Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis following tremelimumab - durvalumab treatment.

BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Extramedullary disease in APL: a real phenomenon to contend with or not?

In the last 2 decades an increasing number of patients reported with extramedullary involvement among relapsed acute promyelocytic leukemia (APL) patients. Several investigators related this phenomenon to the relatively new treatment of all-trans-retinoic-acid (ATRA). In this review article we will examine what has been reported in the medical literature on extramedullary disease in APL: the common sites to be involved, the clinical risk factors to its development, the role of ATRA and arsenic tri-oxide and the recommended treatment.

Daclizumab-induced adverse events in multiple organ systems in multiple sclerosis.

OBJECTIVE: To report 3 patients with multiple sclerosis (MS) who presented with daclizumab-related adverse events (AEs) in multiple organ systems. METHODS: A retrospective chart review was performed of patients with MS who had clinical and histopathologic findings suggestive of daclizumab-induced AEs between 2004 and 2010 at the Johns Hopkins MS Clinic. This study met criteria for exemption from review from the institutional review board. RESULTS: Of 20 total patients with MS who had been treated with daclizumab, 3 patients with clinical and histopathologic findings suggestive of daclizumab-induced AEs were identified. All patients were treated with Zenapax (1 mg/kg monthly IV infusions) outside of a clinical trial setting. Clinical manifestations after a mean treatment duration of 20 months consisted of diffuse rash and alopecia, diffuse lymphadenopathy, and breast nodules. Tissue histopathology demonstrated lymphocytic infiltrates with CD56-expressing cells in 2 patients (lymph node, breast nodule). On daclizumab discontinuation, the rash/alopecia and diffuse lymphadenopathy resolved, while the breast nodules stabilized. CONCLUSIONS: Daclizumab-induced AEs can occur in various organ systems after a relatively prolonged duration of exposure and require clinician awareness. Future studies are needed to better understand the relationship between natural killer cells and daclizumab-related AEs.

Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature.

Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.

Central nervous system complications during treatment of acute lymphoblastic leukemia in a single pediatric institution.

Central nervous system (CNS) complications during treatment of childhood acute lymphoblastic leukemia (ALL) remain a challenging clinical problem. Outcome improvement with more intensive chemotherapy has significantly increased the incidence and severity of adverse events. This study analyzed the incidence of neurological complications during ALL treatment in a single pediatric institution, focusing on clinical, radiological, and electrophysiological findings. Exclusion criteria included CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy, late-onset encephalopathy, or long-term neurocognitive defects. During a 9-year period, we retrospectively collected 27 neurological events (11%) in as many patients, from 253 children enrolled in the ALL front-line protocol. CNS complications included posterior reversible leukoencephalopathy syndrome (n = 10), stroke (n = 5), temporal lobe epilepsy (n = 2), high-dose methotrexate toxicity (n = 2), syndrome of inappropriate antidiuretic hormone secretion (n = 1), and other unclassified events (n = 7). In conclusion, CNS complications are frequent events during ALL therapy, and require rapid detection and prompt treatment to limit permanent damage.

Histopathological changes in the liver and kidney tissues of Wistar albino rat exposed to fenitrothion.

The aim of this study was to investigate the dose-related effects of fenitrothion (FNT) on the liver and kidney. The study was conducted on 8-week-old male Wistar rats that were divided into four groups (three experimental groups and one control group) and were treated orally with different doses (25, 50, 100 mg/kg) of FNT for 28 consecutive days. After treatment, the rats were anesthetized with ether and liver and kidney samples were taken for histological studies. The results showed that the histopathological changes in the liver were mainly represented by parenchymatous degeneration of hepatocytes with mild necrosis, leukocytic infiltration in the portal area, severe congestion, and hemorrhage. These changes were dose dependent. Marked tubular dilation, hydropic degeneration in tubular epithelium, moderate congestion, and hemorrhage in the cortical and medulla part of the kidney were recorded. Histopathologic examination of the liver and kidney indicated a significant injury only in rats receiving 100 mg/kg FNT.

Morphological and functional determinants of fluoxetine (Prozac)-induced pulmonary disease in an experimental model.

Fluoxetine treatment effects were determined by evaluating respiratory mechanics (elastance/resistance) and exhaled nitric oxide, as well as mononuclear and polymorphonuclear cell recruitment into the lungs, in an experimental guinea pig model. Guinea pigs were divided into four groups: Fl (fluoxetine only, n=7); Fl+Sw (fluoxetine and forced swimming, n=7); Ns+Sw (normal saline and forced swimming, n=8); and Ns (normal saline only, n=8). Treated animals received oral fluoxetine (10 mg/(kg day)) for 30 consecutive days. On day 31, all animals were anesthetized and mechanically ventilated so that respiratory system elastance and resistance, as well exhaled nitric oxide, could be determined. The lungs were then excised en bloc for histological and immunohistochemical evaluation. Forced swimming induced bronchodilation in untreated animals and bronchoconstriction in fluoxetine-treated animals. Fluoxetine treatment was also associated with mononuclear infiltration (predominantly into alveolar walls) and neutrophil recruitment. In addition, levels of exhaled nitric oxide, an inflammatory marker, were higher in fluoxetine-treated animals. Swimming-induced stress also amplified mononuclear cell recruitment to the lungs. These results show that, in this experimental model, fluoxetine treatment reproduces the pathology of chronic interstitial pneumonia in humans.

Closure of the pericardium using synthetic bioabsorbable polymers.

BACKGROUND: Pericardial substitutes are known to ensure safer resternotomy at reoperation. A synthetic sheet made from expanded-polytetrafluoroethylene (e-PTFE) has been most commonly used as a pericardial substitute. The e-PTFE sheet, however, can induce severe inflammatory reaction and diffuse fibrosis. This study was designed to investigate the absorption rate and tissue reaction associated with two absorbable pericardial substitutes: a gelatin sheet and L-lactic acid-epsilon-caprolactone copolymer (L-C copolymer). In addition, e-PTFE sheet and autologous pericardium were used as controls. METHODS: Sixty dogs were divided into four groups of 15. In group A, a 3 x 3 cm segment of pericardium was excised, and the autologous pericardium was resutured. In group B, the pericardial defect was replaced with gelatin sheet. In group C, the defect was replaced with L-C copolymer sheet. In group D, the defect was replaced with e-PTFE sheet. For each group, the implanted membranes were retrieved at 2 weeks (n = 1), 4 weeks (n = 3), 12 weeks (n = 5), and 24 weeks (n = 6) after implantation. RESULTS: The e-PTFE sheet produced severe adhesions to the heart and pleura and a more prominent inflammatory reaction, as compared with the gelatin sheet. The absorbable pericardial substitutes were completely absorbed by 24 weeks after implantation, and were replaced with fibrous membrane. CONCLUSIONS: Gelatin sheet may involve less adhesion and a reduced inflammatory reaction compared with e-PTFE.

Unusual cutaneous involvement during plasma cell leukaemia phase in a multiple myeloma patient after treatment with thalidomide: a case report and review of the literature.

We report the case of a 54-year-old African-American male with IgG multiple myeloma (MM) with disease resistant to multiple chemotherapy regimens and immunomodulatory treatment with thalidomide. In spite of achieving a partial remission of short duration, his disease accelerated to peripheral plasmacytosis and subsequent development of cutaneous plasmacytomas. The malignant plasma cells derived from the dermal lesions were CD45+, CD38+, CD138+ and matched the immunophenotype of the plasmacytes during the leukaemic phase. Occurrence of extramedullary lesions in the setting of MM treated with thalidomide is of concern, although currently there are very few reports describing this association. We discuss the possible relationship between the patient's unusual disease course and the administered chemo- and immunotherapy. The significance of the changes in adhesion molecules, especially CD138 and CD56, relevant to the development of cutaneous plasmacytomas is discussed.

Retinoic acid syndrome: manifestations, pathogenesis, and treatment.

All-trans retinoic acid (ATRA) is a potent differentiation agent that is effective therapy in acute promyelocytic leukaemia. Although ATRA is generally well tolerated, some patients develop retinoic acid syndrome. This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure. However, if identified early enough, effective therapy can be administered. This chapter discusses the clinical aspects and pathogenesis of retinoic acid syndrome.

The effects of the levonorgestrel intrauterine system (Mirena coil) on endometrial morphology.

AIMS: The Mirena coil is a levonorgestrel releasing intrauterine device that is in widespread use. This study aims to document the endometrial morphology associated with this device. METHODS: Endometrial specimens from 75 women with the Mirena coil were reviewed and the histological features detailed. RESULTS: Morphological features found in most of the endometria were decidualisation of stroma (72 of 75 cases), atrophy of endometrial glands (65 of 75 cases), a surface papillary pattern (38 of 75 cases), and a stromal inflammatory cell infiltrate (59 of 75 cases). Additional common histological features were the presence of foci of stromal myxoid change (29 of 75 cases) and stromal haemosiderin pigment (24 of 75 cases). Reactive atypia of surface glands, glandular metaplastic changes, stromal necrosis, and stromal calcifications were found in small numbers of cases. CONCLUSION: The endometrial features are characteristic and relatively constant and are in keeping with the effects of both a progestogenic compound and a mechanical device. Pathologists should be aware of these histological features because the Mirena coil is in widespread use.

Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential role in mediating adult T-cell leukemia invasiveness.

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and of tropical spastic paraparesis/HTLV-I-associated myelopathy. Infiltration of various tissues by circulating leukemic cells is a characteristic of ATL. Matrix metalloproteinases (MMPs), which mediate the degradation of the basement membrane and extracellular matrix, play an important role in metastasis and tumor cell dissemination. The aim of this study was to explore whether expression of MMP-2 and MMP-9 was deregulated by HTLV-I infection. The data showed that HTLV-I-infected T-cell lines expressed high levels of MMP-9 compared with uninfected T-cell lines. In contrast, the levels of the related MMP-2 were not significantly altered by HTLV-I infection. In addition, the elevated expression of MMP-9 in HTLV-I-infected cells was attributable to the action of the viral transactivator protein Tax. The results show that Tax can activate the MMP-9 promoter and induce MMP-9 expression in T cells, indicating that the constitutive expression of MMP-9 in virus-infected cell lines is at least in part mediated by Tax. Activation of the MMP-9 promoter by Tax occurs mainly through the action of NF-kappaB and SP-1. The biologic significance of these observations was validated by the following 2 findings: MMP-9 expression was increased in primary ATL cells, and plasma MMP-9 levels were elevated in ATL patients. In addition, plasma levels of MMP-9 correlated with organ involvement in ATL patients. Together these data suggest that overexpression of MMP-9 in HTLV-I- infected cells may be in part responsible for the invasiveness of ATL cells.

Marked granulocytic proliferation induced by granulocyte colony-stimulating factor in the spleen simulating a myeloid leukemic infiltrate.

The authors describe a patient with a long-standing history of systemic lupus erythematosus and leukopenia who received multiple intermittent doses of recombinant granulocyte colony-stimulating factor (G-CSF) and who underwent splenectomy because of a clinical impression of sequestration of granulocytes by the spleen. Histologic evaluation of the spleen revealed marked granulocytic hyperplasia with an increase in immature myeloid precursors, morphologically indistinguishable from a myeloid leukemic infiltrate. A postsplenectomy bone marrow aspirate and biopsy revealed a normocellular bone marrow with active hematopoiesis and trilineage maturation. The bone marrow aspirate cultured cells showed no numeric or structural chromosomal abnormality. Extramedullary hematopoiesis after receipt of G-CSF was previously reported, but, to our knowledge, ours is the first report of morphologic changes virtually identical to a leukemic infiltrate in spleen after G-CSF treatment. We describe the histologic and immunohistochemical findings in the spleen, compare our observations with those of others reported in the literature, and postulate a possible mechanism for this phenomenon.