Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.

A Case of Bing-Neel Syndrome Presenting Like Giant Cell Arteritis.

ABSTRACT: A 55-year-old woman presented with new-onset headache, scalp tenderness, shoulder arthralgias, night sweats, and loss of appetite. She was diagnosed with giant cell arteritis by her primary care physician and commenced on oral corticosteroids. However, her headache, scalp tenderness, and night sweats persisted. She then developed right Horner syndrome and trigeminal hypoesthesia. Extensive blood work-up revealed mildly elevated inflammatory markers and a paraproteinemia. Subsequent bone marrow biopsy showed lymphoplasmacytic lymphoma, with 10% of hemopoiesis, and staging led to the diagnosis of Waldenstrom macroglobulinemia without nodal or central nervous system (CNS) lesions. Immunohistochemical staining of a temporal artery biopsy showed perivascular lymphoplasmacytic cells and paraprotein deposits. She was diagnosed with CNS involvement of her macroglobulinemia-Bing-Neel syndrome (BNS). Identification of rare CNS involvement of lymphoma is challenging when a patient is already on steroid immunosuppression. In the absence of clear diagnostic criteria, the rare and heterogenous BNS remains a clinical diagnosis.

Donor acquired visceral leishmaniasis following liver transplantation.

Patients who undergo solid organ transplantation are at risk of opportunistic infection associated with immunosuppression. We report a case of confirmed donor derived visceral leishmaniasis (VL), in a patient following liver transplantation causing fever and pancytopenia. The diagnosis was confirmed by bone marrow biopsy, with confirmed positive donor serology, with no other route of transmission. To our knowledge, this is the first case report in the United Kingdom and Europe, of confirmed organ donor transmission of VL. This case report highlights an important consideration of donor derived infections, in the context of solid organ transplantation.

Clear Cell Odontogenic Carcinoma: First Report of Novel EWSR1-CREM Fusion Gene in Case of Long-Term Misdiagnosis.

Clear Cell odontogenic Carcinomas (CCOC) are rare, aggressive malignant odontogenic tumours which are often misdiagnosed as benign odontogenic tumours due to the non-specific histologic appearance, and benign early clinical presentation. However, due to their propensity to metastasize, the best outcomes are experienced with they are diagnosed early and treated aggressively. In this paper, we present a case of a CCOC misdiagnosed as a clear cell calcifying epithelial odontogenic tumour which was only found to be a CCOC after cervical node metastasis. The original diagnosis was questioned and confirmed to be a CCOC by identification of the chromosomal translocation EWSR1 on fluorescence in situ hybridization. This has recently been described in CCOC and a wide variety of other mesenchymal and epithelial neoplasms. Previous reports have demonstrated EWSR1-ATF1 and EWSR1-CREB1 fusions in CCOC. Next generation sequencing of this case demonstrated the EWSR1-CREM fusion gene which has not been previously reported for CCOC. CREM fusion proteins have only recently been found in several tumour types including the closely associated hyalinizing clear cell carcinoma of salivary glands. This is discussed in this paper, and the role of the discovery of the CREM fusion protein in CCOC adds to your understating of the role of CREM in oncogenesis, and the possible link between CCOCs and hyalinizing clear cell carcinomas.

Unique features and clinical importance of acute alloreactive immune responses.

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.