Programmed death ligand 1 and CD8+ immune cell infiltrates in resected primary tracheal malignant neoplasms.

OBJECTIVES: Many patients with primary malignant tracheal neoplasms are not surgical candidates nor do they experience residual or recurrent disease after surgery and may benefit from alternative therapies. This study explores the expression of programmed death ligand 1 (PD-L1) in patients with primary tracheal malignancy as a biomarker for candidacy for treatment with immune checkpoint inhibitors. METHODS: We conducted a retrospective review of the medical records of 23 patients with resected primary tracheal malignant tumours from 2010 to 2016. Paraffin-embedded blocks of tumour tissue were evaluated immunohistochemically to determine the expression of PD-L1 and infiltration by CD8+ immune cells. RESULTS: We identified 14 (61%) adenoid cystic carcinomas, 4 (17%) squamous cell carcinomas (SCC), 4 (17%) mucoepidermoid carcinomas and 1 adenosquamous carcinoma. PD-L1 expression was observed in 3 (75%) cases of SCC and 1 (100%) case of adenosquamous carcinoma, but it was absent in cases of adenoid cystic carcinomas and mucoepidermoid carcinomas. PD-L1 expression was significantly higher in tumours with a SCC component than in salivary-type tumours (P = 0.001). The presence of CD8+ immune cells in the tumour or peritumoural stroma was significantly higher in cases of tracheal tumours with a SCC component than in salivary-type tumours. CONCLUSIONS: Salivary-type primary malignant tracheal tumours do not significantly express PD-L1. In contrast, most primary tracheal tumours with a SCC component show membranous expression of PD-L1 and larger numbers of infiltrating CD8+ immune cells. PD-L1 expression may serve as a biomarker in patients with primary tracheal squamous cell malignant neoplasms when the patients are being considered for alternative treatments and inclusion in clinical trials. IRB APPROVAL: Protocol No. 2017P000415 (22 March 2017).

Postoperative radiotherapy for T1/2N0M0 mucoepidermoid carcinoma positive for CRTC1/3-MAML2 fusions.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines recommend considering postoperative radiotherapy (PORT) for completely resected T1/2N0M0 salivary mucoepidermoid carcinomas when they show tumor spillage, perineural invasion, or intermediate/high-grade histology. CRTC1/3-MAML2 fusions have been associated with a favorable clinical outcome. METHODS: Forty-seven T1/2N0M0 mucoepidermoid carcinoma cases positive for CRTC1/3-MAML2 fusions were completely resected and were not treated with PORT. RESULTS: Pathologically, none of the cases showed tumor spillage or perineural invasion. Cases with intermediate/high-grade histology numbered 9 (19%) to 26 (55%) with the currently used 3 different grading systems. During the follow-up (median 60 months), locoregional tumor recurrence occurred in 4 cases, which were treated with surgery alone. At the last follow-up (median 60 months; 7-160), all patients were alive with no evidence of disease. CONCLUSION: An excellent prognosis may be achieved without PORT in T1/2N0M0 mucoepidermoid carcinoma patients positive for CRTC1/3-MAML2 fusions when the tumors are completely resected without tumor spillage.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact.

BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

Antitumor and apoptosis-inducing effects of α-mangostin extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.)in YD-15 tongue mucoepidermoid carcinoma cells.

α-mangostin is a dietary xanthone which has been shown to have antioxidant, anti-allergic, antiviral, antibacterial, anti-inflammatory and anticancer effects in various types of human cancer cells. In the present study, we aimed to elucidate the molecular mechanisms responsible for the apoptosis-inducing effects of α-mangostin on YD-15 tongue mucoepidermoid carcinoma cells. The results from MTT assays revealed that cell proliferation significantly decreased in a dose-dependent manner in the cells treated with α-mangostin. DAPI staining illustrated that chromatin condensation in the cells treated with 15 µM α-mangostin was far greater than that in the untreated cells. Flow cytometric analysis indicated that α-mangostin suppressed YD-15 cell viability by inducing apoptosis and promoting cell cycle arrest in the sub-G1 phase. Western blot analysis of various signaling molecules revealed that α-mangostin targeted the extracellular signal­regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways through the inhibition of ERK1/2 and p38 phosphorylation in a dose­dependent manner. α-mangostin also increased the levels of Bax (pro-apoptotic), cleaved caspase-3, cleaved caspase-9 and cleaved-poly(ADP-ribose) polymerase (PARP), whereas the levels of the anti-apoptotic factors, Bcl-2 and c-myc, decreased in a dose-dependent manner. The anticancer effects of α-mangostin were also investigated in a tumor xenograft mouse model. The α-mangostin-treated nude mice bearing YD-15 tumor xenografts exhibited a significantly reduced tumor volume and tumor weight due to the potent promoting effects of α-mangostin on cancer cell apoptosis, as determined by TUNEL assay. Immunohistochemical analysis revealed that the level of cleaved caspase-3 increased, whereas the Ki-67, p-ERK1/2 and p-p38 levels decreased in the α-mangostin­treated mice. Taken together, the findings of our study indicate that α-mangostin induces the apoptosis of YD-15 tongue carcinoma cells through the ERK1/2 and p38 MAPK signaling pathways.

Extracellular signal­regulated kinase inhibition is required for methanol extract of Smilax china L.­induced apoptosis through death receptor 5 in human oral mucoepidermoid carcinoma cells.

Smilax china L., a well­known Chinese traditional medicine, has been used as an anti­inflammatory, anti­cancer and analgesic agent, but its role has not yet been fully elucidated in oral mucoepidermoid carcinoma (MEC). The present study focused on addressing the anticancer activity and molecular mechanism of methanol extract of Smilax china L. (MESC) in MC­3 human oral MEC cells. The results indicated that MESC inhibited cell growth and induced apoptosis in MC­3 cells. These observations were found to correlate with increases in truncated BH3 interacting­domain death agonist and B­cell lymphoma 2 (Bcl­2) interacting mediator of cell death, but not Bcl­2 homologous antagonist killer, Bcl­2­associated X protein, Bcl­2, B­cell lymphoma­extra large and induced myeloid leukemia cell differentiation protein levels. MESC also damaged the mitochondrial membrane potential, cleaved caspase­8 protein and increased death receptor 5 (DR5) protein levels by enhancing the stability of DR5 protein. Furthermore, MESC affected the phosphorylation of extracellular signal­regulated kinase (ERK) only, and did not affect c­Jun N­terminal kinase or p38 phosphorylation. Co­treatment with MESC and an ERK inhibitor (PD98059) significantly increased the expression of DR5 to induce apoptosis in MC­3 cells. Therefore, these results suggest that MESC may induce apoptosis via the ERK pathway and may be a potential anticancer drug candidate against human oral MEC.

Mucoepidermoid carcinoma of the thyroid: a report of three cases and postulated histogenesis.

BACKGROUND: Primary mucoepidermoid carcinoma (MEC) of the thyroid is a rare clinical and pathological entity that accounts for <0.5% of all thyroid malignancies. Although the histogenesis has been controversial, most investigators now favor it as arising from either metaplasia of thyroid follicular epithelium or heterologous de-differentiation from papillary thyroid carcinoma (PTC). We report three cases of thyroid MEC found in continuity with, and clearly arising from de-differentiation of, well-differentiated thyroid carcinomas (WDTCs). PATIENT FINDINGS AND SUMMARY: The cases presented here included two women (aged 22 and 52) and one man (aged 58). One of these cases arose in conjunction with PTC, one with follicular thyroid carcinoma (FTC), and one with Hurthle cell carcinoma (HCC). In all three cases, there was a gradual transition in morphology between the areas of typical WDTC and the areas showing MEC differentiation. In addition, immunohistochemistry demonstrated a gradual loss of thyroid specific markers (thyroid transcription factor-1, thyroglobulin) mirroring the change in morphology. CONCLUSION: We conclude that thyroid MEC can arise from metaplastic de-differentiation of WDTC, including FTC or HCC in addition to PTC. Currently, we recommend that after excision, each of the WDTC and MEC components of these tumors be treated with targeted adjuvant therapies, which may involve radioactive-iodine ablation, thyrotropin suppression, and external beam radiotherapy.

Mucoepidermoid carcinoma of the ascending colon: report of a case.

Mucoepidermoid carcinoma of the gastrointestinal tract is a rare entity. The present case is the first report of mucoepidermoid carcinoma in the large bowel. A 71-year-old man was admitted to our hospital to undergo surgery for a recurrent chordoma of the hip. A barium enema and colonoscopy were carried out to assess whether there was any relationship between the recurrent chordoma and the rectum. An ulcerating tumor was thus identified in the ascending colon. A radical right hemicolectomy was carried out. In the resected specimen a 3-cm ulcerating lesion was observed. The tumor consisted of PAS-positive mucin-producing cells, epidermoid cells, and intermediate cells. No differentiated squamous cell carcinoma cells were identified in any part of the tumor. The malignant cells proliferated mainly in the submucosa but also invaded the muscularis and serosa. The tumor was diagnosed as a mucoepidermoid carcinoma of the ascending colon. Unfortunately, despite chemotherapy, the patient developed liver metastases and died of liver failure 10 months postoperatively.

Mucoepidermoid carcinoma of the conjunctiva: a series of three cases.

OBJECTIVE: To detail the clinical presentation and outcomes of currently available treatments for mucoepidermoid carcinoma of the conjunctiva (MCC). DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Three patients ranging from 40 to 63 years of age with MCC participated. INTERVENTION: Excisional biopsies and various therapies were performed. MAIN OUTCOME MEASURES: Clinical and surgical outcomes were measured. RESULTS: Patient 1 is a 55-year-old man with right temporal MCC. He underwent two local excisions with adjuvant cryotherapy and has had no recurrence at 31 months follow-up. Patient 2 is a 63-year-old man with right temporal MCC who underwent fractionated iodine 125 plaque radiotherapy. He had a recurrence approximately 8 months after plaque treatment and subsequently underwent enucleation of the right eye. Clinical follow-up examinations revealed no further recurrence at 17 months. Patient 3 is a 40-year-old woman treated for right MCC with carbon dioxide laser with recurrence at 3 weeks. She subsequently underwent radiation treatment with the development of regional lymph node metastases 16 months later. CONCLUSIONS: MCC is a rare neoplasm that displays an extraordinary capacity for aggressive local invasion. This series of three case reports demonstrates the high recurrence rate of MCC and the response of this tumor to different current modalities of treatment. Extended follow-up is required with this tumor because distant metastases can occur very late.

[Mucoepidermoid carcinoma of the submandibular gland after high-dose radioiodine therapy: case report and review of the literature]. / Mukoepidermoid-Karzinom der Glandula Submandibularis nach hochdosierter Radioiodtherapie: Fallpräsentation und Literaturübersicht.

Case report of a 42 year old female, who received 14th-20th year of life six radioiodine therapies with altogether 19.2 GBq131I because of a papillary thyroid carcinoma. 17 years after the last therapy, she developed a histologically proven chronic radiogenic sialadenitis of the left submandibular gland. Further four years later, the right submandibular gland has been extirpated because of a mucoepidermoid carcinoma with infiltration of a regionary lymphatic node. Review of the previous published secondary-malignancies of the salivary glands after high-dose radioiodine therapies.

[Effect of dietary supplementation with gamma-linolenic acid on the growth of a human lung carcinoma implanted in nude mice]. / Efecto de la suplementación dietética con acido gama-linolenico sobre el crecimiento de un carcinoma de pulmón humano implantado en ratones atímicos.

We have studied the effect of a gamma-linolenic acid (18:3 n-6, GLA)-supplemented diet on the growth of a human lung mucoepidermoid carcinoma (HLMC) implanted in athymic mice and on its uptake of human low density lipoproteins labeled with 99mTc (99mTc-LDL). Mice bearing the HLMC were divided into two experimental groups. One of them was administered a control diet (C diet) and the other one was given a diet supplemented with 25 mg GLA/g pellet (GLA diet) for three weeks (Table 1). A tumor growth inhibition with the GLA diet was evident at the second week of treatment, and a marked inhibition (56%) was reached at the end of the third week (Fig. 1). The GLA diet produced some changes in the total fatty acid composition of tumor, plasma and liver of host mice: GLA and arachidonic acid (20:4 n-6, AA) induced significant increases, whereas oleic (18:1 n-9, OA) and linoleic acids (18:2 n-6, LA) were decreased (Table 2). Tumors of those animals fed both diets were labeled by 99mTc-LDL, and no difference was observed in the ratio of tumor/liver and tumor/kidney uptake of host animal (Table 3). Results obtained using this experimental model suggest that the inhibitory effect of GLA on tumor growth is not related to the LDL tumor uptake.

Efecto de la suplementación dietética con ácido gama-linolénico sobre el crecimiento de un carcinoma de pulmón humano implantado en ratones atímicos / Effect of dietary supplementation with gamma-linolenic acid on the growth of a human lung carcinoma implanted in nude mice

Se estudió el efecto de una dieta suplementada con ácido gama-linolénico (18:3 n-6, GLA) sobre el crecimiento de un tumor mucoepidermoide de pulmón humano (HLMC) implantado en ratones atímicos y sobre la captación por el mismo de lipoproteínas de baja densidad humana marcadas con 99mTc (99mTc-LDL). Los ratones portadores de HLMC se dividieron en dos grupos experimentales, uno que recibió dieta control (dieta C) y el otro, dieta suplementada con GLA (dieta GLA), durante tres semanas. Se observó una marcada inhibición del crecimiento tumoral al finalizar el tratamiento. La dieta enriquecida en GLA indujo cambios en la composición en ácidos grasos totales del tumor y del plasma e hígado de los ratones huéspedes. Los tumores de los animales alimentados con ambas dietas captaron radiactividad de las 99mTc-LDL y no se observaron diferencias significativas en la relación entre la captación por el tumor y por el hígado y riñón de los animales huéspedes. Los resultados obtenidos utilizando este modelo experimental sugieren que el efecto inhibitorio del GLA sobre el crecimiento tumoral es independiente de la captación de LDL por parte del tumor.

Efecto de la suplementación dietética con ácido gama-linolénico sobre el crecimiento de un carcinoma de pulmón humano implantado en ratones atímicos / Effect of dietary supplementation with gamma-linolenic acid on the growth of a human lung carcinoma implanted in nude mice

Se estudió el efecto de una dieta suplementada con ácido gama-linolénico (18:3 n-6, GLA) sobre el crecimiento de un tumor mucoepidermoide de pulmón humano (HLMC) implantado en ratones atímicos y sobre la captación por el mismo de lipoproteínas de baja densidad humana marcadas con 99mTc (99mTc-LDL). Los ratones portadores de HLMC se dividieron en dos grupos experimentales, uno que recibió dieta control (dieta C) y el otro, dieta suplementada con GLA (dieta GLA), durante tres semanas. Se observó una marcada inhibición del crecimiento tumoral al finalizar el tratamiento. La dieta enriquecida en GLA indujo cambios en la composición en ácidos grasos totales del tumor y del plasma e hígado de los ratones huéspedes. Los tumores de los animales alimentados con ambas dietas captaron radiactividad de las 99mTc-LDL y no se observaron diferencias significativas en la relación entre la captación por el tumor y por el hígado y riñón de los animales huéspedes. Los resultados obtenidos utilizando este modelo experimental sugieren que el efecto inhibitorio del GLA sobre el crecimiento tumoral es independiente de la captación de LDL por parte del tumor.(AU)