Phase I study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) cells express high levels of epidermal growth factor receptor (EGFR). Cetuximab is an anti-EGFR monoclonal antibody that promotes natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) via engagement of CD16. We studied safety and efficacy of combining cetuximab with autologous expanded NK cells in patients with recurrent and/or metastatic NPC who had failed at least two prior lines of chemotherapy. METHODS: Seven subjects (six patients) received cetuximab every 3 weeks (six doses maximum) in the pre-trial phase. Autologous NK cells, expanded by co-culture with irradiated K562-mb15-41BBL cells, were then infused on the day after administration of cetuximab. Primary and secondary objectives were to determine safety of this combination therapy and to assess tumor responses, respectively. RESULTS: Median NK cell expansion from peripheral blood mononucleated cells after 10 days of culture with K562-mb15-41BBL was 274-fold (range, 36-534, n = 10), and the median expression of CD16 was 98.4% (range, 67.8-99.7%). Skin rash, the commonest side effect of cetuximab in the pre-trial phase, was not exacerbated by NK cell infusion. No intolerable side effects were observed. Stable disease was observed in four subjects and progressive disease in three subjects. Three patients who received NK cells twice had time to disease progression of 12, 13, and 19 months. CONCLUSION: NK cells with high ADCC potential can be expanded from patients with heavily pre-treated NPC. The safety profile and encouraging clinical responses observed after combining these cells with cetuximab warrant further studies of this approach. (clinicalTrials.gov NCT02507154, 23/07/2015). PRECIS: Engaging NK cell-mediated ADCC using cetuximab plus autologous NK cells in EGFR-positive NPC was well tolerated among heavily pre-treated recurrent NPC. Promising results were observed with 3 out of 7 subjects demonstrating durable stable disease.

Occult recurrence of monomorphic epitheliotropic intestinal T-cell lymphoma and the role of MATK gene expression in diagnosis.

Monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL), formerly Type II enteropathy-associated T-cell lymphomas (EATL), are rare peripheral T-cell lymphomas. They are associated with poor survival outcomes, in part because of their late diagnosis. Although MEITLs may be reliably diagnosed based on histological and immunophenotypic findings, overlaps with other NK/T and T-cell lymphomas may confound the diagnosis. The distinctive high-level nuclear staining of the novel marker Megakaryocyte-associated tyrosine kinase (MATK) in MEITLs is an invaluable tool in distinguishing MEITL from classical EATL and other NK/T or T-cell lymphomas. 18-Fluorine-2-fluorodeoxyglucose positron emission tomography (18 F-FDG PET) has been shown to be a useful tool in the staging and follow-up of aggressive lymphomas. Herein, we describe an unusual case of occult hepatic recurrence of MEITL that was non-avid on 18 F-FDG PET, in which diagnosis was confirmed based on the expression of MATK in tumour cells. Copyright © 2016 John Wiley & Sons, Ltd.

Autoclaved autologous bone graft for orbital reconstruction for recurrent temporal bone orbital osteosarcoma.

Post-tumor excision and reconstruction of the craniofacial region is a complex and technically demanding process due to its proximity to numerous vital structures and irregularly shaped bony tissue. As such, novel methods are needed when reconstruction of irregularly shaped structures is necessary. Autoclaving of autologous bone grafts is an established practice in orthopedic and neurosurgical practice, but has only been described twice previously for orbital reconstruction. We performed grafting of an autoclaved autologous bone segment as part of surgery on a 30-year-old man to treat his recurrent temporal osteosarcoma with orbital involvement, which is rare. In addition, we went on to highlight key differences between bone autoclaving and pasteurization, an alternative heat treatment technique, for orbital reconstruction post-tumor excision. Although he suffered a second recurrence 8 months later, there was no evidence of recurrence in the autoclaved bone. To treat his second recurrence, he subsequently underwent a modified eyelid-conjunctiva sparing orbital exenteration, also an uncommonly performed procedure. Also, we subsequently examined the novel technique of a lid-sparing and conjunctiva-sparing orbital exenteration and its benefits. He continues to remain under follow-up.

Multinodular goiter: A study of malignancy risk in nondominant nodules.

The long-standing belief that multinodular goiters are associated with a lower risk of developing into carcinoma has been challenged by the results of some recent studies. In addition, we have noticed in our practice that a sizable proportion of cancers have been arising from nondominant nodules. We performed a retrospective study of 223 cases to determine (1) the incidence of carcinoma in multinodular goiters that required surgical management in our local, predominantly Asian population and (2) the incidence of carcinoma arising from nondominant nodules. We reviewed the records of all patients with a multinodular goiter who had undergone a thyroidectomy over a period of more than 10 years in our Department of Otolaryngology-Head and Neck Surgery. We examined the histopathology reports for (1) the presence of carcinoma, (2) whether the carcinoma was isolated/unifocal or multifocal, (3) the histologic type of cancer, and (4) whether the isolated/unifocal cancers arose from the dominant or nondominant nodule. Our study population was made up of 47 males and 176 females, aged 15 to 90 years (mean: 53). We found that the incidence of malignancy in surgically treated multinodular goiters was 14.3% (32 of 223 patients). Of the 32 malignancies, 18 (56.3%) were isolated/unifocal and 14 (43.8%) were multifocal. In the isolated/unifocal group, 9 malignancies (50.0%) arose from nondominant nodules and 8 (44.4%) from dominant nodules; in the remaining case, the nodule of origin could not be determined. Our findings corroborate those in the recent literature in that the risk of malignancy associated with multinodular goiters is comparable to that of single thyroid nodules. We recommend that physicians be equally vigilant when monitoring dominant and nondominant nodules.

Histopathological features of sinonasal inverted papillomas in chinese patients.

OBJECTIVES/HYPOTHESIS: Nasal inverted papilloma (IP) is a benign tumor with high recurrence rates. Evidence of inflammation has been reported in IP in Caucasian studies. This study aimed to investigate the histopathological patterns and their associations with clinical characteristics in Chinese patients with IP. STUDY DESIGN: Basic science study. METHODS: IP tissues were obtained from 50 Chinese patients with unilateral IPs. Biopsies of inferior turbinate mucosa from 17 healthy subjects were used as controls. The histological patterns and severity of epithelial remodeling and inflammatory cell infiltration were evaluated and analyzed for associations with clinical characteristics. RESULTS: Thirty-one percent of IP specimens were classified as grade I (mild remodeling) and 49% as grade II (moderate and severe remodeling). Concomitant inflammatory nasal polyps were found in 14 patients (28%). Recurrent IP was strongly associated with grade II (odds ratio: 5.81, 95% confidence interval: 1.34-25.18). Except CD4(+) T cells, quantities of neutrophils, macrophages, eosinophils, CD8(+) T cells, and FoxP3(+) T-reg cells were significantly elevated in IP. Of these, neutrophils were the predominant cell type in IP. CONCLUSIONS: Inflammation may have potential roles in IPs and the higher grade of epithelial remodeling was associated with the recurrence of IPs. LEVEL OF EVIDENCE: NA.

The genomic landscape of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.