Purpose:The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci.These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression. Experimental Design: The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARh2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n = 122) was assessed.Results: Here, we show an increase in hypermethylation of theTRGsWIF1,TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31is associated with disease outcome in stage III melanoma. Conclusions: These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.

Purpose: Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers ah are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins. Experimental Design: Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23). Results: We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant a 4 h 1 integrin expression. Conclusions: Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location.Human cutaneous melanoma is the most common cancer to metastasize to the small intestine (1, 2), for reasons that remain unclear. However, small intestinal metastases from other solid tumors are rare when compared with their incidence of hepatic and other organ metastases (3, 4). In the largest reported series of melanoma patients with gastrointestinal metastases, lesions were more common in the small intestine than the stomach, colon, or rectum (5). Diagnosis and management of patients with small intestinal metastases is often difficult due to their insidious nature. Most patients initially have nonspecific symptoms; symptoms caused by gastrointestinal hemorrhage or bowel obstruction are highly specific but also represent a surgical emergency. Several prognostic markers have been investigated for patients with clinically localized primary cutaneous melanoma, but none has been linked to organspecific metastasis. A biomarker for the risk of gastrointestinal metastasis would allow a tailored postoperative follow-up program to identify visceral spread of melanoma at an early, nonemergent stage.Metastasis to certain organ sites, such as bone marrow, lung, and liver, are primari...

Background-Age-related outcomes have become increasingly common in evaluating patients with melanoma. For instance, as age increases, sentinel node (SN) non-identification increases and SN positivity decreases. Furthermore, advanced age is a risk factor for in transit disease. We hypothesized that increasing age is accompanied by alterations in lymphatic function, possibly explaining these findings

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Summary:Primary squamous cell carcinoma (SCC) of the breast comprises less than 0.1% of all breast cancers. Literature review reveals only 1 reported case of an SCC arising from the capsule of a breast implant. The authors describe, herein, a primary SCC arising from the capsule of a long-standing silicone breast implant.

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Mammography and ultrasonography are traditional for preoperative estimation of breast cancer size; magnetic resonance imaging (MRI) is more recent but not as well studied. We compared ultrasonography, mammography, and MRI for preoperative imaging of primary breast cancer presenting as a mass in patients treated at our center over a 2-year period. Of the 61 breast cancers with all three imaging modalities performed, 52 were infiltrating ductal cancer, 5 were infiltrating lobular cancer, 2 were ductal carcinoma in situ, and 2 were other histologic types. When pathologic size was used to determine the accuracy of imaging assessments, the Pearson correlation coefficient was better for MRI (r = 0.80) than ultrasonography (r = 0.57) or mammography (r = 0.26). Mean tumor size was 2.1 cm by mammography, 1.73 cm by ultrasonography, 2.65 cm by MRI, and 2.76 cm by pathology. MRI-based tumor size was within 1 cm of pathologic size in 44 (72%) tumors, > 1 cm above pathologic size in 6 (10%) tumors, and > 1 cm below pathologic size in 11 (18%) tumors. We conclude that MRI is more accurate than either ultrasonography or mammography for assessment of the size of primary breast cancer presenting as a mass.

Background Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient’s immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma. Methods This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months). Results A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041). Conclusions This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development. Trial Registration NCT02301611. Supplementary information The online version contains supplementary material available at (10.1245/s10434-021-09709-1).