Citations

Background: Prophylactic central neck dissection (CND) has been proposed in the treatment of patients affected by papillary thyroid carcinoma (PTC) with clinically negative neck lymph nodes. The procedure allows pathologic staging of lymph nodes of the central compartment and treatment of the micrometastases. Nevertheless, the morbidity that its routine use adds to the total thyroidectomy must be taken into account. The aim of this study was to characterize the morbidity that CND adds to the total thyroidectomy. Methods: This was a retrospective study of 1087 patients with PTC and clinically negative neck lymph nodes. Patients were divided into three study groups: Group A, total thyroidectomy; Group B, total thyroidectomy and ipsilateral CND; Group C, total thyroidectomy and bilateral CND. Primary endpoints of the study were evaluated by comparing the rates of transient and permanent recurrent laryngeal nerve (RLN) injury and hypoparathyroidism in the three study groups. Results: Analysis of data showed no significant differences in the rate of transient (Group A: 3.6%, Group B: 3.9%, and Group C: 5.5%; p =0.404) and permanent (Group A: 1%, Group B: 0.5%, and Group C: 2.3%; p =0.099) RLN injury between the three study groups. Both ipsilateral CND and bilateral CND were associated with a higher rate of transient hypoparathyroidism (Group: A 27.7%, Group B: 36.1%, and Group C: 51.9%; p =0.014; odds ratio [OR]: 1.477; 95% confidence interval [CI]: 1.091–2.001; p <0.001; OR: 2.827; 95% CI: 2.065–3.870, respectively). Bilateral CND had a higher rate of permanent hypoparathyroidism (Group A: 6.3%, Group B: 7%, and Group C: 16.2%; p <0.001; OR: 2.860; 95% CI: 1.725–4.743). Conclusions: The increased rates of transient and permanent hypoparathyroidism in our series suggest a critical review of indications for the routine use of prophylactic CND for PTC. Prophylactic CND ipsilateral to the tumor associated with total thyroidectomy may represent an effective strategy for reducing the rate of permanent hypoparathyroidism. Concomitant completion contralateral paratracheal lymph node neck dissection should be performed in presence of lymph node metastasis on intraoperative frozen-section pathology. This approach limits the use of bilateral CND to patients with intraoperative pathological findings of lymph node metastases.

PurposeThe ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity.Patients and MethodsBetween 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS).ResultsA total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P = .77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P = .44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS.ConclusionFor women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome.

The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 ( SUMF1 ) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1 −/− astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1 , the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.

Abstract Metastatic solid tumors are aggressive and mostly drug resistant, leading to few treatment options and poor prognosis as seen with clear cell renal cell carcinoma (ccRCC) and triple-negative breast cancer (TNBC). Therefore, the identification of new therapeutic regimes for the treatment of metastatic disease is desirable. ccRCC and TNBC cell lines were treated with the HDAC inhibitor romidepsin and the methyltransferase inhibitor decitabine, two epigenetic modifying drugs approved by the U.S. Food and Drug Administration for the treatment of various hematologic malignancies. Cell proliferation analysis, flow cytometry, quantitative PCR, and immunoblotting techniques were used to evaluate the antitumor synergy of this drug combination and identify the reexpression of epigenetically silenced tumor suppressor genes. Combinatorial treatment of metastatic TNBC and stage IV ccRCC cell lines with romidepsin/decitabine leads to synergistic inhibition of cell growth and induction of apoptosis above levels of individual drug treatments alone. Synergistic reexpression of the tumor suppressor gene secreted frizzled-related protein one (sFRP1) was observed in combinatorial drug-treated groups. Silencing sFRP1 (short hairpin RNA) before combinatorial drug treatment showed that sFRP1 mediates the growth inhibitory and apoptotic activity of combined romidepsin/decitabine. Furthermore, addition of recombinant sFRP1 to ccRCC or TNBC cells inhibits cell growth in a dose-dependent manner through the induction of apoptosis, identifying that epigenetic silencing of sFRP1 contributes to renal and breast cancer cell survival. Combinatorial treatment with romidepsin and decitabine in drug resistant tumors is a promising treatment strategy. Moreover, recombinant sFRP1 may be a novel therapeutic strategy for cancers with suppressed sFRP1 expression. Mol Cancer Ther; 11(10); 2105–15. ©2012 AACR.

BACKGROUND AND OBJECTIVES: Infantile hemangiomas (IH) are recognized as growing rapidly during the first months of life, but details of early growth before 3 months of age have not been well-characterized. Our goal was to study early IH growth by using parental photographs of infant children with facial IHs to better understand early hemangioma growth, with the aim of improving guidance for physicians and parents of infants with high-risk IH. METHODS: Serial images of 30 infants showing IH at intervals of 1 to 2 weeks up to 6 months were analyzed for characteristics of color, thickness, and distortion of anatomic landmarks. The presence or absence of an IH precursor at birth was noted. Mean scores per age interval were compiled. Results were analyzed by using signed rank test. An assessment of “optimal time for referral” was made. RESULTS: IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age. The mean “optimal age for referral” was 4 weeks of age. Hemangioma precursors were present at birth in 65% of patients. CONCLUSIONS: The most rapid hemangioma growth occurs before 8 weeks of age, much earlier than previously appreciated. Specialty evaluation and initiation of treatment, however, typically occur after the age of most rapid growth. Our findings suggest a need for a paradigm shift in the timing of referral and initiation of treatment of high-risk IH so that therapy can be initiated before or early in the course of most rapid growth, rather than after it is already completed.

SummaryWe have observed T helper type 2 (Th2) polarization of systemic immunity in patients with metastatic malignant melanoma. We hypothesized that similar changes in systemic immunity occur with ageing and may be permissive for the development of melanoma. We analysed the peripheral blood of 389 healthy blood donors. All subjects were profiled for peripheral blood T cell and B cell subsets, and 58 of these subjects were profiled for antigen-specific cytotoxic T cell subsets [cytomegalovirus (CMV), influenza and melanoma antigen recognized by T cells 1 (MART-1)]. Ninety-five separate healthy subjects underwent profiling of 42 plasma cytokines. Ageing was associated positively with CD4+CD294+ Th2 cells, and associated negatively with CD3+ T cells, cytotoxic T cells and T helper cells. Ageing was also associated negatively with CMV-, influenza- and MART-1-specific naive and CD8+ T cells. There were significant increases in plasma monocyte chemotactic protein 1 (MCP-1) (CCL1) and regulated upon activation normal T cell expressed and secreted (RANTES) (CCL5) with age. We observed differences in cytokine profiles between males and females; specifically, women had higher levels of sCD40L and PDGF-AA. In summary, we demonstrated in healthy blood donors that ageing was associated with an increase in cellular Th2 bias and a decline in total numbers of T cells. Additionally, there was an increase in MCP-1 and RANTES with ageing. Women had higher levels of sCD40L and PDGF-AA than men.