Axl is a receptor tyrosine kinase implicated in cell survival following growth factor withdrawal and other stressors. The binding of Axl's ligand, growth arrest-specific protein 6 (Gas6), results in Axl autophosphorylation, recruitment of signaling molecules, and activation of downstream survival pathways. Pull-down assays and immunoprecipitations using wildtype and mutant Axl transfected cells determined that Axl directly binds growth factor receptor-bound protein 2 (Grb2) at pYVN and the p85 subunit of phosphatidylinositol-3 kinase (PI3 kinase) at two pYXXM sites (pY779 and pY821). Also, p85 can indirectly bind to Axl via an interaction between p85's second proline-rich region and the N-terminal SH3 domain of Grb2. Further, Grb2 and p85 can compete for binding at the pY821VNM site. Gas6-stimulation of Axl-transfected COS7 cells recruited activated PI3 kinase and phosphorylated Akt. An interaction between Axl, p85 and Grb2 was confirmed in brain homogenates, enriched populations of O4+ oligodendrocytes, and O4– flow-through prepared from day 10 mouse brain, indicating that cells with active Gas6/Axl signal through Grb2 and the PI3 kinase/Akt pathways.
A 19-year-old African American woman presented to the emergency department with a history of left upper quadrant pain for a week, associated with nausea, malaise, loss of appetite, subjective fevers and chills. Her family history is significant for thalassemia in her maternal aunt, and hereditary spherocytosis in her brother, sister and cousin. A contrast-enhanced CT scan of the abdomen and pelvis revealed massive splenomegaly and multiple splenic infarcts. On the second day of admission, she developed a fever of 103°F. Further evaluation revealed acute Epstein-Barr virus (EBV) infection and hereditary spherocytosis. Her condition improved after 4 days on piperacillin/tazobactam, intravenous fluids, analgesics and antipyretics. Our case report describes a thorough clinical evaluation of a patient with fever, anaemia, massive splenomegaly and multiple splenic infarcts. It highlights the need for careful interpretation of multiple positive IgM results on viral serological testing that often accompanies acute EBV infections.
A 57-year-old woman with a history of hypertension, diabetes mellitus, obesity, asthma, and hemoglobin SC disease presented to the emergency department by her home health aide after she was found having altered mental status. According to her home health aide, the patient was responding with "Ok" to her questions for more than a day. The hemoglobin on admission was 8.5 g/dL. A magnetic resonance imaging (MRI) without contrast of the brain showed acute cortical infarcts superimposed on the old infarct zone. The patient received 1 unit of packed red blood cells and a session of exchange transfusion, in addition to aspirin, clopidogrel, and atorvastatin during the hospital stay. When a patient known to have sickle cell disease presents with acute neurological deficits, the first consideration is usually acute ischemic stroke due to vasoocclusion in the cerebral vessels. However, it is essential to not overlook other potential causes of acute neurological deficits.
Background Diffuse large B-cell lymphoma (DLBCL) is the most frequent NHL subtype and the risk for it increases with age. At the same time, in advanced countries, the population over 65 years old is increasing because of the continuous increase in life expectancy and as a result the incidence of DLBCL is increasing as well. Increasing age is a major determinant of therapeutic decisions since it is associated with the presence of concomitant diseases, however elderly (over 65 years old) and very elderly (>80 years old) patients are not often included in clinical trials. Consequently, the optimal management of patients in the very elderly has not been identified. We conducted a single-center retrospective study with the objective to compare the comorbidity profiles, chemotherapy offered and tolerance, as well as outcome between elderly and very elderly DLBCL patients. Method A chart review of patients diagnosed with DLBCL in our center from January 2008 to January 2014 identified 33 patients aged between 60 to 79 years (elderly group, EG) and 30 patients aged 80 or more (very elderly group, VEG). We analyzed the clinical and laboratory characteristics (gender, extranodal disease presence, International Prognostic Index (IPI) factors, ECOG performance status (PS), Charlson comorbidity index, B-symptoms, hemoglobin, serum albumin), Progression Free Survival (PFS) and Overall Survival (OS) in comparison between the two groups. Furthermore, we studied the percentage of patients that were offered chemotherapy in each group, the regimen that was offered and the completion of chemotherapy as planned. Results: Median age for the EG was 72 years and for the VEG was 84 years (80 - 93). Significant differences between EG and VEG were found in mean serum albumin concentration at diagnosis (3.48 vs. 2.77, p=0.008), ECOG PS (0.91 vs. 2.36, p=0.000), and International Prognostic Index (IPI) (1.76 vs. 2.54, p=0.023) between EG and VEG. Compared to EG, VEG patients were more likely to have comorbidities (100 vs. 81.8%, p=0.025) and extra-nodal disease (93.3% vs. 66.7%, p=0.012). Though there was no statistically significant difference in percent of patients receiving chemotherapy, greater percent of EG (60.6) received R-CHOP regimen compared to VEG (20.0, p=0.001). There was no significant difference in therapy related toxicity, but fewer patients in the VEG (60 vs. 90.5%, p=0.039) were able to complete the course of chemotherapy planned and fewer achieved CR (35.7% vs. 68.2, p=0.036). Median overall survival was 762 vs. 650 days (p=0.793) and median progression free survival was 704 vs. 331 days (p= 0.180) for EG versus VEG. Conclusion: Very elderly DLBCL patients may differ from elderly patients in ECOG PS, comorbidity profile and chemotherapy regimen. These patients were less likely to complete the course of chemotherapy and fewer achieved complete response compared to the elderly group. There were no statistically significant differences in outcomes between the two groups. Disclosures No relevant conflicts of interest to declare.
Background: Incidence of Diffuse Large B-Cell Lymphoma (DLBCL), one of the most common lymphoid malignancies worldwide, increases with age. With improving life expectancy, its incidence among the elderly population is predicted to rise further. Elderly patients pose unique challenges- multiple co-morbidities, variable life expectancy, poor social support systems, and increased risk of therapy-related toxicity. Management decisions in geriatric patients are usually based on data obtained in younger patients. R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) is the standard chemotherapy for younger patients with DLBCL. Unfortunately, among the patients aged 80 or more, data on the use of R-CHOP and its comparison with other treatment regimens are meager. Also, new data on alternate chemotherapy regimens including R with Bendamustine (R-Benda) and R with low dose CHOP (R-miniCHOP) are emerging. Thus, there is a need for development and validation of treatment strategies for DLBCL in this patient population. Objective of this study is to provide a descriptive data including co-morbidity profile, chemotherapy regimen offered, tolerance of chemotherapy, and outcome of the treatment among the DLBCL patients aged 80 or more. Methodology: A retrospective chart review of 33 DLBCL patients (N) aged 80 or more treated in the last 4 years in a tertiary community hospital. Results: Table 1 Age Charlson Co-morbidity Index (CCI) Serum Lactate Dehydrogenase Serum Albumin Serum Beta2 Microglobulin Median Ki67 Valid N 33 30 23 24 9 11 Mean 83.33 2.87 611.91 2.85 6.77 0.70 Median 83.00 2.00 302 2.95 4.85 0.75 Standard Deviation 5.50 1.94 1033.15 0.78 5.79 0.19 Minimum 69 0 84 1.60 1.90 0.40 Maximum 93 9 5038 4.20 19.70 0.95 Table 2 ECOG Performance Score International Prognostic Index (IPI) BMI Hemoglobin Platelets WBC ANC Valid N 25 16 8 31 30 31 28 Mean 2.16 2.56 25.70 11.58 240.73 8.73 5971 Median 2.00 3.00 25.95 11.60 201 8.20 5400 Standard Deviation 1.17 1.03 2.910 1.94 129.64 3.47 2935 Minimum 0 1 20.98 8.20 62 3.60 1400 Maximum 4 4 29.40 15.10 716 16.10 12800 Table 3 Valid N Categories Percentage Sex 33 Male Female 54.5 45.5 Prior Malignancy 33 No Yes 81.8 18.2 Ann Arbor Staging 22 1 2 3 4 22.7 18.2 22.7 36.4 B symptoms 29 No Yes 62.1 37.9 Node Status 33 Nodal Extranodal Nodal and Extranodal 6.1 42.4 51.5 Chemotherapy offered 28 No Yes 17.9 82.1 Intent of Therapy 20 Curative Palliative 85 15 Chemotherapy regimen 22 R-miniCHOP R R-Bendamustine R-CHOP RCVP RCNOP 22.7 9 18.18 36.36 9 4.54 Adverse effect of Chemotherapy 16 No Yes 18.75 81.25 Hospital admission during Chemotherapy 19 No Yes 47.36 52.63 Growth factors required during Chemotherapy 20 No Yes 25 75 Dose delay 17 No Yes 70.58 29.42 Dose modification 17 No Yes 64.70 35.29 Chemotherapy stopped prior to completion 18 No Yes 66.67 33.33 Radiation therapy 19 No Yes 52.63 47.36 Result of chemotherapy 15 Complete Response (CR) Partial Response (PR)Progression 40 40 20 Relapse 7 No Yes 57.14 42.85 Death 10 No Yes 20 80 ANOVA was used for data analysis. A statistically significant difference in mean CCI between those who completed planned chemotherapy course (2.00) and those who did not (4.75) was observed (p= 0.017). Similarly, difference in the mean CCI among those achieving CR (2.00), PR (2.17) and Progression (7.00) was statistically significant (p= 0.005). There were significant differences in the mean pre-chemotherapy ECOG PS between those who completed planned chemotherapy course (1.27) vs. those who did not (2.75), (p= 0. 001) and those achieving CR (1.60), PR (1.00) and progression (3.00), (p=0.012). No significant association was found between CCI or pre-chemotherapy ECOG PS with various factors like type of chemotherapy offered, incidence of adverse effects, and dose delay/modification. Conclusion: Very elderly patients (≥80 years) with DLBCL having good ECOG PS or lower CCI are more likely to complete planned chemotherapy course and achieve remission. CCI might be a good marker for evaluation of co-morbidities in very elderly patients and could serve as a predictive tool for patient outcomes. We intend to analyze data of DLBCL patients aged 65 – 79 years and perform comparative study with existing cohort. Disclosures No relevant conflicts of interest to declare.
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