A. B. Ackerman

PURPOSE: Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study. PATIENTS AND METHODS: From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization. RESULTS: Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (-30% and -16%) and experienced progression after 3.7 and 3.5 months. CONCLUSION: MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).

BACKGROUND: The immunotherapy (IT) agents ipilimumab and interleukin-2 as well as BRAF inhibitors (BRAFi) vemurafenib and dabrafenib, with or without trametinib (MEK inhibitors), are all FDA-approved treatments for BRAF metastatic melanoma, but there are few studies to guide optimal sequencing. This retrospective analysis describes the outcomes of patients treated with either BRAFi before IT or IT before BRAFi. METHODS: A cohort of patients treated with BRAFi alone or with MEK inhibitor was retrospectively identified. Response rate (RR), overall survival (OS), and progression-free survival (PFS) were evaluated for the entire cohort, subdivided by BRAFi prior to or after IT. RESULTS: RR and median PFS and OS calculated from commencement of BRAFi following IT (N = 32) were 57%, 6.7 months (95% confidence interval [CI] = 4.3-9.1 months), and 19.6 months (95% CI = 10.0-undefined months), respectively; whereas for BRAFi initially (N = 242) were 66%, 5.6 months (95% CI = 4.7-6.8 months), and 13.4 months (95% CI = 10.1-17.0 months). Results were similar when controlled for prognostic variables. A total of 193 patients discontinued BRAFi, with OS of 2.9 months (range of 1.8-4.4 months) from day of BRAFi discontinuation. Forty patients subsequently received IT with ipilimumab. Only half could complete 4 doses of ipilimumab; PFS with ipilimumab was 2.7 months (95% CI = 1.8-3.1 months) and OS was 5.0 months (95% CI = 3.0-8.8 months). CONCLUSIONS: In this retrospective analysis, prior treatment with IT does not appear to negatively influence response to BRAFi. Outcomes for IT with ipilimumab following BRAFi discontinuation are poor. Randomized controlled trials are needed to define if sequencing IT prior to BRAFi therapy is superior to sequencing BRAFi prior to IT.

This assay examines critically the concept of 'dysplasia' as it applies to melanocytic neoplasia and concludes that the concept is flawed. Doubt is cast also upon the validity of the concepts of a dysplastic naevus and a dysplastic naevus syndrome. The author is of the view that most malignant melanomas arise de novo and not in pre-existing dysplastic naevi. Because so-called dysplastic naevi are considered by the author to be the commonest melanocytic naevi in man and devoid of nuclear atypia, he proposes that they be re-named 'common naevi' in the interest of simplicity, accuracy, and care of patients. Lastly, it is suggested that resolution of problems in the sphere of melanocytic neoplasia might be accomplished more readily were terms like dysplasia, dysplastic cells, dysplastic naevi, and the dysplastic naevus syndrome eschewed.

Follicular mucinosis is a histologic term for a reaction pattern in follicular epithelium. Although it is the sine qua non for alopecia mucinosa as a disease sui generis, it may occur in a variety of unrelated conditions, which may be inflammatory, hamartomatous, hyperplastic, or neoplastic. Follicular mucinosis is rare in plaque and nodular lesions of mycosis fungoides, but when it occurs, the malignant lymphoma is not related to the condition known as alopecia mucinosa. In short, alopecia mucinosa is a wholly benign condition and is not premonitory or an early aspect of mycosis fungoides. Follicular mucinosis is not synonymous with alopecia mucinosa but is analogous to other histologic reaction patterns of cutaneous epithelium such as epidermolytic hyperkeratosis, focal acantholytic dyskeratosis, and cornoid lamellation.

This essay places the concept of "primary acquired melanosis" of the conjunctiva in historical perspective and shows that it and its analogs, namely, lentigo-melanosis (Hutchinson), melanotic freckle (Hutchinson), melanose circonscrite precancereuse (Dubrueilh), melanotische precancerose (Miescher), lentigo maligna (Clark), precancerous melanosis (Reese), benign, precancerous, and cancerous melanosis (Zimmerman), atypical melanocytic hyperplasia (Silver et al.), and benign acquired melanosis (Zimmerman), are synonyms for melanoma in situ. The issue is not merely semantic or philosophical; it is urgently practical. If a clinician takes literally the meaning of a lesion designated "benign melanosis" and considers it to be benign, rather than the malignant melanoma that it actually is, a patient who bears that flat pigmented lesion may one day die of metastasis from an elevated sequella of it. The same is true of "primary acquired melanosis," which is not simply a condition of blackening by melanin, but a flat melanoma that, if not removed completely, may give rise one day to metastases that cause death. To avoid such misconstructions, we advocate naming melanomas in all organs "melanoma" and those that are confined to epithelial structures "melanoma in situ." Euphemisms like lentigo maligna and primary acquired melanosis are evasions of the diagnosis of melanoma, and use of them may be harmful. For that reason, they should be eschewed.