Role of Immunohistochemistry in Staging Diffuse Large B-cell Lymphoma (DLBCL)

The use of immunohistochemistry (IHC) in staging bone marrow in non-Hodgkin''s lymphoma (NHL) is largely limited to ambiguous cases, particularly those with lymphoid aggregates. Its role in routine clinical practice remains unestablished. This study aimed to determine whether the routine use of IHC in diffuse large B-cell lymphoma (DLBCL) would improve the detection of lymphomatous involvement in the bone marrow. It also sought to determine the impact of IHC on predicting survival compared with routine histological diagnosis using hematoxylin and eosin (H&E), Giemsa, and reticulin staining. The bone marrow trephines of 156 histologically proven DLBCL cases were assessed on routine histology, and IHC using two T-cell markers (CD45RO and CD3), two B-cell markers (CD20 and CD79a), and κ and λ light chains. IHC detected lymphomatous involvement on an additional 11% cases compared with histology alone. Although both routine histology and IHC were good predictors of survival, IHC was better at predicting survival on stepwise multivariate Cox regression analysis. IHC performed routinely on bone marrow trephines has the ability to improve detection of occult lymphoma in experienced hands. Furthermore, it is a better predictor of survival compared with routine histological examination alone. (J Histochem Cytochem 56:893–900, 2008)     

Basal forebrain cholinergic system in the dementias: Vulnerability,resilience, and resistance

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD-TAU) and the TDP-43 proteinopathy of FTLD-TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD-TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD-TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.

     

Two-hit wonders: The expanding universe of multitargeting epigenetic agents

Multitargeting involves the application of molecules that are deliberately intended to bind to two or more unrelated cellular targets with high affinity. In epigenetic chemical biology and drug discovery, the rational design of multitargeting agents has evolved to a sophisticated level, and there are now five examples that have reached clinical trials. This review covers recent developments in the field and future prospects.     

Increases in lake phytoplankton biomass caused by future climate‐driven changes to seasonal river flow

For the many lakes world‐wide with short residence times, changes to the rate of water throughput may have important effects on lake ecology. We studied relationships between current and predicted residence times and phytoplankton biomass using a eutrophic lake in the north‐west of England with an annual residence time averaging about 20 days, as a test case. Using 32 years of recent hydrological flow data for Bassenthwaite Lake, multiple sets of scaled flow for each year, and the process‐based phytoplankton response model, PROTECH, we modelled the effects of changing river flow on phytoplankton biomass in the lake. The impact on biomass was shown to depend on seasonal changes in flow rather than annual changes. Furthermore, there was a qualitative difference in impact depending on whether the nutrient loading to the lake came principally from flow‐independent sources, or from flow‐dependent ones. Predictions for changes in river flow under future climate scenarios in the north‐west of England have suggested that, despite little change in the annual flow magnitude, there will be a shift to greater flow in the winter and lesser flow in the summer. Applying these flow predictions to our modelling of Bassenthwaite Lake revealed that, with flow‐independent nutrient loading, and no overall increase in nutrient load, phytoplankton abundance in the summer could increase by up to 70%, including an increased proportion of Cyanobacteria. Conversely, were the loading completely dependent on the flow, the biomass would fall. In many parts of the world, river flow is expected to decrease in the summer even more than in England, suggesting these areas may expect substantial changes to seasonal phytoplankton biomass as a result of climate‐driven changes to seasonal river flow. Such changes would be in addition to any other changes owing to warming effects or eutrophication.     

Resting‐state functional connectivity measured by diffuse correlation spectroscopy

Near‐infrared diffuse correlation spectroscopy (DCS) is used to record spontaneous cerebral blood flow fluctuations in the frontal cortex. Nine adult subjects participated in the experiments, in which 8‐minute spontaneous fluctuations were simultaneously recorded from the left and right dorsolateral and inferior frontal regions. Resting‐state functional connectivity (RSFC) was measured by the temporal correlation of the low frequency fluctuations. Our data shows the RSFC within the dorsolateral region is significantly stronger than that between the inferior and dorsolateral regions, in line with previous observations with functional near‐infrared spectroscopy. This indicates that DCS is capable of investigating brain functional connectivity in terms of cerebral blood flow.      

The reflectance properties of plant internodes modify elongation responses to lateral far-red radiation

The quality and quantity of light reflected from Nicotinia tabacum L. internodes was monitored as the angle of incidence was varied. Reflectance of incident light, which was either normal or longitudinal to the internode axis, was investigated. Increasing the angle of incidence caused a greater proportion of incident light to be reflected. Light striking N. tabacum internodes was always modified prior to reflection, and smaller incident angles produced greater modification of the reflected light quality. At larger angles, interactions with the internode were reduced. As a parallel investigation, the extension growth rate of light-grown Sinapis alba L. seedlings was monitored continuously using sensitive linear displacement transducers. When the angle of illumination by fibre-optic probes, presenting far-red light to the growing internode, was changed from 0° to 45°, an increase was observed in stem extension rate. There is a possibility that this rate increase was the result of a fall in the red:far-red ratio (R:FR) present inside the plant internode as the angle of incidence was altered. However, it is more likely that it was due to the larger surface area of stem being illuminated. The consequences of these observations are discussed in relation to the potential influence of such modified reflections on canopy light environments and resultant shade responses which may occur when light of known R:FR impinges on plant internodes at angles other than 0°. The possibility is discussed that plants may perceive the quality of reflected radiation from neighbouring plants to be substantially different dependent upon the angle at which it is reflected.     

The Cancer Mutation D83V Induces an α-Helix to β-Strand Conformation Switch in MEF2B

MEF2B is a major target of somatic mutations in non-Hodgkin lymphoma. Most of these mutations are non-synonymous substitutions of surface residues in the MADS-box/MEF2 domain. Among them, D83V is the most frequent mutation found in tumor cells. The link between this hotspot mutation and cancer is not well understood. Here we show that the D83V mutation induces a dramatic α-helix to β-strand switch in the MEF2 domain. Located in an α-helix region rich in β-branched residues, the D83V mutation not only removes the extensive helix stabilization interactions but also introduces an additional β-branched residue that further shifts the conformation equilibrium from α-helix to β-strand. Cross-database analyses of cancer mutations and chameleon sequences revealed a number of well-known cancer targets harboring β-strand favoring mutations in chameleon α-helices, suggesting a commonality of such conformational switch in certain cancers and a new factor to consider when stratifying the rapidly expanding cancer mutation data.     

Role of endoscopic ultrasound‐guided‐fine needle aspiration biopsy in the diagnosis of lymphoma of the pancreas: A clinicopathological study of nine cases

Objective

Endoscopic ultrasound‐guided‐fine needle aspiration (EUS‐FNA) is an established first‐line procedure in the management of solid and cystic pancreatic masses. Lymphoma is an uncommon diagnosis in EUS‐FNA of the pancreas, and it is more common for such a diagnosis to be because of secondary involvement of the pancreas by a lymphoproliferative disorder than for this to represent isolated primary pancreatic lymphoma (PPL). We present the clinical, EUS and cytological features of these lesions.

Material and methods

After obtaining approval from our Institutional Review Board (IRB), nine cases of lymphoma diagnosed on EUS‐FNA at a tertiary care cancer centre over a period of 8 years from 2008 to 2016 were retrieved from our endoscopy and pathology archives. Rapid onsite evaluation (ROSE) was carried out by a trained cytopathologist in all these cases. Cell blocks were available in seven cases, and immunophenotyping was performed on cell blocks using the immunoperoxidase method. Flow cytometry was performed in two cases.

Results

The most frequent site of involvement was the head of the pancreas (n=5, 55.6%). Four out of nine cases were diagnosed as PPL (44.4%). Five cases were diagnosed as lymphoma secondarily involving the pancreas (55.6%). The most frequent diagnosis was diffuse large B‐cell lymphoma (n=6, 66.7%), followed by Hodgkin's lymphoma (n=2, 22.2%) and peripheral T‐cell lymphoma (n=1, 11.1%).

Conclusion

EUS‐FNA in experienced hands is a valuable diagnostic modality, in conjunction with ROSE, immunohistochemistry and flow cytometry, in the diagnosis and sub‐typing of both primary and secondary pancreatic lymphoma.