Faculty Bibliography

Background: In many of the inflammatory neurologic diseases (IND) of the central nervous system, such as MS, total white blood cell count in the cerebrospinal fluid (CSF) is normal or only mildly elevated, yet ratios of lymphocyte subtypes differ from those seen in the non-inflammatory neurological disease (NIND).
Objective(s): 1. To determine whether lymphocyte ratios in CSF, as assessed by flow cytometry can be used to discriminate between IND and NIND; 2. To determine whether lymphocyte ratios can be used to differentiate between MS and other CNS neuro-inflammatory diseases (such as meningitis, MOG Antibody Syndrome, Susac's syndrome).
Method(s): We retrospectively reviewed the charts of 100 consecutive patients evaluated by NYU neurologists between 1/2013 - 3/2019 for whom lymphocyte subtyping in CSF was carried out. The following lymphocyte markers were assessed: CD19, CD20, kappa-light chain, lambda-light chain, CD20-large (B immunoblasts), CD20-large kappa, CD20-large lambda, CD38bright+/ CD19+/CD20- (plasma cells), CD38bright+/CD19+/CD20- Kappa, CD38bright+/CD19+/CD20- lambda, CD3, CD4, CD8, CD3-/CD7+ (NK-cells), and CD3-/CD4dim + (monocytes). Regression modelling was used to identify lymphocyte subsets that predicted IND vs NIND, as well as MS vs non-MS inflammatory disorder.
Result(s): 62 patients had IND (45 MS, 17 non-MS), 25 had NIND, and 13 did not receive a definitive diagnosis. Regression model that best separated IND from NIND, included CD19+ (higher in IND, p=0.019), CD4+ (higher in IND, p=0.015) and CD3 (nonsignificantly lower in IND, p=0.065). When used as individual predictors, CD19+ >=2% predicted IND with sensitivity of 44%, specificity 88%, positive predictive value of 90% and negative predictive value of 39%, while CD4+ >=55% predicted IND with sensitivity 49.1%, specificity 84.2%, positive predictive value 90% and negative predictive value 35.6%. No NIND patients and 10 IND patients (16%) had CD19+>=5%. Only 2 NIND patients (8%) and 18 IND patients (29%) had CD4+ count >60%. Lymphocyte counts were not useful for differentiating MS from non-MS subgroups except that CD3+ count was lower in the MS group.
Conclusion(s): Flow cytometry of CSF is a useful adjunct in the diagnosis of IND. Higher CD19+ and CD4+ counts were rarely observed in NIND and could be regarded as strong supportive evidence of IND. These results will need to be confirmed in a larger prospective cohort

Interferon-γ (IFNγ), a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in prostate cancer (PCa) patients after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as interferon-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor microRNAs (pre-miRNA) that include pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5'-end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in PCa cells. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade PCa and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a pro-metastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application.

The BRCA1-BRCA2-RAD51 axis is essential for homologous recombination repair (HRR) and is frequently disrupted in breast cancers. PARP inhibitors (PARPis) are used clinically to treat BRCA-mutated breast tumors. Using a genetic screen, we identified EMI1 as a modulator of PARPi sensitivity in triple-negative breast cancer (TNBC) cells. This function requires the F-box domain of EMI1, through which EMI1 assembles a canonical SCF ubiquitin ligase complex that constitutively targets RAD51 for degradation. In response to genotoxic stress, CHK1-mediated phosphorylation of RAD51 counteracts EMI1-dependent degradation by enhancing RAD51's affinity for BRCA2, leading to RAD51 accumulation. Inhibition of RAD51 degradation restores HRR in BRCA1-depleted cells. Human breast cancer samples display an inverse correlation between EMI1 and RAD51 protein levels. A subset of BRCA1-deficient TNBC cells develop resistance to PARPi by downregulating EMI1 and restoring RAD51-dependent HRR. Notably, reconstitution of EMI1 expression reestablishes PARPi sensitivity both in cellular systems and in an orthotopic mouse model.

Intravascular large B-cell lymphoma (IVLBCL) is a very rare extra nodal lymphoma that tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules while sparing the organ parenchyma. The cause of its affinity for the vascular bed remains unknown. Because of its rarity and unremarkable clinical presentation, a timely diagnosis of IVLBCL is very challenging. Here, we describe a case of IVLBCL presenting as pancreatic mass that was ultimately diagnosed at autopsy. A 71-year-old Caucasian female presented with a 3-month history of fatigue, abdominal pain, and weight loss. She was referred to the emergency room with a new diagnosis of portal vein thrombosis and lactic acidosis. During her hospital course she was found to have a 1.9 × 1.8 cm lesion in the pancreatic tail on imaging; The cytologic specimen on the mass showed a high-grade lymphoma. A bone marrow biopsy showed no involvement. The patient's condition rapidly deteriorated and she, later, died due to multi-organ failure. An autopsy revealed diffuse intravascular invasion in multiple organs by the lymphoma cells. Based on our literature review-and to the best of our knowledge-there are virtually no reports describing the presentation of this lymphoma with a discernible tissue mass and associated multi-organ failure. The immunophenotypic studies performed revealed de novo CD5+ intravascular large B-cell lymphoma, which is known to be aggressive with very poor prognosis. Although it is a very rare lymphoma, it should be considered as a potential cause of multi-organ failure when no other cause has been identified. A prompt tissue diagnosis, appropriate high-dose chemotherapy and stem cell transplantation remain the only viable alternative to achieve some kind of remission.