely to be symptomatic and present with elevated serum carbohydrate antigen (CA)19-9 levels. Cancers more commonly presented in the head of the pancreas and were associated with longer hospitalizations after resection. Using multivariate logistic regression, size and elevated CA19-9 were predictors of malignancy whereas male gender and size were predictors of mucinous lesions with or without malignancy. Size, however, was not an accurate test to determine premalignant or malignant lesions using area under the ROC curve analysis whereas CA19-9 performed the best regardless of gender or lesion location. CONCLUSIONS: Based upon our single institution experience with resection of cystic neoplasms of the pancreas, we advocate an aggressive surgical approach to any patient with a cystic neoplasm of the pancreas and associated elevated CA19-9.

VEGF secretion is inhibited by interferon-alpha in several melanoma cell lines.

Interferon-alpha (IFN-alpha) is employed in the treatment of malignant melanoma; however, it mediates regression of disease in only 10-15% of patients. Currently, its mechanism of action is uncharacterized. Low-dose IFN-alpha exerts anti-angiogenic effects when used in the treatment of life-threatening hemangiomas of infancy, suggesting anti-angiogenesis as a mechanism of action. IFN-alpha may exert its anti-tumor effect in the setting of advanced malignancy by inhibiting the secretion of vascular endothelial growth factor (VEGF), a pro-angiogenic substance. We hypothesized that IFN-alpha would decrease the release of VEGF by melanoma tumors. We studied the effect of IFN-alpha on VEGF production in nine human melanoma cell lines. We also examined VEGF levels in 49 patients with advanced malignancies who received low-dose IFN-alpha and interleukin-12 (IL-12) on an NCI-sponsored phase I trial. Human melanoma cell lines produced varying amounts of VEGF in vitro (60-1500 pg/mL at 48 h). Certain melanoma cell lines such as 18105 MEL secreted low levels of VEGF (152 pg/mL) after 48 h of culture, whereas other lines secreted very high levels (FO-1 3,802 pg/mL). Treatment of melanoma cells with IFN-alpha (2000 U/mL) decreased VEGF secretion by 40-60% in VEGF-high cell lines; however, this effect was not demonstrated in VEGF-low cell lines. In cancer patients, pretreatment VEGF plasma levels varied from 471 to 4200 pg/mL. A decrease in VEGF plasma levels after treatment directly correlated with the number of treatment cycles administered (Pearson correlation, p = 0.04). In summary, IFN-alpha inhibits VEGF secretion by melanoma cell lines in vitro and may have similar actions in malignancies that respond to IFN-alpha treatment.