Summary
Melanoma brain metastasis (MBM) is frequent and has a very poor prognosis with no current predictive factors or therapeutic molecular targets. Our study unravels the molecular alterations of ...cell‐surface glycoprotein CD44 variants during melanoma progression to MBM. High expression of CD44 splicing variant 6 (CD44v6) in primary melanoma (PRM) and regional lymph node metastases from AJCC Stage IIIC patients significantly predicts MBM development. The expression of CD44v6 also enhances the migration of MBM cells by hyaluronic acid and hepatocyte growth factor exposure. Additionally, CD44v6‐positive MBM migration is reduced by blocking with a CD44v6‐specific monoclonal antibody or knocking down CD44v6 by siRNA. ESRP1 and ESRP2 splicing factors correlate with CD44v6 expression in PRM, and ESRP1 knockdown significantly decreases CD44v6 expression. However, an epigenetic silencing of ESRP1 is observed in metastatic melanoma, specifically in MBM. In advanced melanomas, CD44v6 expression correlates with PTBP1 and U2AF2 splicing factors, and PTBP1 knockdown significantly decreases CD44v6 expression. Overall, these findings open a new avenue for understanding the high affinity of melanoma to progress to MBM, suggesting CD44v6 as a potential MBM‐specific factor with theranostic utility for stratifying patients.
Expression of specific breast cancer stem cells (BCSCs) is seen in aggressive tumors, but their regulation is unclear. Epigenetic changes influence gene expression and are implicated in breast cancer ...progression. We hypothesized that promoter methylation regulates specific BCSC-related genes CD44 , CD133 , CD24 , MSH1 (alias, Musashi-1 ), and ALDH1 and that this epigenetic profile can identify aggressive subtypes, such as triple-negative breast cancer (TNBC). Methylation analysis was performed using MassARRAY EpiTYPER sequencing; CpG-rich sites were identified in the promoter regions of BCSC genes, except ALDH1 . These sites were screened by treatment with 5-aza-2′-deoxycytidine in four TN and five non-TNBC cell lines. The specific regulatory CpG site demonstrating the most significant inverse correlation between CpG site methylation and mRNA expression was identified for CD44 , CD133 , and Musashi-1 , but not for CD24 . Methylation of CD44 , CD133 , and Musashi-1 was evaluated in 91 American Joint Committee on Cancer stage I to III primary breast cancer tumors, and these sites were significantly hypomethylated in TNBC versus non-TNBC. The IHC staining of primary tumors with the highest and lowest methylation levels revealed the strongest staining in hypomethylated specimens, suggesting that hypomethylation leads to gene activation. We demonstrate that methylation is a significant mechanism regulating CD44 , CD133 , and Musashi-1 , and that gene hypomethylation correlates with TNBC. Assessment of epigenetic changes in BCSC genes may provide a more accurate classification of TNBC and could be developed as potential therapeutic targets.
Epigenetic biomarkers in skin cancer Greenberg, Edward S; Chong, Kelly K; Huynh, Kelly T ...
Cancer letters,
01/2014, Letnik:
342, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract Epigenetic aberrations have been associated with cutaneous melanoma tumorigenesis and progression including dysregulated DNA gene promoter region methylation, histone modification, and ...microRNA. Several of these major epigenetic aberrations have been developed into biomarkers. Epigenetic biomarkers can be detected in tissue and in blood as circulating DNA in melanoma patients. There is strong evidence that biomarkers in cutaneous melanoma will have an important role as companions to therapeutics and overall patient management. Important progress has been made in epigenetic melanoma biomarker development and verification of clinical utility, and this review discusses some of the key current developments and existing challenges.
Background
The ability to distinguish benign from atypical/malignant papillary lesions on core needle biopsy is limited by the representative nature of the biopsy method, thus follow-up excision is ...usually recommended. We aimed to determine if larger samples of tissue obtained by core needle biopsy can more reliably predict the true benign nature of a papilloma.
Methods
We reviewed the pathology slides and medical records of 51 patients who were diagnosed with benign papillomas on core needle biopsy from 2000 to 2010, who subsequently underwent surgical excision. The characteristics of the core needle biopsy that were associated with retention of benign histology on excision were determined and analyzed.
Results
Atypical ductal hyperplasia and carcinoma were identified in 5.8 % (3/51) and 5.8 % (3/51) of papillary lesions, respectively, when excised. Patients whose lesions were diagnosed as benign on excision were significantly distinguished by the area (mm
2
) of tissue sampled by core needle biopsy (mean ± standard deviation (SD): 101.5 ± 106.5) compared with those with atypia or carcinoma on excision (mean ± SD: 41.7 ± 24.0,
P
= 0.003). All biopsies performed with 12-gauge or larger needles retained benign features on excision. Core needle biopsy tissue samples consisting of ≥7 cores, or measuring >96 mm
2
in aggregate, had a negative predictive value for atypia/malignancy of 100 %.
Conclusions
Larger tissue samples significantly improved the predictive value of benign histology on core needle biopsy. A papilloma sampled by a 12-gauge or larger needle, ≥7 cores, or >96 mm
2
retained its benign features upon excision.
Background The need for complete lymph node dissection (CLND) in patients with positive sentinel lymph node biopsy (SNB) is an important unanswered clinical question. Study Design Patients diagnosed ...with positive SNB at a melanoma referral center from 1991 to 2013 were studied. Outcomes of patients who underwent CLND were compared to those who did not undergo immediate CLND (observation group, OBS). Results There were 471 patients who had positive SNB; 375 (79.6%) in the CLND group and 96 (20.4%) in the OBS group. The groups were similar except that the CLND group was younger and had more sentinel nodes removed. Five-year nodal recurrence free survival was significantly better in the CLND group compared to the OBS group (93.1% vs 84.4%, p= 0.005). However, the 5- (66.4% vs 55.2%) and 10- year (59.5% vs 45.0%) distant metastasis free survival was not significantly different (p= 0.061). The CLND group's melanoma specific survival (MSS) was superior to the OBS group; 5 year MSS was (73.7 vs 65.5%) and10 year MSS- (66.8 vs 48.3%, p=0.015). On multivariate analysis, CLND was associated with improved MSS (HR 0.60, 95% CI 0.40-0.89, p= 0.011) and lower nodal recurrence (HR 0.46, 95% CI 0.24-0.86, p=0.016). Increased Breslow thickness, older age, ulceration, and trunk melanoma were all associated with worse outcomes. On subgroup analysis, following factors were associated with better outcomes from CLND- male gender, non-ulcerated primary, intermediate thickness, Clark level IV or lower extremity tumors. Conclusions Treatment of positive SNB with CLND was associated with improved MSS and nodal recurrence rate. Follow up beyond 5 years was needed to see a significant difference in MSS.
Background
The status of the sentinel lymph node in melanoma is an important prognostic factor. The clinical predictors and implications of false-negative (FN) biopsy remain debatable.
Methods
We ...compared patients with positive sentinel lymph node biopsy (SNB) true positive (TP) and negative SNB with and without regional recurrence FN, true negative (TN) from our prospective institutional database.
Results
Among 2986 patients (84 FN, 494 TP, and 2408 TN; median follow-up 93 months), the incidence of FN-SNB was 2.8 %. While calculated FN rate was 14.5 % 84 FN/(494 TP + 84 FN) × 100, when we accounted for local/in-transit recurrence (LITR) this rate was 8.5 % 46 FN/(494 TP + 46 FN) × 100 %. On multivariate analysis, male gender (OR 2.0, 95 % CI 1.1–3.6,
p
= 0.018), head/neck primaries (OR 2.5, 95 % CI 1.3–4.8,
p
< 0.006), and LITR (OR 3.5, 95 % CI 2.1–5.8,
p
< 0.001) were associated with FN-SNB. Melanoma-specific survival (MSS) for the FN group was similar to the TP group at 5 years (68 vs. 73 %,
p
= 0.539). However, MSS declined more for the FN group with a longer follow up and was significantly worse at 10 years (44 vs. 64 %,
p
< 0.001). On multivariate analysis, FN-SNB was a significant predictor of worse MSS in melanomas <4 mm in Breslow thickness (HR 1.6; 95 % CI 1.1–2.5,
p
= 0.021).
Conclusions
Male gender, LITR, and head and neck tumors were associated with FN-SNB. FN-SNB was an independent predictor of worse MSS in melanomas <4 mm in thickness, but this survival difference did not become apparent until after 5 years of follow-up.
Appropriate use of laparoscopic adrenalectomy (LA) for adrenocortical carcinoma (ACC) remains controversial because complete resection with negative margins is the best chance for potential cure. ...This study compared the oncologic outcomes and overall survival (OS) of LA and open adrenalectomy (OA) for ACC.
A retrospective analysis of the National Cancer Data Base (NCDB) between 2010 and 2014 identified 423 European Network for the Study of Adrenal Tumors (ENSAT) stage I to III ACC patients who had LA (n = 137) or OA (n = 286). Outcomes and OS were compared between the 2 groups.
Patients who underwent OA had more advanced stage disease (p = 0.0001), larger (≥5 cm) tumors (p < 0.0001), and were younger (age less than 55 years, p = 0.05). Nodal assessment was rare in LA (n = 4) compared with OA (n = 88) (p < 0.0001). Margin positivity was affected only by surgical approach in patients with T3 tumors (LA 54.6% vs OA 21.7%; p = 0.0009). Neither surgical procedure nor any socio-demographic factor(s) affected OS for the entire cohort. Only positive margins (p = 0.007), positive nodes (p = 0.02), tumor extension (p = 0.01), and more advanced ENSAT stage (p = 0.004) increased mortality. When stratified by disease stage, LA decreased OS for patients with stage II disease (p = 0.04), and remained an independent risk factor for death on multivariate analysis (hazard ratio HR 1.86, 95% CI 1.02 to 3.38; p = 0.04). Only positive margins decreased OS in the entire cohort (HR 2.17, 95% CI 1.32 to 3.57; p = 0.002).
Use of LA may decrease OS in select patients with ACC. Because margin status remains the strongest predictor of mortality, caution should be used in selecting LA for patients with ACC.
The tumor status of the regional lymph nodes is the most important prognostic indicator in colorectal cancer (CRC), as it is in other solid tumors. Sentinel lymph node biopsy (SLNB), which has ...profoundly impacted the treatment of melanoma and breast cancer, has been applied in CRC in an attempt to improve nodal staging accuracy. The challenge lies in identifying patients who have tumor-negative nodes but are at high risk of regional or distant failure and therefore may benefit from adjuvant chemotherapy. Because standard pathological analysis of lymph nodes may incorrectly stage colon cancer, multiple studies have investigated nodal ultrastaging based on identification and immunohistochemical and/or molecular assessment of the sentinel node. This review focuses on the technique of SNLB, its feasibility and validity, and the controversies that remain regarding the clinical significance of nodal ultrastaging in CRC.
Surgical resection of metastases to the adrenal gland can improve overall survival of patients with stage IV melanoma, but its relative value with respect to current nonsurgical therapies is unknown. ...We hypothesized that surgery remains an optimal first-line treatment approach for resectable adrenal metastases. A search of our institution's prospectively collected melanoma database identified stage IV patients treated for adrenal metastases between January 1, 2000, and August 11, 2014. The 91 study patients had a mean age of 60.3 years at diagnosis of adrenal metastasis and 24 had undergone adrenalectomy. Improved survival was associated with an unknown primary lesion, surgical resection, and nonsurgical therapies. Median overall survival from diagnosis of adrenal metastases was 29.2 months with adrenalectomy versus 9.4 months with nonoperative treatment. Adrenalectomy, either as complete metastasectomy or targeted to lesions resistant to systemic therapy, is associated with improved long-term survival in metastatic melanoma.
Background
With the first qualifying examination administered September 15, 2014, complex general surgical oncology (CGSO) is now a board-certified specialty. We aimed to assess the attitudes and ...perceptions of current and future surgical oncology fellows regarding the recently instituted Accreditation Council for Graduate Medical Education (ACGME) accreditation.
Methods
A 29-question anonymous survey was distributed to fellows in surgical oncology fellowship programs and applicants interviewing at our fellowship program.
Results
There were 110 responses (79 fellows and 31 candidates). The response rate for the first- and second-year fellows was 66 %. Ninety-percent of the respondents were aware that completing an ACGME-accredited fellowship leads to board eligibility in CGSO. However, the majority (80 %) of the respondents stated that their decision to specialize in surgical oncology was not influenced by the ACGME accreditation. The fellows in training were concerned about the cost of the exam (90 %) and expressed anxiety in preparing for another board exam (83 %). However, the majority of the respondents believed that CGSO board certification will be helpful (79 %) in obtaining their future career goals. Interestingly, candidate fellows appeared more focused on a career in general complex surgical oncology (
p
= 0.004), highlighting the impact that fellowship training may have on organ-specific subspecialization.
Conclusions
The majority of the surveyed surgical oncology fellows and candidates believe that obtaining board certification in CGSO is important and will help them pursue their career goals. However, the decision to specialize in surgical oncology does not appear to be motivated by ACGME accreditation or the new board certification.
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