Detecting Bacterial-Human Lateral Gene Transfer in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a very common and mostly incurable B-cell malignancy. Recent studies revealed high interpatient mutational heterogeneity and worsened therapy response and survival of patients with complex genomic aberrations. In line with this, a better understanding of the underlying mechanisms of specific genetic aberrations would reveal new prognostic factors and possible therapeutic targets. It is known that chromosomal rearrangements including DNA insertions often play a role during carcinogenesis. Recently it was reported that bacteria (microbiome)-human lateral gene transfer occurs in somatic cells and is enriched in cancer samples. To further investigate this mechanism in CLL, we analyzed paired-end RNA sequencing data of 45 CLL patients and 9 healthy donors, in which we particularly searched for bacterial DNA integrations into the human somatic genome. Applying the Burrows-Wheeler aligner (BWA) first on a human genome and then on bacterial genome references, we differentiated between sequencing reads mapping to the human genome, to the microbiome or to bacterial integrations into the human genome. Our results indicate that CLL samples featured bacterial DNA integrations more frequently (approx. two-fold) compared to normal samples, which corroborates the latest findings in other cancer entities. Moreover, we determined common integration sites and recurrent integrated bacterial transcripts. Finally, we investigated the contribution of bacterial integrations to oncogenesis and disease progression.

Antimicrobial use before chronic lymphocytic leukemia: a retrospective cohort study.

Chronic lymphocytic leukemia (CLL) is accompanied by increased risk of potentially fatal infections. While this can mostly be attributed to disease-related immune dysfunction, it is not known if CLL patients are also constitutionally susceptible to infections. We linked nation-wide Danish registers to explore this possibility, approximating infection susceptibility by use of antimicrobials. We assessed the incidence of antimicrobials among CLL patients and matched controls from the general population for up to 22 years before index diagnosis, and among children and grandchildren of CLL patients and their matched controls. Our analyses showed that for CLL patients overall antimicrobial use began to increase gradually six years before leukemia diagnosis. Before this time point, CLL patients had used significantly more macrolides (relative risk = 1.15; 95% confidence interval 1.10-1.20), antimycotics (1.18; 1.08-1.30), and antivirals (1.62; 1.45-1.81) than controls for up to 22 years before diagnosis. The same pattern of increased use was found among CLL patients' children and grandchildren. Our study suggests that CLL diagnosis is preceded by decades of increased susceptibility to infections. The duration of this time window is compatible with causal roles of immune dysfunction and/or certain infections in CLL pathogenesis, possibly mediating the association between constitutional infection susceptibility and CLL risk.

Characterization of the fecal microbiome in cats with inflammatory bowel disease or alimentary small cell lymphoma.

Feline chronic enteropathy (CE) is a common gastrointestinal disorder in cats and mainly comprises inflammatory bowel disease (IBD) and small cell lymphoma (SCL). Both IBD and SCL in cats share features with chronic enteropathies such as IBD and monomorphic epitheliotropic intestinal T-cell lymphoma in humans. The aim of this study was to characterize the fecal microbiome of 38 healthy cats and 27 cats with CE (13 cats with IBD and 14 cats with SCL). Alpha diversity indices were significantly decreased in cats with CE (OTU p = 0.003, Shannon Index p = 0.008, Phylogenetic Diversity p = 0.019). ANOSIM showed a significant difference in bacterial communities, albeit with a small effect size (P = 0.023, R = 0.073). Univariate analysis and LEfSE showed a lower abundance of facultative anaerobic taxa of the phyla Firmicutes (families Ruminococcaceae and Turicibacteraceae), Actinobacteria (genus Bifidobacterium) and Bacteroidetes (i.a. Bacteroides plebeius) in cats with CE. The facultative anaerobic taxa Enterobacteriaceae and Streptococcaceae were increased in cats with CE. No significant difference between the microbiome of cats with IBD and those with SCL was found. Cats with CE showed patterns of dysbiosis similar to those in found people with IBD.

Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases. OBJECTIVES: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment. METHODS: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software. RESULT: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD. CONCLUSIONS: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.

Epidemiology of bloodstream infections in patients with chronic lymphocytic leukemia: a longitudinal nation-wide cohort study.

Patients with chronic lymphocytic leukemia (CLL) have a high risk of bloodstream infections (BSI). BSI cause significant morbidity and mortality among CLL patients; approximately one-third of fatalities in CLL list infections as cause of death. All CLL patients in Denmark diagnosed between 2008 and 2016 were followed through registries for the event of a BSI. Patient characteristics and bacterial findings were analyzed separately for treatment-naive and treated patients. A total of 3677 and 1020 patients with CLL were followed as treatment-naive and treated patients, respectively. We identified 145 cases of Gram-positive bacteremia. Streptococcus pneumoniae accounted for 32 (22%) cases, while Staphylococcus aureus was found 30 times (21%). Gram-negative microorganisms were found in 166 (46%) cases. Escherichia coli accounted for 77 (46%) cases. Lastly, we identified six episodes of candidemia of which five (83%) were fatal within 30 days of the infection. Based on increased frequency of S. pneumoniae and Pseudomonas aeruginosa and the high mortality of candidemia in CLL, empirical antibiotics with double coverage for S. pneumoniae and P. aeruginosa is recommended; upon suspected or proven candidemia, treatment with broad-spectrum fungicidal agents are recommended.

Relationship of the mucosal microbiota to gastrointestinal inflammation and small cell intestinal lymphoma in cats.

BACKGROUND: The gastrointestinal (GI) microbiota in healthy cats is altered in IBD. Little research has been performed to identify whether specific bacterial groups are associated with small cell GI lymphoma (LSA). HYPOTHESIS: Mucosal bacteria, including Enterobacteriaceae and Fusobacterium spp., are abundant in intestinal biopsies of cats with small cell GI LSA compared to cats with IBD. ANIMALS: Fourteen cats with IBD and 14 cats with small cell GI LSA. METHODS: Retrospective case control study. A search of the medical records was performed to identify cats diagnosed with IBD and with GI LSA. Bacterial groups identified by FISH in GI biopsies were compared between cohorts and correlated to CD11b+ and NF-κB expression. RESULTS: Fusobacterium spp. (median; IQR bacteria/region) were higher in cats with small cell GI LSA in ileal (527; 455.5 - 661.5; P = .046) and colonic (404.5; 328.8 - 455.5; P = .016) adherent mucus, and combined colonic compartments (free mucus, adherent mucus, attaching to epithelium) (8; 0 - 336; P = .017) compared to cats with IBD (ileum: 67; 31.5 - 259; colon: 142.5; 82.3 - 434.5; combined: 3; 0 - 34). Bacteroides spp. were higher in ileal adherent mucus (P = .036) and 3 combined ileal compartments (P = .034) of cats with small cell GI LSA. There were significant correlations between Fusobacterium spp. totals and CD11b+ cell (P = .009; rs .476) and NF-κB expression (P = .004; rs .523). CONCLUSIONS: The bacterial alterations appreciated might be influential in development of small cell GI LSA, and should drive further studies to elucidate the effects of microbial-mediated inflammation on GI cancer progression.

Development of a quantitative PCR detecting Cunninghamella bertholletiae to help in diagnosing this rare and aggressive mucormycosis.

Mucormycosis is an invasive mold infection, frequently fatal in immunocompromised patients. We report the case of a patient with chronic lymphocytic leukemia admitted to the hematology unit for febrile aplasia. Pulmonary lesions suggesting a fungal infection expanded/increased despite a combination of posaconazole and liposomal amphotericin B. The fungal biomarkers performed repeatedly were negative. At D65 after chemotherapy a bronchial biopsy was positive for Cunninghamella bertholletiae. The patient died despite appropriate antifungal management. A qPCR targeting Cunninghamella was developed a posteriori, and a retrospective analysis showed that a sample was positive more than 30 days before culture-based identification could be made.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. Methods: We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses. Results: We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%). Conclusions: Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs.

Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib.

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

[A Listeria breast abscess in a man]. / Un abcès du sein à Listeria chez un homme.

INTRODUCTION: Listeriosis is a food-borne illness leading to bacteriemia or central nervous system infection especially in pregnant women or high-risk patients. It is rarely a localized infection. Breast contamination has rarely been reported in lactating women. We report a breast abscess in man. CASE REPORT: A 80 year old man, hypertensive and arrhythmic, was explored for weakness and dehydration. Type 2 diabetes and chronic lymphocytic leukemia were diagnosed. Clinical examination disclosed a breast abcess related to L monocytogenes infection. Histopathological study also revealed a breast subcutaneous infiltration by chronic lymphocytic leukemia. CONCLUSION: Listeriosis sometimes uncover an unknown immunosuppression, especially in the elderly. Breast is a non-sterile tissue containing a stable microbiome partly from digestive origin. It can thereby be contaminated by Listeria. The specific cutaneous infiltrate of chronic lymphocytic leukemia can create the conditions for a local infection.

Pathways towards indolent B-cell lymphoma - Etiology and therapeutic strategies.

Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas.

Epidemiological and mycological characteristics of candidemia in patients with hematological malignancies attending a tertiary-care center in India.

BACKGROUND AND OBJECTIVES: We undertook the present study to ascertain the contributing risk factors and explore the epidemiological and mycological characteristics of opportunistic candidemia among patients with hematological malignancies. DESIGN AND SETTINGS: Observational cross-sectional study in a tertiary care center. PATIENTS AND METHODS: Consecutive patients with hematological malignancies reporting to the collaborating medical and pediatric units with a febrile episode were recruited and screened for candidemia by blood culture. Recovered Candida isolates were speciated and antifungal susceptibility testing was performed as per Clinical and Laboratory Standards Institute guideline (CLSI) guidelines M44-A. Further analysis was done for potential risk factors and compared between culture positive and negative patients. RESULTS: Of 150 patients recruited, the majority (n=27) were between 51 and 60 years and the male to female ratio was 1.63:1. Fifteen patients (10%) were culture positive. The culture positivity was significantly higher in acute lymphocytic leukemia (ALL) than in non-ALL patients (p=0.03). There was significant association of candidaemia with leucopenia, chemotherapeutic drugs, corticosteroids and presence of indwelling devices. Duration of disease (p=0.032) and duration of hospitalization (p=0.003) were significantly prolonged in culture positive patients. C. tropicalis was the commonest isolate (46.67%), with non- Candida albicans outnumbering C. albicans in all categories of hematological malignancies (2.75:1). All isolates of C. albicans were uniformly sensitive to all the azoles, but only 50% were sensitive to amphotericin B and none to nystatin and flucytosine. CONCLUSIONS: This observational study identifies ALL and chronic lymphocytic leukemia (CLL) as the forms of hematological malignancy predominantly associated with candidemia; specifies risk factors and chemotherapeutic agents predisposing patients towards its occurrence; reports a preponderance of C. tropicalis among the causative agents and finds voriconazole to be the most effective antifungal agent against the recovered isolates. This information could assist in tailoring prophylactic and therapeutic antifungal practices for this infection, according to local epidemiological and mycological characteristics.

The role of oxidative stress and the effects of antioxidants on the incidence of infectious complications of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency predisposing the patients to infections. Oxidative stress leads to an increased immunoglobulin k light chain production in B cells and contributes to the antibodies' deficiency and hypogammaglobulinemia. Aim of the Study. To evaluate the global oxidative status in patients with CLL and to determine whether the administration of antioxidants decreases complications due to infections. Patients and Method. We studied 84 patients with CLL stratified by Binet staging. Free oxygen radicals and antioxidant status were determined by the FORT and FORD test, respectively, at diagnosis and in the presence of infections. The patients were distributed in two groups: group A, treated only with antileukemic treatment, and group B, treated with antileukemic treatment and antioxidants. Results. By FORD and FORT assay, all patients had at diagnosis a low antioxidant capacity, and high levels of hydroperoxides. Infectious complications were more frequent in group A (B/C stages of disease) than in group B. Administrations of antioxidants stimulated the immune response and decreased infectious complications in CLL. Conclusions. Administrations of antioxidants and a healthy life style may improve the quality of life of patients with CLL and reduce the risk of infectious complications.

Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia.

We report the case of a 42-y-old man treated with alemtuzumab for chronic lymphocytic leukaemia, who developed 3 successive deep fungal infections. Despite being treated with liposomal amphotericin B and 5-flucytosine for disseminated cryptococcosis, he developed pulmonary invasive aspergillosis, followed by pulmonary mucormycosis. Several deep fungal infections may occur in association in an immunocompromised host after treatment with alemtuzumab.