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Background: Differentiated thyroid cancer (DTC) is comprised of papillary and follicular subtypes, and both have an overall excellent long-term prognosis. Patients with localized DTC that is successfully treated, usually with surgery, exhibit long-term survival well above 90%. In contrast, patients who develop distant metastatic disease have a significantly worse overall prognosis and outcome, often with disease that is refractory to conventional therapy such as surgery, radioactive iodine, and hormone suppression. For patients who recur with distant metastatic disease, limited effective treatment options are available, and most die of their disease within 5 years of recurrence. Case Report: We report the case of a 26-year-old female who presented with recurrent papillary thyroid cancer and a metastatic lesion isolated to the liver. Because of the extremely large size of the metastatic liver mass upon initial presentation, we took a neoadjuvant, multifaceted approach to treatment that included selective internal radioembolization therapy, an oral multikinase inhibitor, and surgical resection of the tumor mass after maximal reduction in tumor size. However, the patient died of metastatic DTC after 39 months of treatment. Conclusion: A multimodal, comprehensive approach to managing such complex patients is essential to optimize both the sequence and therapeutic approach to treatment. [ABSTRACT FROM AUTHOR]

Background: Male breast cancer (MBC) is an uncommon malignancy with an incidence that accounts for about 1% of all breast cancer cases. It commonly presents as a locally advanced tumor that has already spread to the regional nodal basin. Similar to female breast cancers, MBC gene expression profiling and tumor studies help to detect molecular subtypes of tumors that correlate with clinical outcome and mortality rates. Case Report: We report a relatively uncommon case of a 64-year-old male with a BRCA1þgene mutation that is also found to be HER2þ on receptor analysis. Initial diagnostic studies with mammography and ultrasound revealed a left-sided hypoechoic mass measuring 2.3 cm, located at the 11 o'clock position adjacent to the nipple-areolar complex. Whole body positron emission tomography-computed tomography scan revealed a hypermetabolic retroareolar left breast mass and enlarged, hypermetabolic left axillary lymph nodes. Final pathology revealed an infiltrating ductal carcinoma with a Nottingham histologic score of 3 (mitotic count score, 3; nuclear pleomorphism score, 3). Of the 19 lymph nodes examined, 15 had evidence of macrometastatic disease. Conclusion: This report highlights a novel case of MBC with a rare genotypic presentation. A need exists to further explore this disease process because the literature is scant with information regarding the long-term treatment and outcomes of MBC, especially in the genotypic form presented here. Subsequent studies in the long-term outcomes of various MBC cases will need to be pursued to better understand the optimal screening and treatment strategies for this disease. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced melanoma have a poor outcome. We hypothesize that combination immunotherapy can synergistically activate host immunity to generate an effective treatment for patients with high-risk, resected stage 3, recurrent, refractory, or stage 4 melanoma. Methods: We conducted a phase 2 clinical trial of HyperAcute Melanoma (HAM) vaccine (NLG-12036, NewLink Genetics) combined with pegylated interferon (Sylatron, Merck). Trial design consisted of a 12-week regimen with the initial 4 weekly treatments consisting of HAM alone (intradermally) followed by 8 additional treatments of HAM plus Sylatron (subcutaneously, 6 μg/kg). Trial endpoint outcomes include clinical response, overall safety, and correlative findings for observed antitumor effect. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the role of DNA repair genes in melanoma pathogenesis.

The proper method of biopsy and definitive surgical excision of cutaneous melanoma is vital for optimal patient outcome. Clearly, the present authors’ understanding of the pathophysiology of cutaneous melanoma continues to change at a rapid pace. Indeed, as the present authors’ research efforts begin to expose some of the mysteries of melanoma, so do they begin to better understand the intricacies of this dreaded cancer. This article will highlight methods of biopsy for melanoma and the management of the primary tumor. The present authors review current recommendations for excision margins for the primary tumor, usefulness of lymphoscintigraphy, timing of definitive surgical excision, and issues unique for head and neck melanoma. [ABSTRACT FROM AUTHOR]

Abstract: The immunotherapy of patients with metastatic melanoma is currently at a crossroads. Indeed, recent results from vaccine strategies worldwide have revealed a strikingly low overall response rate in patients with stage IV melanoma. Although disappointing, we have gained valuable insight and knowledge about how vaccines interact with the host immune response and to melanoma. However, although an immunological response to therapy is often reported from various clinical trials, it does not contribute to a patient''s long term survival. It has been proven time and again that an immunological response to therapy does not necessarily translate into a meaningful clinical response. This frustrating dichotomy of response continues to vex investigators, providing a glaring example of our poor understanding of the immunologic response to cancer. Thus, we remain at the crossroads of understanding and treatment. On the one hand, we have dramatically advanced the field of tumor immunology/immunotherapy over the last 20 years. On the other hand, we have made little headway in truly developing effective treatment options for patients with stage IV disease. We must realize our previous shortcomings and failures in order to learn from them and develop improved therapies. The future of immunotherapy remains a bright ray of hope for everyone, with the road to success paved with the previous hard work of thousands of clinicians and researchers everywhere. Towards this end, this review hopes to provide the reader with the current state of affairs for the immunotherapy of melanoma as well as a primer of where we might be heading in the future. [Copyright &y& Elsevier]

Expression of the pigmentation-associated genePMel17is regulated by a 1 kB promoter region shared between thePMel17andCDK2genes. The encoded melanosomal glycoprotein gp100 and the cell cycle regulatory protein CDK2 are transcribed in opposite directions. Luciferase reporter constructs were generated for subregions of the promoter containing 0, 1, 2 or 3 putative binding sites for transcription factors with basic helix–loop–helix (bHLH) motifs. The potential contribution of bHLH transcription factor microphthalmia transcription factor (MITF) to promoter activity was investigated by re-introducing microphthalmia into melanoma cells lacking expression. A bi-directional reporter construct was generated to investigate potential co-regulation of gp100 and CDK2 transcription. Promoter activity was assessed in presence and absence of phorbol ester tetradecanoyl phorbol 13-acetate (TPA). FACS analysis and immunohistology served to evaluate co-regulation of gp100 and CDK2 expression at the protein level. The full-length promoter, including a consensus binding site for MITF was found to contain sequences that suppressed gp100 expression. Introduction of MITF into non-expressing 1123 melanoma cells did not restore gp100 expression levels. A lack of coregulation for gp100 and CDK2 as suggested by immunostaining was supported by findings of dissimilar expression regulation by TPA for either gene. The current study provides insight into transcriptional regulation of thePMel17andCDK2genes, important to identify strategies for modulating expression of gp100 and CDK2 proteins by melanoma cells. [ABSTRACT FROM AUTHOR]

Background: Formerly, anesthetized patients who received intraoperative radiation therapy (IORT) had to be transported from the operating room (OR) to the location of the linear accelerator. With the advent of mobile accelerators, therapy is delivered directly to the patient in the OR, presenting specific challenges for the anesthesiologist. Methods: We review the uses and benefits, operative and anesthetic challenges, and unique issues associated with IORT. Results: Patient safety and precise delivery of the radiation dose are the primary goals of IORT. The anesthesiologist's role in ensuring the success of these two outcomes includes selecting the optimal anesthetic technique to prevent patient movement and permit sentinel node mapping, monitoring the patient's vital signs throughout the procedure, and ensuring that the sterile field is maintained in the OR. Conclusion: Although keeping patients in the OR has simplified the process of providing IORT, the anesthesiologist must be aware of potential problems and plan accordingly. [ABSTRACT FROM AUTHOR]

The chief goal of the Blood Profiling Atlas in Cancer (BloodPAC) consortium is to promote collaborative efforts that support the development and implementation of liquid biopsy tests. Here, we report the results of a pilot study conducted by three BloodPAC members that aimed to demonstrate a multisite liquid biopsy testing framework using longitudinal blood specimens from 38 patients with metastatic breast cancer. Three laboratories receiving identical samples from two clinical sites each applied a different targeted sequencing platform to analyze mutations in cell-free DNA (cfDNA). The resulting mutational profiles reflected common breast cancer alterations, including clinically actionable mutations for 40% of hormone- receptor-positive patients. In 12 genes with shared target regions across sequencing panels, perfect inter-assay concordance was also observed for mutations detected above the lowest common assay limit of detection. Whole-genome copy number profiling of cfDNA and circulating tumor cells (CTCs) further revealed marked heterogeneity in copy number alterations and cfDNA tumor fractions across patients. Additionally, comparison of tumor fraction and CTC abundance demonstrated the complementary nature of cfDNA and CTC analyses. Overall, the framework described in this study may serve as a resource for future trials aiming to identify multimodal liquid biopsy biomarkers to guide clinical care. [ABSTRACT FROM AUTHOR]

Background: Male breast cancer remains relatively underexplored in the medical literature. At present, male patients with breast cancer follow the same treatment guidelines as female patients with breast cancer, principally because of similar outcomes with treatment. However, this practice should not preclude generating evidence for male breast cancer surveillance, diagnosis, and management. BRCA2 gene mutations are associated with an increased risk of male breast cancer, along with lesser-known gene mutations that could also increase this risk, such as mutations of the BRIP1 gene. This case report presents a male patient with dual BRCA2 and BRIP1 deleterious gene mutations. To our knowledge, this combination has not been reported in the medical literature to date. Case Report: A 53-year-old male presented with a palpable symptomatic mass underneath the right nipple-areolar complex. Biopsies confirmed a poorly differentiated, infiltrating ductal carcinoma that was estrogen and progesterone receptor positive and human epidermal growth factor receptor-2 negative. The patient underwent a left modified radical mastectomy, with a right prophylactic simple mastectomy. Postoperatively, he underwent adjuvant chemotherapy and endocrine therapy. Conclusion: This novel case of genetically based male breast cancer with dual deleterious gene mutations provides insight into current treatment recommendations and the subtle differences between male breast cancer and female breast cancer. Engaging in discussions surrounding such rare cases not only raises awareness of male breast cancer but also indicates the need for further research aimed at establishing evidence-based management strategies for male patients with breast cancer. [ABSTRACT FROM AUTHOR]

The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated gene 9) system is an RNA-guided, DNA editing method that has been widely used for gene editing, including human viruses. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), following latent infection in human cells, can cause a variety of malignancies, such as Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), with a high prevalence in immunocompromised patients. Of significant concern, the latent infection with KSHV has been shown to lead to increased resistance to antiviral therapies. MicroRNAs (miRNAs) are a set of non-coding, small RNA molecules that regulate protein-coding genes at the post-transcriptional and translational levels. KSHV has its miRNAs, most of which are expressed in latently infected cells and play a crucial role in maintaining KSHV latency. Notably, by regulating the expression of the downstream target genes in host cells, KSHV miRNAs can interact with the host environment to promote the development of KSHV-related diseases. Although CRISPR/Cas9 has been reported to edit KSHV protein-coding genes, there is no published literature on whether the CRISPR/Cas9 system can regulate the expression of KSHV miRNAs. In this study, we used CRISPR/Cas9 to inhibit the expression of KSHV miRNAs by directly editing the DNA sequences of individual KSHV miRNAs, or the promoter of clustered KHSV miRNAs, in latent KSHV-infected PEL cells. Our results show that CRISPR/Cas9 can ablate KSHV miRNAs expression, which in turn leads to the upregulation of viral lytic genes and alteration of host cellular gene expression. To the best of our knowledge, our study is the first reported demonstration of the CRISPR/Cas9 system editing KSHV miRNAs, further expanding the application of CRISPR/Cas9 as a novel antiviral strategy targeting KSHV latency. • CRISPR/Cas9 can robustly and precisely regulate KSHV miRNAs in KSHV-infected PEL cells. • CRISPR/Cas9 downregulating KSHV miRNAs can alter the expression of their downstream target genes and KSHV lytic genes in host PEL cells. • CRISPR/Cas9 is a novel antiviral strategy targeting KSHV latency. [ABSTRACT FROM AUTHOR]

Background: Frailty is characterized by reduced physiologic reserve, and for patients with colon cancer, frailty is associated with increased morbidity after resection. One commonly cited reason for performing an end colostomy vs a primary anastomosis in left-sided colon cancer is the belief that frail patients do not have the physiologic reserve to withstand the morbidity associated with an anastomotic leak. We explored the impact of frailty on the type of operation performed in patients with left-sided colon cancer. Methods: We queried the American College of Surgeons National Surgical Quality Improvement Program for patients with colon cancer who underwent a left-sided colectomy from 2016 to 2018. Patients were categorized using the modified 5-item frailty index. Multivariate regression was used to identify independent predictors of complications and type of operation performed. Results:Of 17,461 patients, 20.7% were considered frail. Frail patients received an end colostomy more often than nonfrail patients (11.3% vs 9.6%, P=0.01). On multivariate analysis, frailty was a significant predictor for total medical complications (odds ratio [OR] 1.45, 95% CI 1.29-1.63) and readmission (OR 1.53, 95% CI 1.32-1.77) but was not independently associated with organ space surgical site infections or reoperation. Frailty was independently associated with receiving an end colostomy vs a primary anastomosis (OR 1.23, 95% CI 1.06-1.44), but an end colostomy did not decrease the risk of reoperation or organ space surgical site infections. Conclusion: Frail patients with left-sided colon cancer are more likely to receive an end colostomy, but an end colostomy does not lower the risk of reoperation or organ space surgical site infections. Based on these results, frailty alone should not prompt the decision to perform an end colostomy, but further studies are needed to guide surgical decision-making in this understudied population. [ABSTRACT FROM AUTHOR]

The metastasis suppressor, BRMS1, has been demonstrated to cause dramatic regression of metastatic lesions without blocking orthotopic tumor growth. The role of BRMS1 is well-documented for several non-melanoma malignancies, such as breast cancer, ovarian cancer and non-small-cell lung cancer. However, its role in melanoma is just beginning to be understood, with a recent article by Slipicevic et al. highlighting the levels of expression of BRMS1 in benign nevi, primary and metastatic melanoma samples. Their findings emphasize that the intracellular location of BRMS1 protein (cytoplasmic or nuclear), appears to have a significant impact upon the metastatic capacity of melanoma cells. Interestingly, this selective localization translates into a statistically significant decrease in the relapse-free period in melanoma patients, further associated with a thicker Breslow's depth of primary melanomas. However, and more importantly, this study begins to define a clearer role for BRMS1 in melanoma that is strictly dependent upon its cellular location, with nuclear expression associated with invasive and metastatic capacity and cytoplasmic expression resulting in repressive effects upon progression and metastasis. [ABSTRACT FROM AUTHOR]

Background: Allergic reactions including anaphylaxis resulting from isosulfan blue dye are rare but warrant a thorough review given that lymph node mapping has become an increasingly common procedure, putting more patients at risk. Case Report: Our patient was an 82-year-old female who underwent elective excision of a right forearm melanoma and right axillary sentinel lymph node mapping and suffered an anaphylactic reaction approximately 15 minutes after injection of isosulfan blue dye. The procedure was aborted. She was intubated; diphenhydramine and dexamethasone were administered; her blood pressure was stabilized with phenylephrine, epinephrine, and intravenous fluids; and she was transferred to the intensive care unit. She was extubated on postoperative day 1 and discharged home on postoperative day 2. Conclusion: Sentinel lymph node biopsy is the standard of care for staging several cancers, and isosulfan blue is the dye most commonly used for this procedure. Reactions to the dye occur in some patients; however, we recommend the continued use of isosulfan blue dye for lymph node mapping given the low incidence of adverse effects, with no reported mortalities. Physicians should be prepared for the potential risk of anaphylactic shock. [ABSTRACT FROM AUTHOR]

Background: To meet increased community and regional needs for quality services, our hospital systemconcluded that its established surgical oncology program--consisting of gynecologic oncology (4 physicians), surgical oncology (2 physicians), and otolaryngologic oncology (2 physicians)--would be best served by the transition of the comprehensive surgical oncology program to a new oncology-naive hospital. We describe the overall strategy and approach involved with this move, its implementation, operating room efficiency results, and physician satisfaction associated with the relocation. Methods: The purpose of the systematic plan for relocation, which was developed and refined during the 2 years preceding the move, was to facilitate a collective awareness and understanding of important patient-centered concepts and essential workflow. All parties involved in direct patient cancer care participated in multiple workgroups to successfully transition the surgical oncology practice. Following the transition to the oncology-naive hospital, components of the operative cases and surgical data were prospectively collected for the initial 6weeks and compared to retrospective data fromthe last 8weeks at the established hospital. The surgical day for each surgeon was deconstructed, and measured variables included total surgical cases, total surgical hours, surgical minutes per case, total anesthesia hours, first case on-time surgical starts, surgical stretcher wheels out to surgical stretcher wheels in, surgical stretcher wheels out to next case start, case end to postanesthesia care unit (PACU), and case end to case start. Results: Five hundred twenty-nine surgical cases encompassing 1,076 anesthesia hours and 710 surgical hours were completed during the 14-week evaluation period. The gynecologic oncologists completed themajority of surgical procedures in both settings. The percentage of first case on-time surgical starts initially decreased during the 6-week interval at the oncology-naive hospital, but interval subset analysis suggested a return to the pre-move norm. Surgical stretcher wheels out to surgical stretcher wheels in had a wide range (9 minutes to 305 minutes) for all surgical sections, but no statistically significant difference was seen overall or for any surgical section. Case end to PACU significantly increased for gynecologic oncology but not for surgical oncology or otolaryngologic oncology. Overall case end to case start times decreased nonsignificantly (63.7 ± 3.1 mean minutes vs 60.3 ± 1.7 mean minutes) following the move. A physician survey found that physicians' expectations were met in terms of the move occurring smoothly without major issues, surgical scheduling and accommodation, anesthesia services, and surgical personnel. Physicians indicated less satisfaction with quality and availability of instrumentation. Conclusion: The transfer of established surgical oncology services to an oncology-naive hospital was associated with early surgeon and operating room staff support, as well as process and programmatic alignment among stakeholders. The success of this transition required transparency, open and honest communication, and problem solving at all levels. The move of a surgical oncology program to an oncology-naive hospitalwas deemed successful without deterioration of time-related variables associated with operating room efficiency and physician satisfaction. The breakdown and analysis of key components of the surgical day offered additional opportunities for quality improvement in operating room efficiency. [ABSTRACT FROM AUTHOR]

Background: Enhanced Recovery after Surgery formastectomy has resulted in increased use of outpatient same-daymastectomy (SDM). Whether SDM leads to increased readmissions or reoperations is not well documented. This study examines national data to compare outcomes of SDM to an overnight stay. Methods: We analyzed the American College of Surgeons National Surgical Quality Improvement Program Participant Use Data File from 2016 to 2018 for all mastectomy cases. Cases with a length of stay (LOS) >1 day were excluded. Cases were then categorized into 2 LOS cohorts: SDM vs 1-day LOS. Results: A total of 22,642 cases (80.8% 1-day LOS vs 19.2% SDM) were identified for the final analysis. Patients in the 1-day LOS group were more likely to be older (57.9 vs 54.0 years, P<0.01), be female (98.0% vs 79.8%, P<0.01), and have greater comorbidity (38.1% vs 30.7% American Society of Anesthesiologists classification 3 or 4, P<0.01) compared to the SDM group. Multivariate analysis demonstrated no difference in risk for 30-day wound complications between the SDM and 1-day LOS groups. The risks for 30-day medical complications (1.60 odds ratio [OR], 95% CI 1.06-2.42, P=0.02), reoperations (1.46 OR, 95% CI 1.17-1.81, P<0.01), and readmissions (1.60 OR, 95% CI 1.25-2.05, P<0.01) were higher in the 1-day LOS group. Even after excluding patients undergoing reoperation on the day of surgery, the risk for reoperations (2.3% vs 3.3%, P<0.01) remained higher in the 1-day LOS group. Characteristics associated with 1-day LOSwere hypertension, steroid use, diabetes, dyspnea, dependent functional status, bilateral procedures, and breast reconstruction. Conclusion: We demonstrate that SDM is a safe procedure, with no increase in risk for 30-day postoperative complications. Appropriate patients should be offered SDM. [ABSTRACT FROM AUTHOR]

Objective: Breast cancer metastasis suppressor 1 (BRMS1) has been shown to functionally reduce the metastatic potential of melanoma. We also previously reported that BRMS1 negatively regulates the expression of the oncoprotein osteopontin (OPN). This study was carried out to assess the clinical relevance of BRMS1 and OPN in melanoma. Methods: Epigenetic regulation of BRMS1 was assessed by treating clinically derived melanoma cell lines with the demethylating agent 5-aza-2′-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA), followed by sodium bisulfite modification and methylation-specific PCR. Assessments of BRMS1 and OPN levels were performed using immunoblotting, quantitative real-time RT-PCR or reporter assays. RNA silencing was employed to abrogate the expression of OPN in melanoma-derived cell lines. The in vivo relevance of our findings was determined with experiments using athymic nude mice. Results: The reduced expression of BRMS1 in surgically excised melanoma specimens correlated with increased OPN expression during the progression from primary to metastatic melanoma. Treatment with DAC and TSA elevated BRMS1 levels, but caused an inconsistent change in OPN gene expression. Abrogating the expression of OPN in BRMS1-deficient metastatic melanoma-derived cell lines retarded the growth of melanoma tumor xenografts in athymic nude mice. Conclusion: While treatment with DAC and TSA may not be a universally applicable treatment alternative in melanoma, silencing the expression of OPN in metastatic melanomas that have lost expression of BRMS1 is a potential option for therapeutic intervention. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The significance of micrometastatic disease in the sentinel lymph nodes (SLN) of patients with invasive breast cancer has been questioned. The objective of our study was to review the impact of micrometastatic carcinoma detected by SLN biopsy. Study Design: Between January 1997 and May 2004, 2,408 patients with invasive breast cancer and an SLN with micrometastatic (N0[i+], N1mi) or no metastatic (N0[i−]) disease were identified through our breast database. Slide review was performed and reclassified by the 6th edition of the American Joint Committee on Cancer Staging Manual. Of these, 27 were excluded from analysis because of evidence of macrometastatic disease on slide review or enrollment in the American College of Surgeons Oncology Group Z10 study. Results: Of 2,381 patients, 2,108 were N0(i−), 151 were N0(i+), and 122 were N1mi. Overall and disease-free survivals of patients with an N1mi SLN were substantially worse than those in patients with an N0(i−) SLN (p < 0.001 and p=0.006, respectively). Additional positive non-SLNs were identified in 15.5% (15 of 97) of N1mi patients and 9.3% (10 of 107) of N0(i+) patients undergoing completion axillary lymph node dissection. Overall survival of the N0(i+) SLN patients not undergoing axillary dissection was substantially less than those undergoing axillary dissection (p=0.02). Conclusions: Detection of micrometastatic carcinoma (N1mi) in the SLNs of invasive breast cancer patients is a major indicator of poorer survival compared with N0(i−) patients. Although survival of patients with an N0(i+) SLN does not statistically differ from that of N0(i−) patients, 9.3% of these patients had additional axillary nodal disease on axillary dissection, and N0(i+) patients had a decreased survival when axillary dissection was omitted. [Copyright &y& Elsevier]

Background: National data demonstrate a trend toward outpatient same-day mastectomy. The possible drivers of this change include the costs related to hospital admission and effectivemanagement of postoperative pain. We retrospectively analyzed our single-institution experience with outpatient same-day mastectomy that incorporates a multimodal pain management regimen. Methods:We retrospectively reviewed themedical records of patientswhounderwent same-daymastectomy at a single academic hospital. All patients received a multimodal, perioperative pain management regimen consisting of the intraoperative administration of 1,000 mg of intravenous (IV) acetaminophen and 30 mg of IV ketorolac, combined with the operating surgeon performing a 4- to 5-level, midaxillary, intercostal nerve block using liposomal bupivacaine. All patients were discharged with a prescription for acetaminophen with codeine, along with options for nonnarcotic alternatives as needed for pain. Results: We reviewed the data on 72 patients who underwent mastectomies: 11 (15.3%) bilateral and 61 (84.7%) unilateral. The average age was 57 years, and average body mass index was 30 kg/m2. The average length of stay of 4 to 6 hours was a marked reduction compared to a 23-hour observational period or an inpatient hospital stay. The average follow-up was 20.1 weeks. Five patients presented to the emergency department (ED) within the 30-day postoperative period, with 2 patients (2.8%) requiring readmission to the hospital for non-pain-related issues. The other 3 patients (4.2%) were evaluated for specific pain-related issues but did not require admission and were discharged home from the ED. Conclusion: Our data support outpatient same-day mastectomy incorporating a multimodal, perioperative pain management regimen as a safe and feasible treatment option. Potential additional benefits may include decreased oral opioid use and cost savings for the hospital. [ABSTRACT FROM AUTHOR]

Metaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, with similar features to basal-like breast cancers. Due to rapid growth rates and characteristic heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in various cancers, including basal-like breast cancers. We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, and in vivo implanted tumors were treated. Finally, we tested the effects of combining DACi with approved chemotherapeutics on relative cell biomass. DACi significantly suppressed the total number of lung metastasis in vivo using our PDX model, suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites. These data were supported by our findings that DACi reduced cell migration, populations, and expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-regulating genes in vitro, tumor growth was not affected compared to controls. Importantly, gene expression results varied depending on the cellular or tumor system used, emphasizing the importance of using multiple derivations of cancer models in preclinical therapeutic discovery research. Furthermore, DACi sensitized and produced a synergistic effect with approved oncology therapeutics on inherently resistant MBC. This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 inhibitors exerts a synergistic effect on MBC cells was also demonstrated. [ABSTRACT FROM AUTHOR]

Background: Desmoid tumors are relatively uncommon tumors, and those occurring sporadically and in an intraabdominal location are especially rare. Although desmoid tumors have a benign histologic appearance and lack the ability to metastasize, they can invade locally, often aggressively, grow to large sizes, and recur repeatedly. Case Report: We present the case of a symptomatic, giant mesenteric desmoid tumor discovered incidentally during workup for the patient's previous history of lung cancer. The patient elected to undergo palliative resection of the tumor because of persistent and unrelenting abdominal pain. Conclusion: Because of the rarity of the disease, no clear evidence-based guidelines exist for the treatment of sporadic mesenteric desmoid tumors. Review of the available literature suggests that surgical resection with negative margins is a reasonable approach for patients with symptomatic tumors. [ABSTRACT FROM AUTHOR]

Background: Imiquimod is a topical cream approved by the US Food and Drug Administration for treatment of superficial basal cell carcinoma, actinic keratosis, and genital-perianal warts. Its successful use in patients with persistently positive margins of melanoma in situ (MIS) after surgical excision has been previously reported. Case Report: A 75-year-old female presented with a primary melanoma that was removed through an elliptical excision with 1 cm margins. Pathology revealed 3 involved margins with residual MIS without an invasive component. After a second operation removed an additional 1 cm margin, pathology revealed 2 positive margins with residual MIS. Rather than undergoing a third excision, the patient decided to pursue a nonsurgical approach with topical imiquimod, and at the 4-month follow-up examination, the incision was completely healed with no clinical evidence of tumor recurrence. Conclusion: A nonsurgical approach with 5% topical imiquimod cream applied along the incision was utilized. In specific patient populations, the use of imiquimod is a reasonable alternative approach for the management of persistently positive MIS margins. Long-term follow-up is necessary to assess for evidence of recurrence and the ultimate success of this nonsurgical approach. [ABSTRACT FROM AUTHOR]

Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow’s 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Background: Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue tumor with intermediate malignant potential. It most commonly occurs in children and young adults. Case Report: We report a case of a recurrent AFH of the back, locally recurring within 14 months of the original operation. We also review the literature for this uncommon entity. The patient underwent a wide resection of the recurrent AFH, obtaining negative surgical margins. Postoperatively, he has done well. Conclusion: Twelve months since his re-excision, the patient shows no evidence of recurrence to date. He is seen every 6 months for continued clinical examinations. [ABSTRACT FROM AUTHOR]

Background: Amyloidosis of the breast is an unusual diagnosis. Overall, only 2 major case series have been published in the literature since the time amyloidosis was first reported in 1973, highlighting the rare nature of this disease. Clinically, the patient may present with a breast mass or simply increased breast density and skin thickening. As such, amyloidosis may mimic the appearance of a number of pathologies, both benign and malignant. Case Report: We report a single case of a patient who presented with a breast mass and was ultimately diagnosed with primary amyloidosis of the breast. We also present a review of the literature to date. Conclusion: The main treatment for primary amyloidosis of the breast is surgical removal, most often accomplished with breast conservation via lumpectomy. In performing the lumpectomy, the goal should be to obtain negative surgical margins; however, no strong data exist to suggest that such lesions would recur with a microscopically positive margin. [ABSTRACT FROM AUTHOR]

Abstract: The integral membrane channel protein aquaporin (AQP) is aberrantly expressed with oncogenic characteristics in various human cancers. In this study, we analyzed the expression pattern of all subtypes of AQPs, and found that 8 out of 13 AQPs expressed in melanoma cells. To understand the role of aberrant expression of AQP in this disease, we over-expressed AQP3 and AQP9 in human melanoma WM266.4 cells and found that both AQPs significantly increased the chemoresistance of WM266.4 cells to arsenite. Functional studies showed that AQP3 and AQP9 can inhibit cell apoptosis induced by arsenite through down-regulating p53 and up-regulating Bcl-2 and XIAP. Our data suggest the implication of APQ in melanoma progression and that the over-expression of AQP3 and AQP9 contributes to the chemoresistance of melanoma to arsenite. [Copyright &y& Elsevier]

Paclitaxel (Taxol) is an effective chemotherapeutic agent for treatment of cancer patients. Despite impressive initial clinical responses, the majority of patients eventually develop some degree of resistance to Taxol-based therapy. The mechanisms underlying cancer cells resistance to Taxol are not fully understood. MicroRNA (miRNA) has emerged to play important roles in tumorigenesis and drug resistance. However, the interaction between the development of Taxol resistance and miRNA has not been previously explored. In this study we utilized a miRNA array to compare the differentially expressed miRNAs in Taxolresistant and their Taxol-sensitive parental cells. We verified that miR-125b, miR-221, miR-222, and miR-923 were up-regulated in Taxol-resistant cancer cells by real-time PCR. We further investigated the role and mechanisms of miR-125b in Taxol resistance. We found that miR-125b was up-regulated in Taxolresistant cells, causing a marked inhibition of Taxol-induced cytotoxicity and apoptosis and a subsequent increase in the resistance to Taxol in cancer cells. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bakl) is a direct target of miR-125b. Down-regulation of Bakl suppressed Taxol-induced apoptosis and led to an increased resistance to Taxol. Restoring Bakl expression by either miR-125b inhibitor or re-expression of Bakl in miR-125b-overexpressing cells recovered Taxol sensitivity, overcoming miR-125-mediated Taxol resistance. Taken together, our data strongly support a central role for miR-125b in conferring Taxol resistance through the suppression of Bakl expression. This finding has important implications in the development of targeted therapeutics for overcoming Taxol resistance in a number of different tumor histologies. [ABSTRACT FROM AUTHOR]

Motivation: MicroRNA (miRNA) is a set of newly discovered non-coding small RNA molecules. Its significant effects have contributed to a number of critical biological events including cell proliferation, apoptosis development, as well as tumorigenesis. High-dimensional genomic discovery platforms (e.g. microarray) have been employed to evaluate the important roles of miRNAs by analyzing their expression profiling. However, because of the small total number of miRNAs and the absence of well-known endogenous controls, the traditional normalization methods for messenger RNA (mRNA) profiling analysis could not offer a suitable solution for miRNA analysis. The need for the establishment of new adaptive methods has come to the forefront. [ABSTRACT FROM PUBLISHER]

Background: High activity of cysteine proteases such as legumain and the cathepsins have been shown to facilitate growth and invasion of a variety of tumor types. In breast cancer, several recent studies have indicated that loss of the cysteine protease inhibitor cystatin E/M leads to increased growth and metastasis. Although cystatin E/M is normally expressed in the skin, its role in cysteine protease regulation and progression of malignant melanoma has not been studied. Methods: A panel of various non-melanoma and melanoma cell lines was used. Cystatin E/M and C were analyzed in cell media by immunoblotting and ELISA. Legumain, cathepsin B and L were analyzed in cell lysates by immunoblotting and their enzymatic activities were analyzed by peptide substrates. Two melanoma cell lines lacking detectable secretion of cystatin E/M were transfected with a cystatin E/M expression plasmid (pCST6), and migration and invasiveness were studied by a Matrigel invasion assay. Results: Cystatin E/M was undetectable in media from all established melanoma cell lines examined, whereas strong immunobands were detected in two of five primary melanoma lines and in two of six lines derived from patients with metastatic disease. Among the four melanoma lines secreting cystatin E/M, the glycosylated form (17 kD) was predominant compared to the non-glycosylated form (14 kD). Legumain, cathepsin B and L were expressed and active in most of the cell lines, although at low levels in the melanomas expressing cystatin E/M. In the melanoma lines where cystatin E/M was secreted, cystatin C was generally absent or expressed at a very low level. When melanoma cells lacking secretion of cystatin E/M were transfected with pCST6, their intracellular legumain activity was significantly inhibited. In contrast, cathepsin B activity was not affected. Furthermore, invasion was suppressed in cystatin E/M over-expressing melanoma cell lines as measured by the transwell Matrigel assay. Conclusions: These results suggest that the level of cystatin E/M regulates legumain activity and hence the invasive potential of human melanoma cells. [ABSTRACT FROM AUTHOR]

Background: Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation. Methods: Full length MITF-M and its splice variant cDNA were cloned from human melanoma cell line 624 mel by reverse transcription polymerase chain reaction (RT-PCR). Expression was investigated using regular and quantitative RT-PCR in three normal melanocytes (NHEM), 31 melanoma cell lines, 21 frozen melanoma tissue samples, 18 blood samples (pheripheral blood mononuclear cell; PBMC) from healthy donors and 12 non-melanoma cancer cell lines, including three breast, five glioma, one sarcoma, two kidney and one ovarian cancer cell lines. Results: A novel splice variant of MITF-M, which we named MITF-Mdel, was identified. The predicted MITF-Mdel protein contains two in frame deletions, 56- and 6- amino acid deletions in exon 2 (from V32 to E87) and exon 6 (from A187 to T192), respectively. MITF-Mdel was widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines or PBMC from healthy donors. Both isoforms were expressed significantly higher in melanoma tissues than in cell lines. Two of 31 melanoma cell lines expressed only one isoform or the other. Conclusion: MITF-Mdel, a novel melanocyte/melanoma-specific isoform of MITF-M, may serve as a potential candidate biomarker for diagnostic and follow-up purposes in melanoma. [ABSTRACT FROM AUTHOR]

Background: Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells. Results: Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDHA by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells. Conclusion: LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer. [ABSTRACT FROM AUTHOR]

The role of Hedgehog (Hh) signaling as a developmental pathway is well established. Several recent studies have implicated a role for this pathway in multiple cancers. In this study we report that expression of GLIJ and osteopontin (OPN) increase progressively with the progression of melanoma from primary cutaneous cancer to metastatic melanoma in clinically derived specimens. We have further determined that OPN is a direct transcriptional target of GLI1. We have observed that OPN expression is stimulated in the presence of Hh ligands and inhibited in the presence of the Smoothened (SMO) inhibitor, cyclopamine. Transcriptional silencing of GUi negatively impacts OPN expression and compromises the ability of cancer cells to proliferate, migrate, and invade in vitro and interferes with their ability to grow as xenografts and spontaneously metastasize in nude mice. These altered attributes could be rescued by re-expressing OPN in the GLI1-silenced cells, suggesting that OPN is a critical downstream effector of active GLI1 signaling. Our observations lead us to conclude that the GLI1-mediated upregulation of OPN promotes malignant behavior of cancer cells. [ABSTRACT FROM AUTHOR]

Background: Recent evidence demonstrates that 14-3-3σ acts as a tumor suppressor gene inactivated by methylation of its 5' CpG islands in epithelial tumor cells, while remaining un-methylated in normal human epithelia. The methylation analysis of 14-3-3σ has been largely overlooked in melanoma. Methods: The methylation status of 14-3-3σ CpG island in melanocytes and melanoma cells was analyzed by methylation-specific sequencing (MSS) and quantitative methylation-specific PCR (Q-MSP). 14-3-3σ mRNA and protein expression in cell lines was detected by real-time RT-PCR and western blot. Melanoma cells were also treated by 5-aza-2'-deoxycytidine (DAC), a demethylating agent, and/or histone deacetylase inhibitor, Trichostatin A (TSA), to evaluate their effects on 14-3-3σ gene expression. Results: 14-3-3σ is hypermethylated in both human melanocytes and most melanoma cells in a lineage-specific manner, resulting in the silencing of 14-3-3σ gene expression and the active induction of 14-3-3σ mRNA and protein expression following treatment with DAC. We also observed a synergistic effect upon gene expression when DAC was combined with TSA. The promoter methylation status of 14-3-3σ was analyzed utilizing Q-MSP in 20 melanoma tissue samples and 10 cell lines derived from these samples, showing that the majority of melanoma samples maintain their hypermethylation status of the 14-3-3σ gene. Conclusion: 14-3-3σ is hypermethylated in human melanoma in a cell-linage specific manner. Spontaneous demethylation and re-expression of 14-3-3σ is a rare event in melanoma, indicating 14-3-3σ might have a tentative role in the pathogenesis of melanoma. [ABSTRACT FROM AUTHOR]

The inactivation of tumor-related genes through the aberrant methylation of promoter CpG islands is thought to contribute to tumor initiation and progression. We therefore investigated promoter methylation events involved in cutaneous melanoma by screening 30 genes of interest for evidence of promoter hypermethylation, examining 20 melanoma cell lines and 40 freshly procured melanoma samples. Utilizing quantitative methylation-specific PCR, we identified five genes (SOCS1, SOCS2, RAR-beta 2, TNFSF10C, and TNFSF10D) with hypermethylation frequencies ranging from 50% to 80% in melanoma cell lines as well as freshly procured tissue samples. Eighteen genes (LOX, RASSF1A, WFDC1, TM, APC, TFPI2, TNFSF10A, CDKN2A, MGMT, TIMP3, ASC, TPM1, IRF8, CIITA-PIV, CDH1, SYK, HOXB13, and DAPK1) were methylated at lower frequencies (2–30%). Two genes (CDKN1B and PTEN), previously reported as methylated in melanoma, and five other genes (RECK, IRF7, PAWR, TNFSF10B, and Rb) were not methylated in the samples screened here. Daughter melanoma cell lines showed identical methylation patterns when compared with original samples from which they were derived, as did synchronous metastatic lesions from the same patient. We identified four genes (TNFSF10C, TNFSF10D, LOX, and TPM1) that have never before been identified as hypermethylated in melanoma, with an overall methylation frequency of 60, 80, 50, and 10%, respectively, hypothesizing that these genes may play an important role in melanoma progression. [ABSTRACT FROM AUTHOR]

Abstract: There has been recent interest in the depletion of regulatory T cells (Tregs) as part of a multi-faceted approach to the immunotherapy of melanoma patients. This is in part due recent findings that convincingly show that Tregs are an integral part of regulating and even suppressing an immune response to growing tumor cells. We therefore compared three methods of Treg depletion and/or elimination, utilizing low dose cyclophosphamide (CY), a specific antibody directed against the IL-2 receptor found on Tregs (PC61) and the use of denileukin diftitox (DD), which is a fusion protein designed to have a direct cytocidal action on cells which express the IL-2 receptor. We show that CY administration resulted in the highest reduction in Tregs among the three reagents. However, the reduction in Tregs with CY was also associated with the concomitant reduction of CD8(+) T cells and a lack of tumor antigen priming. Utilization of DD resulted in a >50% Treg cell reduction without parallel cytocidal effects upon other T cell subsets but did not enhance anti-tumor immunity against B16 melanoma. Lastly, the PC61 showed a moderate reduction of Tregs that lasted longer than the other reagents, without a reduction in the total number of CD8(+) T cells. Furthermore, PC61 treatment did not abrogate tumor antigen-specific immunity elicited by dendritic cells (DC). We therefore conclude that PC61 administration was the most effective method of reducing Tregs in a murine melanoma model in addition to providing evidence of a synergistic effect when combined with DC-based immunotherapy. [Copyright &y& Elsevier]

The correct name is: Luis Del Valle. The correct initials are: Del Valle L. Reference 1 Chang TC, Matossian MD, Elliott S, Burks HE, Sabol RA, Ucar DA, et al. (2020) Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor. [Extracted from the article]

HER3 is the third member of the human epidermal growth factor receptor (HER/EGFR) family, and unlike its other family members, is unique due to its minimal intrinsic kinase activity. As a result, HER3 has to interact with another receptor tyrosine kinase (RTK), such as EGFR or HER2, in order to activate the PI-3 K/Akt, MEK/MAPK, Jak/Stat pathways, as well as Src kinase. Over-expression of HER3 in various human cancers promotes tumor progression by increasing metastatic potential and acting as a major cause of treatment failure. Effective inhibition of HER3, and/or the key downstream mediators of HER3 signaling, is thought to be required to overcome resistance and enhance therapeutic efficacy. To date, there is no known HER3-targeted therapy that is approved for breast cancer, with a number of anti-HER3 antibodies current in various stages of development and clinical testing. Recent data suggests that the epigenetic strategy of using a histone deacetylase (HDAC) inhibitor, or functional cooperative miRNAs, may be an effective way to abrogate HER3 signaling. Here, we summarize the latest advances in our understanding of the mechanism of HER3 signaling in tumor progression, with continuing research towards the identification of therapeutic anti-HER3 antibodies. We will also examine the potential to develop novel epigenetic approaches that specifically target the HER3 receptor, along with important key downstream mediators that are involved in cancer treatment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Risk-Adapted Targeted Intraoperative Radiotherapy Versus Whole-Breast Radiotherapy for Breast Cancer: 5-Year Results for Local Control and Overall Survival From the TARGIT-A Randomised Trial," by J. S. Vaidya et al in the February 15, 2014 issue.

Background: High activity of cysteine proteases such as legumain and the cathepsins have been shown to facilitate growth and invasion of a variety of tumor types. In breast cancer, several recent studies have indicated that loss of the cysteine protease inhibitor cystatin E/M leads to increased growth and metastasis. Although cystatin E/M is normally expressed in the skin, its role in cysteine protease regulation and progression of malignant melanoma has not been studied.Methods: A panel of various non-melanoma and melanoma cell lines was used. Cystatin E/M and C were analyzed in cell media by immunoblotting and ELISA. Legumain, cathepsin B and L were analyzed in cell lysates by immunoblotting and their enzymatic activities were analyzed by peptide substrates. Two melanoma cell lines lacking detectable secretion of cystatin E/M were transfected with a cystatin E/M expression plasmid (pCST6), and migration and invasiveness were studied by a Matrigel invasion assay.Results: Cystatin E/M was undetectable in media from all established melanoma cell lines examined, whereas strong immunobands were detected in two of five primary melanoma lines and in two of six lines derived from patients with metastatic disease. Among the four melanoma lines secreting cystatin E/M, the glycosylated form (17 kD) was predominant compared to the non-glycosylated form (14 kD). Legumain, cathepsin B and L were expressed and active in most of the cell lines, although at low levels in the melanomas expressing cystatin E/M. In the melanoma lines where cystatin E/M was secreted, cystatin C was generally absent or expressed at a very low level. When melanoma cells lacking secretion of cystatin E/M were transfected with pCST6, their intracellular legumain activity was significantly inhibited. In contrast, cathepsin B activity was not affected. Furthermore, invasion was suppressed in cystatin E/M over-expressing melanoma cell lines as measured by the transwell Matrigel assay.Conclusions: These results suggest that the level of cystatin E/M regulates legumain activity and hence the invasive potential of human melanoma cells. [ABSTRACT FROM AUTHOR]

Background: Recent evidence demonstrates that 14-3-3sigma acts as a tumor suppressor gene inactivated by methylation of its 5' CpG islands in epithelial tumor cells, while remaining un-methylated in normal human epithelia. The methylation analysis of 14-3-3sigma has been largely overlooked in melanoma.Methods: The methylation status of 14-3-3sigma CpG island in melanocytes and melanoma cells was analyzed by methylation-specific sequencing (MSS) and quantitative methylation-specific PCR (Q-MSP). 14-3-3sigma mRNA and protein expression in cell lines was detected by real-time RT-PCR and western blot. Melanoma cells were also treated by 5-aza-2'-deoxycytidine (DAC), a demethylating agent, and/or histone deacetylase inhibitor, Trichostatin A (TSA), to evaluate their effects on 14-3-3sigma gene expression.Results: 14-3-3sigma is hypermethylated in both human melanocytes and most melanoma cells in a lineage-specific manner, resulting in the silencing of 14-3-3sigma gene expression and the active induction of 14-3-3sigma mRNA and protein expression following treatment with DAC. We also observed a synergistic effect upon gene expression when DAC was combined with TSA. The promoter methylation status of 14-3-3sigma was analyzed utilizing Q-MSP in 20 melanoma tissue samples and 10 cell lines derived from these samples, showing that the majority of melanoma samples maintain their hypermethylation status of the 14-3-3sigma gene.Conclusion: 14-3-3sigma is hypermethylated in human melanoma in a cell-linage specific manner. Spontaneous demethylation and re-expression of 14-3-3sigma is a rare event in melanoma, indicating 14-3-3sigma might have a tentative role in the pathogenesis of melanoma. [ABSTRACT FROM AUTHOR]