Novel Hematological Biomarker Adopted for Early Sepsis Detection Emerges as Predictor of Severity for COVID Infection.

Sepsis is a major health care burden with significant contribution to morbidity, mortality, and hospital resource utilization. Monocyte Distribution Width (MDW), the novel hematological biomarker, was clinically implemented in our laboratory for early detection of sepsis (ESId) in 2019. When COVID-19 pandemic hit in 2020, we noticed some similarities of the laboratory data of the COVID patients with patients previously diagnosed with sepsis. The aim of this study was to evaluate the value of the hematological data including MDW in predicting COVID disease severity and outcome. A retrospective study was conducted on 130 COVID-infected patients who presented at our hospital during March and April 2020. Collected data included clinical, laboratory, and radiological findings. This study demonstrates a unique pattern of three hematological biomarkers that predicted severity and outcome in COVID patients at their initial presentation in the Emergency Room (ER): higher absolute neutrophil count (ANC), lower absolute lymphocyte count (ALC), and higher MDW.

A Case Report of Acquired Factor X Deficiency in a Patient With Multiple Myeloma.

Multiple myeloma is a plasma cell neoplasm characterized by clonal proliferation of immunoglobulin producing terminally differentiated B cells. Classically patients are described to present with bone pain, hypercalcemia, anemia, and/or renal impairment. A less described clinical manifestation related to the myeloma is acquired coagulation abnormalities including paraprotein interfering with the coagulation cascade or exhibiting specific antibody activity. Factor X deficiency is reported in patients with secondary amyloidosis. We describe a patient who presented with bleeding tendency and an abnormal prothrombin and activated partial thromboplastin times (PT/PTT) due to factor X deficiency. A thorough workup revealed the diagnosis of multiple myeloma with the presence of monoclonal lambda light chain restricted plasma cells with qualifying end-organ damage without evidence of amyloidosis. Prior to the ultimate diagnosis, the patient succumbed to septic shock and acute respiratory distress syndrome due to Streptococcus Pneumonia infection.

Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer.

CONTEXT: Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3-5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases. OBJECTIVE: We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target. DESIGN: Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry. SETTING: The study was conducted at the University of Colorado Hospital. PATIENTS: Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURE: Immune markers were analyzed for association with disease severity. RESULTS: Immune markers were commonly expressed at the RNA level. PD-L1 was higher (P = .0443) in patients with nodal metastases. FoxP3(+) (P < .0001), PD-1(+)CD8(+) (P = .0058), and PD-1(+)CD4(+) (P = .0104) T cells were enriched in DTC biopsies. CD8(+) and FoxP3(+) T cells were detected by immunohistochemistry in all pT4 tumors and a subset of metastases. PD-1(+) lymphocytes were found in 50% of DTCs. PD-L1 was expressed by tumor and associated leukocytes in 13 of 22 cases, and expression was more diffuse in anaplastic thyroid cancer (P = .0373). BRAF(V600E) mutation was associated with higher frequencies of tumor-associated lymphocytes (P = .0095) but not PD-L1 expression. CONCLUSIONS: PD-1 checkpoint blockades may have therapeutic efficacy in patients with aggressive forms of thyroid cancer.

PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer.

Regional metastatic differentiated thyroid cancer (mDTC) provides a unique model in which to study the tumor-immune interface. These lymph node metastases persist for years, generally without progression to distant metastases. Although the immune system likely impedes disease progression, it is unsuccessful in eliminating disease. Our previous studies revealed that programmed death-1 (PD-1)(+) T cells were enriched in tumor-involved lymph nodes (TILN). Tumor-associated leukocytes and tumor cells were collected from grossly involved lymph nodes from 12 patients to further characterize the phenotype and functional potential of mDTC-associated PD-1(+) T cells. PD-1(+)CD4(+) and PD-1(+)CD8(+) T cells were enriched in 8 of 12 TILN samples. PD-1(+) T cells coexpressed Tim-3 and CD69 and failed to downregulate CD27. CD8(+) T cells, but not CD4(+) T cells, from these samples were variably deficient in their ability to produce effector cytokines when compared with control TILNs that lacked resident PD-1(+) T cells. PD-1(+)CD8(+) T cells were capable of exocytosis but lacked intracellular perforin. Surprisingly, T-cell proliferative capacity was largely maintained in all samples. Thus, although PD-1 expression by mDTC-associated CD8(+) T cells was associated with dysfunction, exhaustion was not complete. Notably, molecular markers of exhaustion did not translate to dysfunction in all samples or in CD4(+) T cells. Regulatory T cells (Treg), PD-L1, and galectin-9 were commonly found in mDTC and likely contributed to the initiation of T-cell exhaustion and disease progression. Therapies that release the effects of PD-1 and Tim-3 and reduce the suppressive effects of Tregs may encourage tumor elimination in patients with mDTC.