Clinical Outcomes of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia in a County Hospital System.

BACKGROUND: Major advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50% to 60% in T cell ALL, and 60% to 70% in Philadelphia chromosome-positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT). PATIENTS AND METHODS: The purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX. RESULTS: One hundred forty-six patients were included, with newly diagnosed pre-B-ALL (n = 127), T-ALL (n = 18), and chronic myeloid leukemia and/or lymphoid blast crisis (n = 1). Median age was 35 years (16-82) at diagnosis, and 81(55%) were male. The majority of patients with pre-B ALL identified as Hispanic (n = 118, or 92%). Ninety-eight (67%) of patients were uninsured or indigent, receiving care under the county's financial assistance programs. Hyper-CVAD-based induction chemotherapy was administered in 134 (92%) of patients, while 9 (6%) were treated on different protocols, and 3 (2%) were not treated due to early death, or patient refusal. Imatinib was the most common TKI used in 17 of 30 or 57% of patients with Ph+ disease. Out of 137 evaluable for response patients, 117 (85%) achieved complete remission (CR + CRi), 19 (14%) had refractory disease, and 1 (1%) died within 4 weeks of diagnosis. Median follow-up time was 50 months (1.5-135). For the entire study cohort, the median duration of CR/CRi was 15.4 months. Out of 62 patients who were eligible for consolidative HSCT at first CR, 52 (89%) did not receive it, with lack of insurance being the most common reason (n = 29, or 56%). Barriers to utilization of novel therapies such as blinatumomab or CAR-T were also observed. Patient-caused delays in administration of chemotherapy and treatment interruptions of at least 30 days were seen in 31(23%) patients. At 1, 2, and 5 years, relapse rates were 37%, 56%, and 70%. Recurrent and/or refractory disease was the cause of death in most patients (n = 69 [85%]). Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL. Median OS was significantly increased (not reached [NR] vs. 24 months; P = .00088) in patients with an indication for HSCT in first CR due to high-risk features who underwent HSCT, versus those who did not. CONCLUSION: Addressing barriers raised by socioeconomic disparities, increasing access to effective therapies, and including patients with ALL treated in the community in clinical trials may improve survival for underserved populations.

Autoimmune hemolytic anemia in a patient with chronic lymphocytic leukemia.

Peripheral blood smear for patients with CLL and AIHA usually shows lymphoid cells with scant cytoplasm and small round nuclei with condensed chromatin, smudge cells and spherocytes.

Bortezomib, Ifosfamide, Carboplatin, and Etoposide in a Patient with HIV-Negative Relapsed Plasmablastic Lymphoma.

Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma (DLBCL), often associated with HIV infection. We present a case of a 53-year-old HIV-negative man with untreated hepatitis C viral infection who presented with abdominal pain and lymphadenopathy. Lymph node and bone marrow biopsies were consistent with plasmablastic lymphoma. He had partial response (PR) to 6 cycles of EPOCH but disease progressed seven weeks later. Repeat biopsy was consistent with plasmablastic lymphoma. Three cycles of bortezomib, ifosfamide, carboplatin, and etoposide (B-ICE) chemotherapy resulted in a partial response (PR). Five months later, he presented with widespread lymphadenopathy and tumor lysis syndrome with circulating blasts. Flow cytometry revealed a different population of lymphoma cells, this time positive for CD5, CD19, CD20, and CD22, with dim expression of CD45 and CD38. The patient died on the first day of ESHAP chemotherapy. There are no treatment recommendations or standard of care for plasmablastic lymphoma. A literature search yielded 10 cases in which bortezomib was administered in either HIV-positive or HIV-negative PBL. Six reported a partial response, 3 reported a complete response, and 1 was a near-complete response. Bortezomib, in combination with chemotherapy, may be an effective treatment option in PBL as reported here.

Treatment of refractory thrombotic thrombocytopenic purpura with N-acetylcysteine: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease resulting in systemic microvascular thrombosis. The disease is caused by excessive platelet (PLT) adhesion to ultra-large (UL) von Willebrand factor (VWF) multimers inadequately cleaved by the processing enzyme ADAMTS-13. While many cases respond to plasma exchange performed with or without concurrent corticosteroids, treatment of the 10% to 20% of patients with refractory disease is difficult. Experimental studies demonstrating that N-acetylcysteine (NAC) inhibits PLT binding to endothelial cell-secreted and anchored UL VWF multimers suggest that NAC may be useful in the treatment of TTP. CASE REPORT: A 44-year-old woman presented with malaise, confusion, chest and abdominal pain, and transient visual loss. Laboratory results and peripheral blood smear were consistent with TTP. The patient was begun on plasma exchange and corticosteroid treatment, but after 10 days the PLT count was still less than 10.0 × 10(9) /L and she developed a fever. Rituximab was initiated, but the patient's condition worsened and she became comatose. Antibiotics were initiated, but cultures remained sterile. After 3 days of coma and further clinical deterioration, treatment with NAC was begun. The patient received a loading dose of 150 mg/kg NAC intravenously (IV) over 1 hour. Within 18 hours the patient awakened abruptly and began communicating with medical personnel. Plasma exchange, corticosteroids, rituximab, and NAC infusion (150 mg/kg IV over 17 hr daily × 10 days) were continued and by Day 17 the PLT count was more than 50 × 10(9) /L. The patient fully recovered and was discharged on Day 31. CONCLUSION: This is the first complete report of a TTP patient treated with NAC. NAC was a safe and effective supplementary treatment for refractory TTP in this patient.

Howell-Jolly bodies: a brief historical review.

Understanding the process by which red cell precursors lose their nuclei developed in the late 19th and early 20th centuries led to the identification of nuclear remnants in circulating red cells in certain pathological states, particularly absence or decreased function of the spleen. William Howell, an American, and Justin Jolly, a Frenchman, were among a number of early contributors to this field. Early on, their names were applied, singly or in tandem, to these red cell inclusions, and the eponym, Howell-Jolly bodies, has stuck. It was, however, not until after the mid-20th century that Howell-Jolly bodies were clearly differentiated from basophilic stippling and that the mechanisms of their formation and removal from red cells were understood.

Internal medicine clerkship characteristics associated with enhanced student examination performance.

PURPOSE: To determine which internal medicine (IM) clerkship characteristics are associated with better student examination performance. METHOD: The authors collected data from 17 U.S. medical schools (1,817 students) regarding characteristics of their IM clerkships, including structural characteristics, pedagogical approaches, patient contact, and clinical teacher characteristics. Outcomes of interest were postclerkship National Board of Medical Examiners (NBME) subject examination score, United States Medical Licensing Examination (USMLE) 2 score, and change in score from USMLE 1 to 2. To examine how associations of various clerkship characteristics and examination performance may differ for students of different prior achievement, the authors categorized students into those who scored in the top (1/4) of the cohort on USMLE 1 and the bottom (1/4). The authors conducted analyses at both the school and the individual student levels. RESULTS: In school-level analyses (using a reduced four-variable model), independent variables associated with higher NBME subject examination score were more small-group hours/week and use of community-based preceptors. Greater score increase from USMLE 1 to 2 was associated with students caring for more patients/day. Several variables were associated with enhanced student examination performance at the student level. The most consistent finding was that more patients cared for per day was associated with higher examination performance. More structured learning activities were associated with higher examination scores for students with lower baseline USMLE 1 achievement. CONCLUSION: Certain clerkship characteristics are associated with better student examination performance, the most salient being caring for more patients per day.

Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles.

Plasmablastic lymphoma is an aggressive neoplasm that shares many cytomorphologic and immunophenotypic features with plasmablastic plasma cell myeloma. However, plasmablastic lymphoma is listed in the World Health Organization (WHO) classification as a variant of diffuse large B-cell lymphoma. To characterize the relationship between plasmablastic lymphoma and plasmablastic plasma cell myeloma, we performed immunohistochemistry using a large panel of B-cell and plasma cell markers on nine cases of plasmablastic lymphoma and seven cases of plasmablastic plasma cell myeloma with and without HIV/AIDS. The expression profiles of the tumor suppressor genes p53, p16, and p27, and the presence of Epstein-Barr virus (EBV) and human herpes virus type 8 (HHV-8) were also analyzed. All cases of plasmablastic lymphoma and plasmablastic plasma cell myeloma were positive for MUM1/IRF4, CD138, and CD38, and negative for CD20, corresponding to a plasma cell immunophenotype. PAX-5 and BCL-6 were weakly positive in 2/9 and 1/5 plasmablastic lymphomas, and negative in all plasmablastic plasma cell myelomas. Three markers that are often aberrantly expressed in cases of plasma cell myelomas, CD56, CD4 and CD10, were positive in 5/9, 2/5, and 6/9 plasmablastic lymphomas, and in 3/7, 1/5, and 2/7 plasmablastic plasma cell myelomas. A high Ki-67 proliferation index, overexpression of p53, and loss of expression of p16 and p27 were present in both tumors. No evidence of HHV-8 infection was detected in either neoplasm. The only significant difference between plasmablastic lymphoma and plasma cell myeloma was the presence of EBV-encoded RNA, which was positive in all plasmablastic lymphoma cases tested and negative in all plasma cell myelomas. In conclusion, most cases of AIDS-related plasmablastic lymphoma have an immunophenotype and tumor suppressor gene expression profile virtually identical to plasmablastic plasma cell myeloma, and unlike diffuse large B-cell lymphoma. These results do not support the suggestion in the WHO classification that plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma.

Review of studies concerning the tumorigenicity of 2-butoxyethanol in B6C3F1 mice and its relevance for human risk assessment.

The U.S. National Toxicology Program (NTP) has completed 2-yr inhalation exposures in rats and mice with 2-butoxyethanol (BE). This review concerns the most significant findings from those studies and describes recent research into the mechanistic aspects of BE-mediated tumorigenesis in the mouse and the relevance of such effects to humans. Two tumor types were increased in B6C3F1 mice leading to the classification of "some evidence" of carcinogenicity: liver hemangiosarcomas in male mice and forestomach tumors in female mice (primarily benign papillomas). The results of research collected to date indicate that the tumorigenesis noted for BE was produced by indirect mechanisms. In particular, the occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to red blood cell hemolysis and iron deposition in this organ. Oral administration of BE in mice up to 600 mg/kg/d for up to 90 d produces a dose-related increase in iron (Perl's staining) in Kupffer cells and hepatocytes, increased DNA synthesis in endothelial cells, and enhanced oxidative damage. Further, iron alone, and not BE or BAA, is responsible for producing oxidative damage in cultured hepatocytes from rats or mice. Forestomach neoplasms in female mice were most likely a result of prolonged exposure-induced irritation with compensatory hyperplasia and subsequent tumor promotion. This mechanism is supported by studies indicating elevated levels of BE and BAA in the mouse forestomach tissues and stomach contents following multiple routes of exposure, forestomach epithelial cell cytotoxicity and cell proliferation following administration of BE and BAA, and the increased capacity of forestomach tissues from female mice to metabolize BE to the more irritating metabolite, BAA. The current article summarizes the results of a number of in vivo and in vitro studies designed to elucidate the underlying mechanisms of tumorigenesis by BE in the mouse and discusses the relevance of these for human risk.

Pappenheimer bodies: a brief historical review.

Pappenheimer is credited with describing the intraerythrocytic collections of iron, or siderotic granules, as they appear on Wright-stained blood smears of certain patients after splenectomy. The history of their description and elucidation of their origin and disposition shows the interaction of morphology with the increasing understanding of red cell physiology in the mid-twentieth century.

Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures.

BACKGROUND: Patients with heparin-induced thrombocytopenia (HIT) (with or without thrombosis) require alternative anticoagulation because of their extreme risk of new thromboembolic complications. The first effective agent for this purpose may be danaparoid, a less-sulfated low molecular weight heparinoid. Recently, direct thrombin inhibitors have been used. OBJECTIVE: Five HIT patients, who developed new thromboembolic complications while receiving danaparoid, were analyzed to consider possible reasons for treatment failure and to promulgate strategies that improve efficacy. RESULTS: Three patients had acute HIT, one had recent HIT, and one with remote HIT was re-exposed to heparin during heart surgery. Danaparoid was started as intravenous bolus and infusion in one patient, and as 1250 units subcutaneously twice daily in four patients. The new complications that emerged on danaparoid were new venous thrombi in three patients (one with pulmonary emboli), lower extremity arterial thrombosis in one, myocardial ischemia in one, thromboembolic cardiovascular accidents in one, and fatal bowel necrosis in one (two patients suffered more than one complication). Platelet counts did not improve or worsened in four, improved partially in the other, and parameters of disseminated intravascular coagulation failed to improve in one patient. Four patients responded relatively dramatically when direct thrombin inhibitors were substituted. Possible reasons for danaparoid failure include that: 1) no treatment is expected to completely prevent complications, 2) antithrombin III consumption can blunt efficacy in some patients, 3) low or intermediate doses may be insufficient, and 4) there was clinically significant cross-reactivity of the pathogenic HIT antibodies. CONCLUSIONS: It is emphasized that the possibility of clinically significant antibody cross-reactivity and that low or intermediate dosage may be inadequate when using danaparoid in therapy of HIT. The latter problem probably extrapolates to other anticoagulants used for HIT.

Does being a clerkship director benefit academic career advancement: results of a national survey.

BACKGROUND: Changes in academic medicine have left clerkship directors (CDs) anxious about their career pathway, because clerkship administrative efforts may detract from other activities. PURPOSE: The Clerkship Directors in Internal Medicine (CDIM) asked members about benefits of being a CD or CDIM membership toward career development. METHODS: Responses were on 1-5 Likert scales with 5 (strongly agree). Background and demographic issues were analyzed for associations with the career benefits statements. RESULTS: The response rate was 75% (n = 92). Mean agreement with CD benefit was 4.2 (SD = 0.82) and CDIM membership 3.8 (SD = 0.95). Eighty-one percent and 58% of CDs agreed with the respective statements. Significant predictors of CD benefit were CD and coordinator salary support, years as CD, and receiving a university teaching award. Structured discussions of expectations strongly predicted perceiving CDIM benefit. CONCLUSIONS: Most CDs agreed that their CD role and CDIM benefited their careers. Salary support and clearly defining expectations may increase the likelihood of perceiving benefit.

HIV-related Hodgkin's disease with central nervous system involvement and association with Epstein-Barr virus.

Central nervous system (CNS) involvement is a rare occurrence in the course of human immunodeficiency virus (HIV)-related Hodgkin's disease (HD). We report the clinical course of a patient with HIV infection who developed systemic HD, mixed cellularity subtype, later complicated by leptomeningeal involvement. The patient died from his illness, and autopsy was performed. Examining the brain lesion, Epstein-Barr virus (EBV) presence was demonstrated in Reed-Sternberg cells by immunohistochemistry using an EBER probe for EBV RNA. This is the second case report in the English literature of HD involving the CNS in an HIV-positive individual, and the first demonstrating EBV presence. Extranodal presence of Hodgkin's disease in patients with HIV infection is probably related to immunosuppression, and physicians treating this illness should be alert to the potential of unusual sites of involvement.

In vitro sub-hemolytic effects of butoxyacetic acid on human and rat erythrocytes.

When 2-butoxyethanol (2-BE) is administered to rats, hemolysis occurs as the active metabolite butoxyacetic acid (BAA) is formed. Human red blood cells appear to be relatively resistant to the hemolytic effects of BAA in vitro, whereas rat red blood cells undergo changes in deformability, cell swelling, and hemolysis. In this study, exposure of human red blood cells to high concentrations of BAA resulted in loss of deformability and a small increase in mean cellular volume, but no significant hemolysis. These changes resembled the changes that occur in rat erythrocytes exposed to much lower concentrations of BAA. Therefore, a comparison was made between the sub-hemolytic effects of BAA at high concentrations (up to 10 mM) on human red cells with the sub-hemolytic effects of lower concentrations of BAA (up to 0.1 mM) on rat erythrocytes. Under these conditions, human and rat erythrocyte deformability decreased, while mean cellular volume (MCV) and osmotic fragility increased. Although there was a substantial shift in rat erythrocytes to lower densities, human erythrocyte density was only slightly decreased. Human and rat erythrocyte sodium also increased. Rat erythrocytes demonstrated increased spherocytosis. In a survey of blood samples from adults and children, none demonstrated an increase in hemolysis (n = 97) or MCV (n = 65) after exposure to 10 mM BAA for 4 h. In these experiments, in which hemolysis was not evident, human erythrocytes required exposure to a 100-fold greater concentration of BAA to develop changes in red cell deformability, osmotic fragility, and sodium content similar to those observed in rat erythrocytes. These concentrations are not likely to occur under normal human use of 2-BE-containing products.

Sickle erythrocytes increase prostacyclin and endothelin-1 production by cultured human endothelial cells under flow conditions.

We investigated the effects of sickle erythrocytes on the production of vasotone mediators in endothelial cells (ECs) using an in vitro recirculating flow system. Sickle erythrocytes increased the EC production of two important vasoactivators, prostacyclin and endothelin-1, under venous wall shear stress conditions of 1dyncm2. The presence of interleukin-1 in the perfusion system, as a model for inflammatory cytokine effects, enhanced the overall amounts of released prostacyclin but did not affect the production of endothelin-1. This study demonstrates the effects of sickle erythrocytes on the function and metabolism of ECs under vascular flow environments. The altered production of vasoactivators may contribute to the vasotone instability and vasoocclusive crises in sickle cell anemia.

Regression of a plasmablastic lymphoma in a patient with HIV on highly active antiretroviral therapy.

We describe an HIV-infected 44-year-old man who presented 1 month after discontinuation of HAART therapy with a large mass extending from the mediastinum, enclosing the heart and extending through the diaphragm to the epigastric region. Biopsies subsequently revealed a highly aggressive non-Hodgkin's lymphoma (NHL) producing sheets of cells with an organoid distribution. The cells had abundant basophilic cytoplasm and a plasmacytic appearance. Although immunohistochemistry failed to show either B- or T-cell markers, antigens consistent with plasma cells were found. An immunoglobulin heavy chain clonal rearrangement was identified by PCR analysis. These studies were supportive of a diagnosis of a plasmablastic lymphoma. While awaiting the results of these tests, the patient was reinitiated on his HAART regimen. He was found on follow-up a month later to have complete resolution of his bulky mediastinal mass. He remained free of disease for 3 months with subsequent rectal and abdominal recurrence. Treatment with CHOP chemotherapy with filgrastim support was begun which resulted in another remission. Plasmablastic lymphoma is now reported in some studies to account for 2.6% of all HIV-related NHL. Originally described in 1997 in a series of 16 patients, this entity is highly associated with HIV infection in its later stages. Often, patients present with oral or jaw lesions with a rapidly progressive course. The tumors have the morphologic appearance of a plasmacytoid tumor with high proliferative index. Markers are positive mainly for LCA, CD79a, VS38C, and CD138. Co-infection with HHV-8 and EBV has not been consistently reported. Therapy with standard regimens has variable response. One case has been reported with a 3.5 year disease free survival. The regression of disease after resumption of HAART therapy alone in this patient suggests that HAART has an important role in the treatment of lymphoma in the HIV infected patient.