Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-alpha

Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-a is responsible for accelerated Mtb growth, and TNF-a neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-a immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-a concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-a secretion.</p

Role of fine needle aspiration cytology in nodular sclerosis variant of Hodgkin\u92s lymphoma

Objective To assess the efficacy of fine needle aspiration cytology (FNAC) in the diagnosis of nodular sclerosis variant of Hodgkin\u92s lymphoma (NSHL) and to analyze cytologic features that could help in subtyping a case of Hodgkin\u92s lymphoma into this variant. Study Design FNAC smears of 18 histopathologically proven cases of NSHL were analyzed for a variety of features. Results On initial cytologic assessment, 14 of 18 cases were diagnosed as Hodgkin\u92s lymphoma. No further subtyping was performed. In this retrospective analysis it was possible to revise the diagnosis in the remaining 4 cases. Of the various cytologic features analyzed, presence of numerous lacunar-type cells along with fibroblasts and collagenous material were useful pointers toward a diagnosis of nodular sclerosis variant. Fibroblasts were seen in 83.33%, collagenous material in 27.77% and numerous lacunar cells in 77.77%. Conclusion Subtyping of NSHL based on cytologic features alone has been a matter of debate for a long time. Of the various subtypes, nodular sclerosis poses the greatest diagnostic difficulty. Though certain cytologic features may help in suggesting a diagnosis of nodular sclerosis variant, the primary role of fine needle aspiration is to diagnose a case of Hodgkin\u92s lymphoma as such and advise histopathologic examination for further categorization

Fine needle aspiration cytology of hodgkin\u92s lymphoma: a cytohistologic correlation study from a cancer center in Kuwait

Objective To assess the diagnostic accuracy of fine needle aspiration cytology (FNAC) in the diagnosis of Hodgkin\u92s lymphoma (HL). Study Design We selected all the cases in which a cytologic diagnosis of HL, suggestive of or suspicious for HL, or HL as the prime differential diagnosis was offered on FNAC. These cases were correlated with histopathologic follow-up. Cases of primary HL diagnosed on cytology but without histopathology were excluded from the study. Results Histopathologic follow-up was available in 46 cases. Of these, 42 were correctly diagnosed as HL, and there was a discorrelation in 4 cases, comprising 3 cases of non-HL (T-cell\u96rich B-cell lymphoma [TCRBCL]\u962, anaplastic large cell lymphoma\u961) and 1 case of metastatic carcinoma. Overall accuracy was 91.3%. In 14 cases, the cytologic features were diagnostic of recurrence; hence, no histopathologic examination was done. No follow-up was available for the remaining 19 cases, which were excluded from the study. Conclusion FNAC is very useful for rapid and accurate approach to the diagnosis of recurrent and most cases of primary HL. Because of morphologic similarities, it is difficult to differentiate HL from anaplastic large cell lymphoma and TCRBCL on FNAC. It is advisable to request a histopathologic examination in all cases of primary HL

Thyroid paraganglionoma

Paraganglionoma of the thyroid is an extremely rare tumour, with fewer than thirty cases reported in the literature. These tumours are believed to arise from the inferior laryngeal paraganglia and are most common in females of middle age. Approximately 30% of head and neck paraganglionomas are hereditary, most frequently due to germline mutations in the succinate dehydrogenase gene family, but also in association with disorders including multiple endocrine neoplasia and von-Hippel-Lindau disease. This entity is frequently mistaken for other lesions, including secondary neuroendocrine tumours and follicular neoplasm. Treatment is by total thyroidectomy, or lobectomy for a solitary lesion. Despite the presence of atypical features, malignant transformation of these tumours has not been observed, with no reported recurrences following resection.</p

Epstein-Barr virus associated mucocutaneous ulcer of the gingiva

Epstein-Barr virus associated mucocutaneous ulcer is a lymphoproliferative disorder of B cells in the oral cavity, oropharynx, skin and gastrointestinal tract, usually occurring in immunosuppressed patients. A 54-year-old female presented with a 5-week history of an ulcer which was present on the anterior gingival surface of her lower incisors. The patient subsequently developed an enlarged node in the ipsilateral neck. An array of investigations including histopathological analysis and an ultrasound guided fine-needle aspiration led to a final diagnosis of an Epstein-Barr virus associated mucocutaneous ulcer.These cases are rare and can present with significant diagnostic and therapeutic challenges to the clinicians due to their rarity, and similarity with other lesions including malignancy. We discuss our case and the relevant literature, with a focus on the challenging decision-making and multidisciplinary input to reach a satisfactory outcome for the patient

CD8 T-cell-mediated cerebellitis directed against Purkinje cell antigen after ipilimumab for small cell lung cancer

We report a rapidly progressive and fatal CD8 T-cell-mediated cerebellitis after ipilimumab (cytotoxic T-lymphocyte-associated protein 4 inhibitor) for small cell lung cancer. Clinical features and histopathology were consistent with an accelerated form of paraneoplastic cerebellar degeneration. A patchy CD8 T-cell infiltrate spatially corresponded to areas of Purkinje cell loss, with occasional CD8 polarisation towards Purkinje cells. CD20-positive B cells were sparse. CD8 T-cell-mediated cerebellitis after immune checkpoint inhibitor treatment may recapitulate the early stages of paraneoplastic cerebellar degeneration.</p