Second Malignancies and Richter's Syndrome in Patients with Chronic Lymphocytic Leukemia

Second malignancies are frequent complications in patients with chronic lymphocytic leukemia (CLL). Patients with this leukemia may develop large cell lymphoma (LCL) known as Richter's syndrome (RS). RS occurs in CLL patients of about 3% and may develop in a single lymph node or more often in a group of nodes. However, in some patients extranodal localization of aggressive lymphoma in RS has been observed. Besides LCL, Hodgkin's disease, prolymphocytoid leukemia, multiple myeloma and acute lymphoblastic leukemia may also occur as RS variants. The origin of lymphoid cells in RS remains tentative. However, CLL and RS originate from the same clone for some patients, whereas, in other patients cells of aggressive lymphoma do not have the features of the same clone as the CLL cells. The prognosis of RS is poor. Survival in different studies will be usually 2-5 months. The secondary development or coexistence of myeloproliferative disorders or myelodysplastic syndrome and solid tumors have also been rarely documented in CLL patients. It is of great concern that therapy may further increase the risk of a second neoplasm. However, until now, there are no clear evidence that alkylating agents or purine nucleoside analogs may be associated with an increased incidence of second malignancies in patients with CLL. In this review, epidemiology, biology, clinical characteristic and treatment approaches in RS and other secondary neoplasms in patients with CLL are discussed.     

Simultaneous Presence of Two Hematological Malignancies: Chronic Lymphocytic Leukemia and Myelofibrosis in a Patient

Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.     

Trisomy 12 and t(14;22)(q32;q11) in a Patient with B-cell Chronic Lymphocytic Leukemia

Recurrent cytogenetic abnormalities are typically found in about one third of B-cell chronic lymphocytic leukemia patients (B-CLL) by standard cytogenetic analysis and their prognostic relevance is well known. We report a case of a B-CLL patient showing both trisomy 12 and a t(14;22)(q32;q11). Trisomy 12 is often associated with aggressive disease and resistance to chemotherapy, however, our patient is in good health and currently untreated after 7 years, suggesting in this case a relatively good prognosis and a questionable role for translocations involving the 14q32 locus.     

Mixed-Type Autoimmune Hemolytic Anemia following Fludarabine Treatment in a Patient with Chronic Lymphocytic Leukemia/Small Cell Lymphoma

Background and objectives : Mixed-type autoimmune hemolytic anemia (AIHA) is a rare complication of chronic lympocytic leukemia (CLL). We report a patient with small lymphocytic lymphoma (phenotypic CLL) who developed symptomatic anemia 3 weeks after her fifth cycle of fludarabine, a T cell immunosuppressant. Materials and methods : An antibody screen and panel, direct antiglobulin test, rapid acid eluate, rabbit erythrocyte stroma (RESt) adsorption, and autoadsorption were performed. Results : Warm and cold autoantibodies were detected. Prompt treatment with corticosteroids and minimal blood transfusions led to marked improvement. Conslusion : Normally, T cells suppress polyclonal lymphocytes that produce autoantibodies. Suppression of T cells in this patient, in addition to the underlying disease process, may explain this mixed-type AIHA, the first reported case to occur following fludarabine treatment.     

Vanishing Bile Duct Syndrome in a Hodgkin's Lymphoma Patient with Fatal Outcome Despite Lymphoma Remission

Vanishing bile duct syndrome (VBDS) is a condition resulting from severe bile duct injury, progressive destruction, and disappearance of intrahepatic bile ducts (ductopenia) leading to cholestasis, biliary cirrhosis, and liver failure. VBDS can be associated with a variety of disorders, including Hodgkin''s lymphoma (HL). We describe a 33-year-old male patient who presented with lymphadenopathy and jaundice, and was diagnosed to have HL. Serum bilirubin worsened progressively despite chemotherapy, with a cholestatic pattern of liver enzymes. Diagnosis of VBDS was established on liver biopsy. Although remission from HL was achieved, the patient died of liver failure. Presence of jaundice in HL patients should raise the possibility of VBDS. This report discusses the difficulties of delivering chemotherapy in patients with liver dysfunction. HL-associated VBDS carries a high mortality but lymphoma remission can be achieved in some patients. Therefore, liver transplantation should be considered early in these patients.     

Exaggerated Cutaneous Response to Mosquito Bites in a Patient with Chronic Lymphocytic Leukemia

Although various cutaneous manifestations can occur in patients with chronic lymphocytic leukemia (CLL), bullous lesions due to mosquito bites are rare. We describe a patient with a typical case of CLL complicated by exaggerated cutaneous response to mosquito bites. The symptoms of this patient were self-limited and not severe, but it has been reported that the treatment of such symptoms is sometimes difficult. Because exaggerated cutaneous hypersensitivity to mosquito bites can be observed even before the diagnosis of hematological malignancies such as CLL, careful examinations are recommended to find underlying diseases in cases in which this type of cutaneous reaction occurs.     

Acquired von Willebrand's Syndrome and Thrombopathy in a Patient with Chronic Lymphocytic Leukaemia

This paper reports the biological data found during an acquired bleeding disorder occurring in a 65-year-old woman affected with chronic lymphocytic leukaemia. They consists of haemostatic abnormalities which resemble an presently undescribed association of an acquired von Willebrand's syndrome with a thrombopathy. von Willebrand abnormalities were temporarily corrected by infusion of normal cryoprecipitate and reproduced in vitro by the incubation of normal platelets with the patient's IgA. The platelet defect was partially corrected after corticotherapy. The possible relationship of the associated defects is discussed.     

Gastric Cancer Developing in a Patient with Chronic Lymphocytic Leukemia with Massive Gastrointestinal Involvement

Massive infiltration of neoplastic lymphocytes caused a variety of gross gastrointestinal manifestations in a 71-year-old patient with chronic lymphocytic leukemia (CLL). These included plaque-like elevations in the esophagus, convoluted gyrus-like folds in the stomach, and many polypoid lesions in the stomach and duodenum. No gross lesions were noted in the large intestine. Four years later, systemic chemotherapy reduced the gastrointestinal involvement, but a papillary elevation grew at the gastric angle, which was shown to be an early cancer on histological examination. Gastrointestinal involvement in CLL and second cancers associated with CLL are reviewed, with special reference to the possible relationship between CLL and gastric cancer.     

Severe Liver Injury Associated with Glecaprevir Plus Pibrentasvir Therapy in a Patient with Treatment-naïve Hepatitis C Virus Infection

A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient’s history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.     

Naïve Human Macrophages Are Refractory to SARS-CoV-2 Infection and Exhibit a Modest Inflammatory Response Early in Infection

Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN-α and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the E viral gene for SARS-CoV-2 or M gene for influenza and TCID₅₀ or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 exposed MDM with notable absence of IFN-β induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN-α enhanced proinflammatory cytokine expression upon exposure to virus. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.     

Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn's disease

BACKGROUND AND AIMS: New lesions of Crohn's disease occur early after ileal or ileocolonic resection and ileocolonic anastomosis. We performed a double blind controlled trial to evaluate the safety and tolerance of recombinant human interleukin 10 (IL-10; Tenovil) in subjects operated on for Crohn's disease. We also assessed the effect of Tenovil in preventing endoscopic recurrence 12 weeks after surgery. METHODS: Patients with Crohn's disease who underwent curative ileal or ileocolonic resection and primary anastomosis were randomised within two weeks after surgery to receive subcutaneous Tenovil 4 microg/kg once daily (QD) (n=22) or 8 microg/kg twice weekly (TIW) (n=21), or placebo (QD or TIW) (n=22). An ileocolonoscopy was performed after 12 weeks of treatment. RESULTS: Compliance was excellent. The most frequently observed adverse events were mild and moderate in severity and equally distributed across treatment groups. Thirty seven patients in the pooled Tenovil group and 21 patients in the pooled placebo group were evaluable by endoscopy. At 12 weeks, 11 of 21 patients (52%) in the placebo group had recurrent lesions compared with 17 of 37 patients (46%) in the Tenovil group (ns). The incidence of severe endoscopic recurrence was similar in both groups (9%). CONCLUSION: Tenovil treatment for 12 consecutive weeks in patients with Crohn's disease after intestinal resection was safe and well tolerated. No evidence of prevention of endoscopic recurrence of Crohn's disease by Tenovil was observed.     

Gastro-colic Fistula-associated Hypersplenism Causes Pancytopenia in a Patient with Crohn's Disease

A 24-year-old woman was admitted to our hospital due to abdominal pain and a high fever. She was diagnosed with ileocolonic Crohn''s disease (CD), complicated with a gastro-colic fistula and splenomegaly. After initial treatment with an infliximab-biosimilar, all blood cell line counts markedly decreased. Three-dimensional reconstructed computed tomography revealed splenic vein narrowing. Thus, her pancytopenia was deemed to have likely been caused by hypersplenism. Surgery was performed, and clinical remission was maintained without pancytopenia. This is the first report of a CD patient with pancytopenia caused by hypersplenism that was triggered by gastro-colic fistula-associated splenic vein obstruction.     

Salivary and serum hyaluronic acid concentrations in patients with Sjögren's syndrome

OBJECTIVE—To evaluate salivary hyaluronic acid (HA) concentration in patients with primary Sjögren's syndrome (SS).
METHODS—Salivary and serum HA concentrations were evaluated using a radiometric assay. Thirty nine patients with SS served as the study group and their results were compared with 19 patients having clinical symptoms and signs of dry mouth and with 10 normal controls.
RESULTS—Salivary HA concentrations were significantly increased (p < 0.05) in the 39 patients with SS compared with the 19 patients with dry mouth and the 10 normal controls (240.7 (38.5) v 99.8 (14.6) and 91.3 (7.9) ng/ml, respectively) (mean (SEM)). No significant differences were noted in the serum HA concentrations between the three groups (42 (3.9) v 36.3 (4.1) and 32 (4.3) ng/ml, respectively) (mean (SEM)). No correlation could be found between salivary HA concentrations and the focus score of lip biopsies, nor between salivary HA concentrations and erythrocyte sedimentation rate or other serological tests.
CONCLUSION—Increased salivary HA concentrations can serve as a marker of local inflammation and may be of value in the diagnosis of SS.

Keywords: saliva; hyaluronic acid; Sjögren's syndrome     

Effect of aprepitant on kynurenine to tryptophan ratio in cART treated and cART naïve adults living with HIV

Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials “Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant”-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.     

Sjögren's Syndrome with Pleural Effusion: Difficult to Distinguish from Tuberculous Pleurisy Because of a High Adenosine Deaminase Level

An 84-year-old woman visited our hospital for dyspnea due to right pleural effusion, with lymphocytic dominance and a high adenosine deaminase (ADA) level, that had been noted 1 month earlier. She was suspected of having tuberculosis pleurisy; however, anti-tuberculosis treatment yielded no improvements. She was diagnosed with pleural effusion due to primary Sjögren''s syndrome (SjS) based on her dry eyes and mouth, positivity for anti-Sjögren''s-syndrome-related antigen A/B, and histopathologic findings of a lip biopsy and thoracoscopic pleural biopsy. Her symptoms improved after starting steroid therapy. Cases of pleural effusion due to SjS with a high ADA level may be misdiagnosed as tuberculosis pleurisy.     

Blastic Transformation after Splenectomy in a Patient with Nonvillous Splenic Marginal Zone Lymphoma with p53 Overexpression: A Case Report

A 61-year-old man with no subjective symptom was admitted to our hospital for further examination of the causes of anemia (hemoglobin, 9.5 g/dL) and thrombocytopenia (platelets, 9.2 x 10(4)/microL), which had been pointed out in a medical checkup half a year previously. A bone marrow examination showed 73% lymphoid cells. Immunophenotyping of these cells were CD19+CD20+CD3-CD5-CD10-CD23-, and light chain restriction (kappa) was positive by fluorescence-activated cell sorting analysis. A computed tomography scan showed mild splenomegaly. To confirm the diagnosis histologically, we performed a splenectomy. Finally, we diagnosed the patient's disease as nonvillous splenic marginal zone lymphoma (SMZL). A month after the splenectomy, the white blood cell count was remarkably increased to 7 x 10(4)/microL with the blastic transformation of lymphoid cells. We first treated the patient with fludarabine and then with the CHOP regimen (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone), but the disease was so refractory that the patient died of the disease 13 months after the splenectomy. Immunohistochemical staining and a molecular examination for p53 were carried out with specimens from the splenectomy. We found overexpression of the p53 protein in lymphoid cells and a point missense mutation in codon 280 at exon 8 that changed AGA (Arg) to AGT (Ser). This case may indicate the existence of a more aggressive subset of SMZL, suggesting a reconsideration of the roles of splenectomy and p53 overexpression in the diagnostic and therapeutic approaches to patients with SMZL.     

Trisomy 8-positive Polycythemia Vera Complicated with Intestinal Behçet's-like Disease: A New Perspective for a Clinical Approach

Behçet''s disease (BD) is a multisystem inflammatory disease of unknown origin. It rarely but occasionally occurs together with myelodysplastic syndrome and primary myelofibrosis. Trisomy 8 is one of the most common cytogenetic abnormalities in myeloid neoplasms; however, the association of BD with polycythemia vera (PV) and trisomy 8 has not been reported. A 70-year-old woman, diagnosed with PV and treated with hydroxyurea, had bloody stool due to multiple ulcers in the ileocecal region. Considering the lack of a response to treatment and other features, we suspected complication with intestinal Behçet''s-like disease. Our case suggests relationships among BD, trisomy 8, and PV.     

Low-dose Cytosine Arabinoside Therapy in a Patient with Myelofibrosis during Transformation to Acute Non-lymphocytic Leukemia

ABSTRACT. A patient with myelofibrosis transforming into acute non-lymphocytic leukaemia (ANLL) was treated with low doses of cytosine arabinoside (ARA-C). Complete remission was obtained twice without serious toxicity. It is suggested that low-dose ARA-C may be an effective and rather non-toxic therapy in patients with myeloproliferative disorders transforming to ANLL.