Anti-CD40L therapy prevents the formation of precursor lesions to gastric B-cell MALT lymphoma in a mouse model.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a B-cell tumour that develops over many decades in the stomachs of individuals with chronic Helicobacter pylori infection. We developed a new mouse model of human gastric MALT lymphoma in which mice with a myeloid-specific deletion of the innate immune molecule, Nlrc5, develop precursor B-cell lesions to MALT lymphoma at only 3 months post-Helicobacter infection versus 9-24 months in existing models. The gastric B-cell lesions in the Nlrc5 knockout mice had the histopathological features of the human disease, notably lymphoepithelial-like lesions, centrocyte-like cells, and were infiltrated by dendritic cells (DCs), macrophages, and T-cells (CD4+ , CD8+ and Foxp3+ ). Mouse and human gastric tissues contained immune cells expressing immune checkpoint receptor programmed death 1 (PD-1) and its ligand PD-L1, indicating an immunosuppressive tissue microenvironment. We next determined whether CD40L, overexpressed in a range of B-cell malignancies, may be a potential drug target for the treatment of gastric MALT lymphoma. Importantly, we showed that the administration of anti-CD40L antibody either coincident with or after establishment of Helicobacter infection prevented gastric B-cell lesions in mice, when compared with the control antibody treatment. Mice administered the CD40L antibody also had significantly reduced numbers of gastric DCs, CD8+ and Foxp3+ T-cells, as well as decreased gastric expression of B-cell lymphoma genes. These findings validate the potential of CD40L as a therapeutic target in the treatment of human gastric B-cell MALT lymphoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma

Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose (MTD) of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory (R/R) T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with R/R TCL and NKTL were treated with standard dose ICE, dexamethasone 20mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose level (DL) 1, 2 and 3 were 40, 60 and 80mg respectively. Eleven patients with a median age of 60 were enrolled; 6 at DL1 and 5 at DL2. Patients had received a median of 2 (range 1-4) prior lines of treatment and 7 had primary refractory disease at study entry. Patients received a median of 3 cycles (range 1-6) of selinexor-DICE. The most common grade (G) 1/2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common G 3/4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed doselimiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the 10 evaluable patients, the overall and complete response rates were 91% and 82% respectively. The MTD of selinexor was 40mg when combined with DICE. The combination showed promising CR rates in patients with R/R TCL and NKTL but was poorly tolerated.

Simultaneous assessment of plaque morphology, cerebral micro-embolic signal status and platelet biomarkers in patients with recently symptomatic and asymptomatic carotid stenosis.

The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation.We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray-Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as 'MES+ve' or 'MES-ve'. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets.Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 109/L), neutrophil-platelet (3.3 vs. 2.7%), monocyte-platelet (6.3 vs. 4.55%) and lymphocyte-platelet complexes (2.91 vs. 2.53%) than 'asymptomatic patients with GSM-echodense plaques' (P ≤ 0.03).Recently, symptomatic carotid stenosis patients with 'GSM-echodense plaques' have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.

Conservative management of L-asparaginase-induced hypertriglyceridemia in an adult patient: a case report and review of the literature.

BACKGROUND: L-Asparaginase (L-Asp) may induce hypertriglyceridemia; however, this has been mainly observed among pediatric patients. Treatment for L-Asp-induced hypertriglyceridemia is not standardized, ranging from fasting and diet restriction to the invasive plasmapheresis procedure. CASE REPORT: We describe a 53-year-old male patient who presented with L-Asp-induced severe hypertriglyceridemia. He was receiving L-Asp as part of his chemotherapy regimen for natural killer T-cell lymphoma. After the 20th dose, his serum triglyceride level was 3,552 mg/dl, with a total cholesterol of 418 mg/dl. Despite the high triglyceride, the patient did not present with acute pancreatitis symptoms. Treatment comprising fasting, fenofibrate, and omega-3 fatty acids was initiated. Triglyceride levels dropped rapidly to 1,000 mg/dl within 2 days, and to 268 mg/dl after 10 days. The chemotherapy regimen was subsequently switched to exclude L-Asp. CONCLUSION: L-Asp-induced severe hypertriglyceridemia may occur in adults and may be conservatively managed with fasting, fibrates, and omega-3 fatty acids. Plasmapheresis or continuous insulin infusion may be used for symptomatic patients with high triglyceride levels. Lipidlowering agents should be continued for patients previously treated for hyperlipidemia. Regular monitoring of lipid levels for patients receiving L-Asp is important, especially for those with a prior history of dyslipidemia. Re-challenge with L-Asp can be undertaken on an individual basis.

Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres (pattern 1) shows superior survival to patterns 2 and 3: a meta-analysis of 56 cases.

AIMS: Angioimmunoblastic T-cell lymphoma (AITL) may present in patterns 1, 2 or 3, representing those with hyperplastic, regressed or effaced germinal centres (GCs), respectively, but the prognostic utility of this subclassification has not been previously validated. METHODS AND RESULTS: Twenty-five cases of AITL were reviewed immunohistologically and with in-situ hybridization for Epstein-Barr virus-encoded RNA and polymerase chain reaction for T-cell receptor gamma and immunoglobulin heavy chain clonality and followed for up to 120 months. Four cases had conventional hyperplastic GCs, two had floral GCs, and one had progressively transformed GCs, consistent with pattern 1 and one additional case had hyalinized GCs, consistent with pattern 2. The remaining 17 (pattern 3) cases lacked morphologically discernible GCs. The Kaplan-Meier survival distribution of pattern 1 cases (5-year survival 83%) was superior to that of pattern 2 and 3 cases [5-year-survival 36% (P = 0.0417)] only when combined with the 31 cases, seven of which were pattern 1, that Attygalle et al. had followed for up to 247 months and previously published. Furthermore, the development of B-lineage (classical Hodgkin or diffuse large-cell) lymphoma was associated exclusively with pattern 3 (P = 0.0057). CONCLUSIONS: Pattern 1 represents an indolent phase/grade of AITL, unassociated with the development of secondary B-lineage lymphoma and uninfluenced by treatment regimen.

Single mode, polarization-independent submicron silicon waveguides based on geometrical adjustments.

In this work, we demonstrate via computer simulation the single mode and zero birefringence conditions for photonic wires with height and width less than 600 nm. We report on the simulation conditions for both single mode and zero birefringence in silicon-on-insulator photonic wires and sub-micron rib waveguides using a 3-dimensional imaginary beam propagation method. The results show that operation in both single mode and zero birefringence is possible under certain circumstances and that the conditions are restricted by fabrication processes where birefringence is strongly dependent upon waveguide dimensions. A matrix of waveguide parameters has been identified at both operating wavelengths of 1310 nm and 1550 nm, which can satisfy single mode and zero birefringence conditions simultaneously. This is to provide a general design rule for waveguides in small dimensions on the order of hundreds of nanometres.

Flat spectral response silicon arrayed waveguide gratings via ion implantation.

A flat spectral response has long been a requirement in photonic networking. In order to find a low cost alternative compared to some other technologies, a novel method is demonstrated to achieve such a response in silicon-on-insulator arrayed waveguide gratings (AWG) through free carrier absorption, implemented by ion implantation of dopant species. The AWG is designed using 1.5mum Si-overlayer on an SOI wafer utilising rib waveguides with a width of 1.1mum and an etch-depth of 0.88mum to facilitate the single-mode, birefringence-free operation. It is also essential to achieve a uniform dopant concentration throughout the guiding region to avoid any phase errors resulting from the free carriers. This can be achieved using multiple ion implantation steps. Both n and p type dopants are investigated and results showed significant reduction of doping length is achieved by using n-type dopant as compared to a p-type dopants. The broadened passband is measured to be 0.5nm, a 5 times broadening from the Gaussian peak.