Luca Fumagalli

Isolated bone marrow manifestation of HIV-associated Hodgkin lymphoma

Human immunodeficiency virus-associated Hodgkin lymphoma frequently involves the bone marrow and is usually recognized at staging after Hodgkin lymphoma diagnosis on a lymph node or other tissue biopsies, but occasionally the marrow involvement is the only apparent manifestation of disease. In the latter setting, diagnosis can be problematic. From a total of 42 patients with newly diagnosed human immunodeficiency virus–associated Hodgkin lymphoma, 22 subjects had positive marrow involvement at diagnosis; 16 of them had additional substantial histological and/or clinical extramedullary Hodgkin lymphoma. In the remaining 6 patients the bone marrow was the only site of disease at diagnosis. In all six cases, bone marrow biopsy revealed obvious lymphomatous involvement. Reed-Sternberg cells were identified both morphologically and immunophenotypically in all cases. Spared marrow tissue consistently showed fibrosis. All patients were males with a median age of 35 years (range, 31–58 years). All presented with fever, blood cytopenias, and severe CD4+ lymphocyte depletion (median, 70 cells/mm3). After diagnosis, all staging procedures were negative, and all patients were treated with chemotherapy. Median survival was 4 months (range, 2–118 mo). Longer survival was achieved in the patients who completed chemotherapy regimens; three subjects, however, died shortly before the full completion of chemotherapy, two of them from Hodgkin lymphoma. Isolated bone marrow HIV-associated Hodgkin lymphoma may be an underestimated condition in HIV-infected patients; in those individuals with unexplained fever and blood cytopenias, bone marrow biopsy should be performed with the aim of assessing for Hodgkin lymphoma, even in the absence of nodal and visceral lymphomatous involvement. A rapid diagnosis of isolated bone marrow HIV-associated Hodgkin lymphoma could expedite therapy.

The pharmacokinetics of liposomal encapsulated daunorubicin are not modified by HAART in patients with HIV-associated Kaposi's sarcoma.

Purpose: To investigate the pharmacokinetics of liposomal daunorubicin (DaunoXome) administered alone or in combination with antiviral therapy including protease inhibitors (PI) to HIV-positive patients affected by Kaposis sarcoma (KS). Patients and methods: A group of 18 patients with extensive or rapidly progressing AIDS-related KS received DaunoXome at a dose of 40 mg/m2 alone or in association with a triple combination therapy consisting of one PI plus two nucleoside reverse transcriptase inhibitors (NRTI). Daunorubicin pharmacokinetics were determined in a total of 23 cycles, 6 with DaunoXome alone, 9 in combination with indinavir, 6 with ritonavir and 2 with saquinavir. Plasma samples were obtained at different times during the 72 h after DaunoXome administration. Daunorubicin and daunorubicinol plasma levels were determined by high-performance liquid chromatography. Results: After the DaunoXome infusion, daunorubicin was rapidly cleared from the body following, in most cases, a one-compartment open kinetic model. The daunorubicin peak concentrations, clearances and elimination half-lives were (means ± SD): 16.3 ± 2.8 μg/ml, 0.3 ± 0.1 l/h per m2 and 5.6 ± 2.6 h after DaunoXome alone; 15.1 ± 4.9 μg/ml, 0.5 ± 0.3 l/h per m2 and 5.8 ± 2.1 h after the combination with indinavir; and 14.5 ± 2.8 μg/ml, 0.4 ± 0.2 l/h per m2 and 6.5 ± 3.9 h after the combination with ritonavir. In all groups, daunorubicinol plasma levels were approximately 25–30 times lower than those of the parent drug. Conclusion: Our data show that there are no significant differences in the pharmacokinetic parameters of daunorubicin in patients receiving DaunoXome in combination with indinavir and ritonavir compared with those in patients not receiving PIs. Therefore in patients affected by AIDS-related KS treated with Highly Active AntiRetroviral Therapy (HAART) there is no pharmacokinetic justification for reducing the doses of DaunoXome.

Diagnosis of infection in patients undergoing extracorporeal membrane oxygenation: A case-control study

OBJECTIVE Diagnosis of infection in patients receiving extracorporeal membrane oxygenation is challenging in clinical practice but represents a crucial aspect of the upgrading of therapeutic options. The aim of this study was to analyze the role of C-reactive protein and procalcitonin in the diagnosis of infection in patients requiring extracorporeal membrane oxygenation and to assess the difference between venovenous and venoarterial extracorporeal membrane oxygenation settings. METHODS A case-control study was performed on 27 patients. Serum values of procalcitonin and C-reactive protein were analyzed according to the presence of infection. RESULTS Forty-eight percent of patients had infection. Gram-negative bacteria were the predominant pathogens, and Candida albicans was the most frequent isolated microorganism. Procalcitonin had an area under the curve of 0.681 (P = .0062) for the diagnosis of infection in the venoarterial extracorporeal membrane oxygenation group but failed to discriminate infection in the venovenous extracorporeal membrane oxygenation group (P = .14). The area under the curve of C-reactive protein was 0.707 (P < .001) in all patients receiving extracorporeal membrane oxygenation. In patients receiving venoarterial extracorporeal membrane oxygenation, procalcitonin had good accuracy with 1.89 ng/mL as the cutoff (sensitivity = 87.8%, specificity = 50%) and C-reactive protein with 97.70 mg/L as the cutoff (sensitivity = 85.3%, specificity = 41.6%). The procalcitonin and C-reactive protein combined assay had a sensitivity of 87.2% and specificity of 25.9%. Four variables were identified as statistically significant predictors of infection: procalcitonin and C-reactive protein combined assay (odds ratio, 1.184; P < .001), age (odds ratio, 0.980; P < .001), presence of infection before extracorporeal membrane oxygenation implantation (odds ratio, 1.782; P < .001), and duration of extracorporeal membrane oxygenation support (odds ratio, 1.056; P < .001). CONCLUSIONS Traditional and emerging inflammatory biomarkers, especially if compounded in the procalcitonin and C-reactive protein combined assay, can aid in the diagnosis of infection in patients undergoing venoarterial extracorporeal membrane oxygenation.

Ten-year survival among HIV-1-infected subjects with AIDS or non-AIDS-defining malignancies.

Few data are available regarding the 10‐year survival among subjects with HIV and cancer. The aim of this study was to evaluate the 10‐year survival of HIV‐infected subjects with AIDS‐defining malignancies (ADM) or non‐AIDS‐defining malignancies (NADM). This was a single center, retrospective, observational study of subjects with HIV infection and a subsequent cancer diagnosis; the data were collected from January 1991 to April 2010. Malignancies were divided into ADM or NADM on the basis of the Centre of Diseases Control‐1993 classification. Survival curves were estimated using Kaplan–Meyer method and compared by the log‐rank test. Six hundred and fifteen (9.5%) of the 6,495 subjects recorded in the San Raffaele Infectious Diseases Database developed a malignancy: 431 (70%) an ADM and 184 (30%) a NADM. In the case of ADM, survival was more favorable when cancer was diagnosed during post‐highly active antiretroviral therapy (HAART) era (10‐year survival: 43.2% ± 4.4%) than when diagnosed during the pre‐HAART era (10‐year survival: 16.4% ± 2.7%; log‐rank test: p < 0.001). The same was true in the case of NADM (10‐year survival: 44.7% ± 5.5% vs. 33.3 ± 9.6%; log‐rank test: p = 0.03). An evaluation of survival probability by cancer type showed higher survival rates during the post‐HAART era in the case of non‐Hodgkin lymphoma (10‐year survival: 42.1% ± 5.3% vs. 11.4% ± 3.3%; log‐rank test: p = <0.001), Kaposis sarcoma (10‐year survival: 44.0% ± 8.4% vs. 23.5% ± 3.9%; log‐rank test: p < 0.001) and Hodgkins disease (10‐year survival: 49.5% ± 14.5% vs. 40.0% ± 12.7%; log‐rank test: p = 0.005). Despite the better cancer prognosis during the post‐HAART era, the 10‐year survival of HIV‐infected subjects with an ADM or NADM is poor.

Infections occurring in adult patients receiving mechanical circulatory support: The two-year experience of an Italian National Referral Tertiary Care Center

OBJECTIVE Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). DESIGN, SETTING, AND PARTICIPANTS An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. INTERVENTIONS None. RESULTS Thirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram-negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93-7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09-0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42-8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77-19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15-132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04-1.56, p=0.02) to be associated with infection. CONCLUSIONS Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role.

Safety and activity of a new intensive short-term chemoimmunotherapy in HIV-positive patients with Burkitt lymphoma

The treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients with Burkitt lymphoma (HIV-BL) is a difficult challenge, requiring multidisciplinary efforts and demanding strategies. While the worldwide use of highly active antiretroviral therapy (HAART) resulted in improved tolerability and efficacy of standard chemotherapy in HIV-positive patients with diffuse large B-cell lymphomas, it has not been associated with better outcome in HIV-BL, with respect to the pre-HAART era, suggesting that more intensive treatments should be used (Lim et al, 2005). Currently, a few, small studies addressing feasibility and activity of dose-dense chemotherapeutic regimens in HIV-BL are available (Table S1). Reported regimens display high efficacy, but are often associated with important dose-limiting side-effects, prolonged hospitalization and treatment-related mortality (TRM) of 15–20%. A dose-dense, short-term chemotherapy program including seven active drugs and intrathecal drug delivery has showed excellent activity and safety profiles in HIV-negative patients with BL in the pre-rituximab era (Di Nicola et al, 2004). We introduced a few changes to this regimen to maintain efficacy and improve tolerability in HIV-BL. In particular, six doses of rituximab were added and methotrexate dose was reduced, from 150 and 250 mg/kg to 3 g/m, mostly to avoid mucositis, which constitutes an important route of access for infectious agents and one of the main causes of death in these patients (Galicier et al, 2007). We used this modified chemoimmunotherapy regimen in 15 consecutive HIV-BL (median age 42 years old, range 27–63) between July 2009 and July 2011 (Table S2). Treatment consisted of a 36-day induction phase including sequential doses of fractionated cyclophosphamide, high doses of methotrexate and cytarabine, doxorubicin, vincristine, and etoposide, rituximab and intrathecal prophylaxis/ treatment (Table I). Subsequent treatment was then tailored according to the objective response to induction phase (Fig. 1): patients in complete response (CR) were referred to a high-dose cytarabine-based consolidation phase (Table I); patients in partial response (PR) were referred to consolidation followed by BEAM (carmustine, etoposide, cytarabine, melphalan) plus autologous stem cell transplant (ASCT); patients with stable or progressive disease were referred to intensification phase, followed by BEAM + ASCT. At the end of chemoimmunotherapy, patients with initial bulky disease or with a residual positron emission tomography-positive single lesion were evaluated for 36-Gy involved-field irradiation. Treatment was safe and well tolerated. All patients but one completed the induction phase (median duration: 49 d; range 34–108); methotrexate and etoposide occasionally required delivery delay due to G3 transaminase increase or G4 neutropenia. Cytostatics dose reductions were recorded only in two patients. There was a single toxic death, which was due to pneumonia in a patient with extensive bone marrow infiltration and baseline CD4+ count of 0 017 9 10/l. As expected, haematological toxicity was common, but manageable (Table S3); with conventional antimicrobial prophylaxis and rHuG-CSF support, infective complications were mild and no systemic fungal infections occurred. The most relevant toxicity was recorded after consolidation: the original cytarabine-cisplatin consolidation regimen (Di Nicola et al, 2004) used in the first four patients was too toxic, with prolonged G4 neutropenia and severe infections in all cases. The exclusion of cisplatin, the change of cytarabine administration schedule and the addition of rituximab (Table I) were associated with a strikingly improved tolerability in subsequent patients, with only two cases of well-controlled febrile neutropenia. Of note, there was a single case of G4 non-haematological toxicity (transient diarrhoea). Patients with hepatitis B virus or hepatitis C virus positivity completed the planned treatment (ASCT in three), and experienced only transient G3 increase of transaminase serum level, without significant chemotherapy delay. HAART was discontinued during chemoimmunotherapy in four patients: three patients exhibited an increase of plasmatic HIV-RNA levels at day 45 followed by undetectable levels at day 90 in two cases, while the third patient needed for a further HAART line; the fourth patient was the toxic death. CD4+ cell counts remained unchanged in the three assessed patients, but were < 0 05 9 10/l in two of them. Response after induction phase was complete in six patients and partial in seven [overall response rate risk (ORR) = 87%; 95% confidence interval CI: 70–100%], one patient had meningeal dissemination and one died of sepsis (Fig. 1). Thirteen patients were referred to consolidation phase, 11 of them were referred to APBSC collection, which was successful in nine (median: 14 10 CD34+ cells/ kg; range 7 20–20 02). The six patients in CR after inducCorrespondence