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Background: Bone tissue homeostasis relies on the coordinated activity of the bone‐forming osteoblasts and bone‐resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown. Methods: We present a case report encompassing clinical assessments, imaging studies, and whole‐exome sequencing analysis, complemented by functional in vitro experiments. Results: This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation. Conclusion: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors. [ABSTRACT FROM AUTHOR]

The small GTPase Rac1 (Ras‐related C3 botulinum toxin substrate 1) has been implicated in cancer progression and in the poor prognosis of various types of tumors. Rac1 SUMOylation occurs during epithelial‐mesenchymal transition (EMT), and it is required for tumor cell migration and invasion. Here we identify POTEE (POTE Ankyrin domain family member E) as a novel Rac1‐SUMO1 effector involved in breast cancer malignancy that controls invadopodium formation through the activation of Rac1‐SUMO1. POTEE activates Rac1 in the invadopodium by recruiting TRIO‐GEF (triple functional domain protein), and it induces tumor cell proliferation and metastasis in vitro and in vivo. We found that the co‐localization of POTEE with Rac1 is correlated with more aggressive breast cancer subtypes. Given its role in tumor dissemination, the leading cause of cancer‐related deaths, POTEE could represent a potential therapeutic target for these types of cancer. [ABSTRACT FROM AUTHOR]

IRF5–TNPO3 polymorphisms have previously been related to immune response, and TNPO3 plays a role in human immunodeficiency virus (HIV)‐1 infection after nuclear import. Therefore, we analyzed the genetic association between IRF5–TNPO3 polymorphisms and the HIV elite control in long‐term nonprogressors (LTNPs). We performed a retrospective cohort study on 183 LTNPs, who were antiretroviral therapy‐naïve with CD4+ ≥ 500 cells/mm3, viral load ≤10 000 copies/mL, and asymptomatic over 10 years after HIV seroconversion. The primary outcome variable was HIV elite control (undetectable viral load in at least 90% of the measurements for at least 1 year). Seven IRF5–TNPO3 polymorphisms were genotyped using Agena Bioscience's MassARRAY platform. We found a significant association between specific IRF5–TNPO3 genotypes and HIV elite control: rs2004640 TT (aOR = 2.05; p = 0.041), rs10954213 AA (aOR = 1.95; p = 0.035), rs2280714 TT (aOR = 2.02; p = 0.031), and rs10279821 CC (aOR = 2.12; p = 0.017). We also found a significant association between IRF5‐TNPO3 haplotype TATC composed of the favorable significant polymorphisms (rs2004640, rs10954213, rs2280714, and rs10279821) and the HIV elite control (aOR = 1.59; p = 0.048). IRF5–TNPO3 rs2004640, rs10954213, rs2280714, and rs10279821 polymorphisms were related to HIV elite control in LTNPs. Our data provide new knowledge about the impact of IRF5–TNPO3 polymorphisms on HIV pathogenesis to understand the phenomenon of natural HIV control. [ABSTRACT FROM AUTHOR]

Objectives: To describe prevalence and factors associated with unplanned pregnancies, and social and partner support during pregnancy among women from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: We included all women recruited in CoRIS from 2004 to 2019, aged 18–50 years at recruitment who were pregnant during 2020. We designed a questionnaire, organized into the following domains: sociodemographic characteristics, tobacco and alcohol consumption, pregnancy and reproductive health, and social and partner support. The information was gathered via telephone interviews conducted from June to December 2021. We calculated prevalence of unplanned pregnancies as well as odds ratios (ORs) of association and 95% confidence intervals (CIs) according to sociodemographic, clinical and reproductive characteristics. Results: Among 53 women who were pregnant during 2020, 38 (71.7%) answered the questionnaire. Median age at pregnancy was 36 years [interquartile range (IQR) 31–39], 27 (71.1%) women were born outside of Spain, mainly in sub‐Saharan Africa (39.5%) and 17 (44.7%) were employed. Thirty‐four (89.5%) women had been through previous pregnancies and 32 (84.2%) had experienced previous abortions/miscarriages. Seventeen (44.7%) women had shared with their clinician their desire to get pregnant. Thirty‐four (89.5%) pregnancies were natural and four used assisted reproductive techniques (in vitro fertilizations; one additionally used oocyte donation). Of 34 women with natural pregnancies, pregnancy was unplanned in 21 (61.8%) and 25 (73.5%) had information on how to become pregnant avoiding HIV transmission to the baby and partner. Women who did not seek advice from their physician about becoming pregnant had a significantly increased risk of unplanned pregnancy (OR = 71.25, 95% CI: 8.96–566.67). Overall, 14 (36.8%) women reported having low social support during pregnancy and 27 (71.0%) had good/very good support by their partner. Conclusions: Most pregnancies were natural and unplanned and very few women had talked with their clinician about their desire to become pregnant. A high proportion of women reported low social support during pregnancy. [ABSTRACT FROM AUTHOR]

Objectives: To pinpoint factors associated with low‐level viraemia (LLV) and virological failure (VF) in people living with HIV in the era of high‐efficacy antiretroviral treatment (ART) and widespread use of integrase strand transfer inhibitor (INSTIs)‐based ART. Methods: We included adults aged > 18 years starting their first ART between 2015 and 2018 in the Spanish HIV/AIDS Research Network National Cohort (CoRIS). Low‐level viraemia was defined as plasma viral load (pVL) of 50–199 copies/mL at weeks 48 and 72 and VF was defined as pVL ≥ 50 copies/mL at week 48 and pVL ≥ 200 copies/mL at week 72. Multivariable logistic regression models assessed the impact on LLV and VF of baseline CD4 T‐cell count, CD4/CD8 T‐cell ratio and pVL, initial ART classes, age at ART initiation, time between HIV diagnosis and ART initiation, gender and transmission route. Results: Out of 4186 participants, 3120 (76.0%) started INSTIs, 455 (11.1%) started boosted protease inhibitors (bPIs) and 443 (10.8%) started nonnucleoside reverse transcriptase inhibitors (NNRTIs), either of them with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs). Low‐level viraemia was met in 2.5% of participants and VF in 4.3%. There were no significant differences throughout the years for both virological outcomes. Baseline HIV‐1 RNA > 5 log10 copies/mL was the only consistent predictor of higher risk of LLV [adjusted odds ratio (aOR) = 9.8, 95% confidence interval (CI): 2.0–48.3] and VF (aOR = 5.4, 95% CI: 1.9–15.1), even in participants treated with INSTIs. Conclusions: The rates of LLV and VF were low but remained steady throughout the years. Baseline HIV‐1 RNA > 5 log10 copies/mL showed a persistent association with LLV and VF even in participants receiving INSTIs. [ABSTRACT FROM AUTHOR]

Objectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID‐19 with [people with HIV (PWH)] and without (non‐PWH) HIV co‐infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active‐follow‐up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non‐PWH of the same age and sex randomly selected from COVID‐19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID‐19. The main outcome was all‐cause in‐hospital mortality. Results: Forty‐five PWH with PCR‐confirmed COVID‐19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex‐matched controls were selected from the COVID‐19@Spain cohort. The median age in both groups was 53 (Q1–Q3, 46–56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV‐RNA < 50 copies/mL, and the median (Q1–Q3) CD4 count was 595 (349–798) cells/μL. No statistically significant differences were found between PWH and non‐PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non‐PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non‐PWH (P = 0.800). Conclusions: Our findings suggest that well‐controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID‐19 hospitalization. [ABSTRACT FROM AUTHOR]

Introduction: Weight gain after starting antiretroviral therapy (ART) is a major problem that can increase morbidity. Our main objective was to evaluate the effects of initial ART on weight change in a large prospective cohort of HIV‐positive individuals. Methods: This was a prospective cohort study of 13,198 subjects included in the Spanish HIV Research Network (CoRIS) between January 2004 and November 2018. We included subjects who started triple ART and achieved HIV RNA suppression within 48 weeks. We fitted linear mixed models adjusted for potential confounders to compare longitudinal changes in weight. We used Cox proportional‐hazard models to compare treatment groups' times to transition to a higher body mass index (BMI) category. Results: We analysed data from a total of 1631 individuals resulting in 14,965 persons/years and 14,085 observations. Individuals retained in the final multivariable model were representative of the overall cohort. NNRTI‐based first‐line ART was associated with a lower average weight gain compared to PI‐ (+0.7 kg per year, 95% CI 0.5 to 1.0, p < 0.001) and INSTI‐based (+0.9 kg per year, 95% CI 0.7 to 1.1, p < 0.001) regimens. Individuals starting ART with TAF+FTC had greater weight gain than those receiving TDF+FTC (+0.8 kg per year, 95% CI 0.3 to 1.4, p = 0.004). Women and black persons presented a greater weight gain than men and non‐black individuals. Differences in weight trajectories were driven mainly by changes during the first year of ART. The NNRTI group was less likely to transition from normal weight to overweight than the PI (aHR 1.48, 95% CI 1.18 to 1.85) and INSTI groups (aHR 1.30, 95% CI 1.03 to 1.64). PIs but not INSTIs were associated with a higher rate of overweight‐to‐obesity shift (aHR 2.17, 95% CI 1.27 to 3.72). No differences were found among INSTIs in the transition to a higher BMI category. Conclusions: INSTI‐ and PI‐based first‐line ARTs are associated with greater weight gain compared to NNRTI‐based ART. Within the NRTIs, TAF+FTC was most strongly associated with weight gain. This heterogeneous effect of ART on body weight could affect the long‐term risk of some non‐communicable diseases. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) and HIV are major causes of worldwide disease. We aimed to evaluate the effect of a combined screening programme, which included a risk‐assessment questionnaire and rapid tests for point‐of‐care diagnosis, on screening and new diagnosis rates. This prospective, cluster randomized study was carried out in primary care. The intervention arm included a 4‐hour educational programme, the use of a risk‐assessment questionnaire and rapid tests. In the control centres, only the educational intervention was provided. The main variables compared were the screening coverage and the number and rate of new HCV and HIV diagnoses. Of a total of 7991 participants, 4670 (58.5%) and 2894 (36.2%) presented a risk questionnaire for HIV or HCV, respectively. The younger participants, men and those from Latin America and Eastern Europe, showed the greatest risk of presenting with a positive questionnaire. The overall screening coverage was higher within the intervention arm (OR 17.7; 95% CI 16.2‐19.5; P <.001). Only two HIV‐positives were identified compared to one in control centres. The rate of HCV diagnoses was higher among intervention centres, with 37 versus seven positive tests (OR 5.2; 95% CI 2.3‐11.6; P <.001). Of them, 10 were new diagnoses and 27 had been previously diagnosed, although not linked to care. In conclusion, a simple operational programme can lead to an increase in HCV and HIV screening rates, compared to an exclusively educational programme. The selection of at‐risk patients with a self‐questionnaire and the use of rapid tests significantly increased the diagnostic rate of HCV infection. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate adherence to the recommendations of the Spanish guidelines for the initial assessment of patients with HIV infection in the multicentre Cohort of the Spanish HIV/AIDS Network (CoRIS) during the years 2004–2017. Methods: We calculated the percentage of patients who had each of 11 clinical and analytical recommended examinations performed in their initial evaluation. We evaluated the factors associated with not performing each examination with multivariable logistic regression models. Results: We included 13 612 patients in the study. In the initial assessment, CD4 count and viral load were determined in more than 98.0% of the patients. Serologies for hepatitis A, B and C and syphilis were determined in 55.8%, 66.4%, 89.8% and 81.7% of the patients, respectively. Total cholesterol and creatinine were determined in 78.7% and 78.9% of the patients, respectively. The lowest proportions of examinations were observed for blood pressure, smoking status and latent tuberculosis screening, which were performed in 43.2%, 50.6% and 53.9% of the patients, respectively. Injecting drug users and heterosexual patients (compared to men who have sex with men) and patients with a lower educational level had a higher risk of having an incomplete initial assessment for a substantial number of examinations. Latent tuberculosis screening was less likely in patients with CD4 counts < 200 cells/µL. Conclusions: The initial assessment of HIV‐infected patients is suboptimal for the evaluation of cardiovascular risk, smoking status, screening of syphilis and viral hepatitis, and diagnosis of latent tuberculosis: adherence to the guidelines was low for these examinations. [ABSTRACT FROM AUTHOR]

Sir: Lymphoplasmacytic lymphoma (LPL)/WM is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes and plasma cells, which usually involves the bone marrow and sometimes lymph nodes and spleen,[1] and has an associated IgM monoclonal component.[2] In most cases, MYD88L265P somatic mutation is the driver mutation.[[3]] Patients with IgG or IgA monoclonal proteins and those with non-secretory LPL exist and show clinical and pathological heterogeneity.[[7]] The bone marrow core biopsy shows paratrabecular and interstitial infiltration of small lymphocytes some with plasmacytoid features and plasma cells (20% of marrow cellularity). The bone marrow core biopsy shows a diffuse-solid interstitial infiltrate of small lymphocytes, plasmacytoid lymphocytes and plasma cells (80% of the marrow cellularity). Histopathological features in the bone marrow of IgA-LPL are the same as IgM-LPL/WM, including paratrabecular and interstitial clonal B cell infiltrates with plasma cell differentiation. [Extracted from the article]

Summary: We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem‐cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3‐year progression‐free survival (PFS). Sixty patients (median age 55 [28–71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9–72) and 14 (4–53) days to achieve neutrophil and platelet counts of >0.5 × 109/l and >20 × 109/l, respectively. Non‐relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow‐up of 67 (40–77) months, the estimated 3‐year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12–0.56]) and OS (RR, 0.40 [95% CI 0.17–0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein–Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B‐cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV– tumours, EBV+ DLBCLs derived predominantly from IGVH‐hypermutated CLL, and they also showed CLL‐unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo‐immunotherapy, a non‐germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy‐related immunosuppression can transform either CLL cells or non‐tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B‐cell lymphocytosis (MBL) was performed in Rag2–/– IL2γc–/– mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B‐cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL‐unrelated but also CLL‐related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B‐cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article examines whether p-mitogen activated protein kinase (MAPK1) expression was of any biological relevance in n-peripheral T-cell lymphomas (PTCL). Topics include characteristics of PTCLs, pathways involved in PTCL tumourigenesis in a series of n-PTCLs samples, and the lack of association between positive p-MAPK1 expression and prognosis in the series.

Plasma cell proliferations in specific cutaneous lesions of angioimmunoblastic T-cell lymphoma( AITL) are very uncommon. Here, we report a case of clonal plasma cell proliferation in skin with heavy-chain-immunoglobulin-isotype-switch after cutaneous disease progression. Histopathologically, initial plaque lesions were suggestive of marginal-zone B-cell-lymphoma. Nevertheless, this 77-year-old lady was diagnosed with AITL after the progression of skin lesions from plaques to nodular tumors. A lymph node biopsy confirmed the diagnosis. Both cutaneous specimens showed a polymorphic cellular infiltrate with atypical T-cell-lymphocytes arranged in a pseudonodular pattern that expressed CD3, PD1 and BCL6, with patchy expression of CD30. Interestingly, a slight IgG-Lambda plasma cell component was seen at the periphery of the infiltrate in the first specimen which increased in number in the later nodular lesion, showing not only Lambda light chain restriction and IgG but also IgG4. PCR studies for IgH and TCR genes showed an IgH clonal peak on both skin lesions but not on lymph node biopsy. On the contrary, the same clonal TCR peak was found in the three specimens. Neoplastic follicular helper T-cells within cutaneous-specific microenvironment could be responsible for the modulation of the immunoglobulin isotype class switch change. Further studies are needed to support this hypothesis. [ABSTRACT FROM AUTHOR]

Objectives Chronic oxidative stress ( OS) may play a role in cardiovascular disease in HIV-infected patients, and increased bilirubin levels may have a beneficial role in counteracting OS. Atazanavir ( ATV) inhibits UDP-glucuronosyl-transferase 1A1 ( UGT1A1), thus increasing unconjugated bilirubin levels. We aimed to compare changes in OS markers in patients on ATV/ritonavir ( ATV/r)- vs. efavirenz ( EFV)-based first-line antiretroviral therapy ( ART). Methods A multicentre, prospective cohort study of HIV-infected patients who started first-line ART with either ATV/r or EFV was conducted. Lipoprotein-associated phospholipase A2 (Lp- PLA2), myeloperoxidase ( MPO) and oxidized low-density lipoprotein (ox LDL) were measured for 145 patients in samples obtained at baseline and after at least 9 months of ART during which the initial regimen was maintained and the patient was virologically suppressed. The change in OS markers was modelled using multiple linear regressions adjusting for baseline values and confounders. Results After adjustment for baseline variables, patients on ATV/r had a significantly greater decrease in Lp- PLA2 [estimated difference −16.3; 95% confidence interval ( CI) −31.4, −1.25; P = 0.03] and a significantly smaller increase in Ox LDL (estimated difference −21.8; 95% CI −38.0, −5.6; P < 0.01) relative to those on EFV, whereas changes in MPO were not significantly different (estimated difference 1.2; 95% CI −14.3, 16.7; P = 0.88). Adjusted changes in bilirubin were significantly greater for the ATV/r group than for the EFV group (estimated difference 1.33 mg/ dL; 95% CI 1.03, 1.52 mg/ dL; P < 0.01). Changes in bilirubin and changes in OS markers were significantly correlated. Conclusions When compared with EFV, ATV/r-based therapy was associated with lower levels of oxidative stress biomarkers, which was in part attributable to increased bilirubin levels. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma ( DLBCL) patients failing rituximab-containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose ( MTD) of lenalidomide in combination with R- ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) ( LR- ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1-14 of every 21-day cycle, in combination with R- ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem-cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose-limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR- ESHAP cycles resolved appropriately and no grade 4-5 non-haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow-up of 24·6 (17·4-38·2) months, the 2-year progression-free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR- ESHAP regimen is feasible and yields encouraging outcomes. [ABSTRACT FROM AUTHOR]

Aims: Here we report two cases of follicular lymphoma that transformed to CD30 positive diffuse large B cell lymphoma and review the literature on this topic. Results: The first case represents an example of early transformation of conventional low-grade follicular lymphoma to CD30-positive large B cell lymphoma. Immunoglobulin (Ig)H and cytogenetic identity was demonstrated between both components. High-dose and auto-stem cell transplant (SCT) was applied and complete response was achieved. The second case represents an example of d'emblee transformation of intrafollicular neoplasia to CD30-positive large B cell lymphoma. Immunoglobulin K deleting element (IgKde) and cytogenetic identity between both phases was demonstrated. The patient was in partial response after four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Conclusions: CD30 expression was found to be associated in these cases to the transformation event and could be considered a therapeutic target to add to conventional immunochemotherapeutic regimens, even in combination with auto-SCT. We suggest looking for CD30 expression in transformed follicular lymphoma cases. [ABSTRACT FROM AUTHOR]

Aims CD30-positive primary cutaneous lymphoproliferative disorders include several entities with differing clinical presentation but overlapping histological features, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (C- ALCL). DUSP22- IRF4 locus translocation is present in 20-57% of C- ALCLs, and has also been described in a series of 11 lymphomatoid papulosis patients, where it was associated with a particular biphasic histological pattern, including pagetoid reticulosis-type epidermal infiltration. We aimed to study whether the presence of this translocation may define distinctive histological features in C- ALCL. Methods and results We collected three cases of C- ALCL with histological features similar to those described in the new variant of lymphomatoid papulosis with 6p25.3 rearrangement. We studied their histological features and immunophenotype, using a panel of antibodies against CD30, TCR-βF1, TCR-γ, CD4, CD8, CD20, Ki-67 and ALK. FISH analyses were performed using an IRF4- DUSP22 break-apart probe for the study of the 6p25.3 rearrangement. FISH results were positive in the three cases, which all showed distinctive histological and immunohistochemical features: a diffuse dermal infiltrate of atypical medium-to-large cells, and marked epidermotrophism with small, atypical intra-epidermal lymphocytes. Conclusions Our findings suggest that the presence of 6p25.3 rearrangement might be related to this particular biphasic pattern. [ABSTRACT FROM AUTHOR]

This prospective multi-institutional phase II study was designed to assess the efficacy and safety of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab ( DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphomas. Eighty-one patients diagnosed with diffuse large B-cell lymphoma ( DLBCL, n = 68), primary mediastinal DLBCL ( n = 6) and follicular lymphoma Grade 3b ( n = 7), with an age-adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21-77). Sixty-five patients (80·2%) achieved complete response. After a median follow-up time of 64 months, 10-year event-free survival and overall survival ( OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10-year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B-cell tumours and germinal centre B-cell without BCL2 rearranged tumours. Results achieved with DA-EPOCH-R showed a good long-term outcome and a tolerable toxicity profile in high-risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high-risk DLBCL patients. [ABSTRACT FROM AUTHOR]

Aims Immunoglobulin light-chain expression is used routinely as an indirect marker of clonality for recognizing B cell lymphoproliferative disorders. Methods and results Here we describe four floral follicular hyperplasia cases in the gastrointestinal tract (appendix and rectum) of children (4 to 6 years). Immunohistochemical studies revealed lambda light-chain restriction that was associated with polyclonal IgH pattern. Clinical features and follow-up of the patients did not reveal any other systemic symptoms, laboratory abnormalities or organ alterations. Conclusions Recognition of this phenomenon is useful in the diagnosis of nodular lymphoid hyperplasia of the gastrointestinal tract, for avoiding overdiagnosis of lymphoid malignancies, and raises concerns that the identification of light-chain restriction is not necessarily a marker of monoclonality. [ABSTRACT FROM AUTHOR]

We conducted a multicentre, phase II study of interim positron emission tomography ( PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma ( DLBCL). Patients achieving negative fluorodeoxyglucose ( FDG)- PET after three courses of R-Mega CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R- IFE (rituximab, ifosfamide, etoposide) followed by BEAM ( BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival ( PFS). 71 patients (median age 55 years, range 25-69) were enrolled. With a median follow-up of 42·8 months (range 7·2-58·4), the estimated 4-year PFS and overall survival ( OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET ( N = 36) had significantly better 3-year PFS than those with partial response ( N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02-6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35-20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89-97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria. [ABSTRACT FROM AUTHOR]

BACKGROUND Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression. METHODS The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1. All patients who were cyclin D1-positive according to immunohistochemistry were also assessed for rearrangements of the cyclin D1 gene ( CCND1) using fluorescence in situ hybridization. Gene expression profiling was performed to compare patients who had DLBCL with and without cyclin D1 expression. RESULTS In total, 30 patients (2.1%) who had DLBCL that expressed cyclin D1 and lacked CCND1 gene rearrangements were identified. Patients with cyclin D1-positive DLBCL had a median age of 57 years (range, 16.0-82.6 years). There were 23 males and 7 females. Twelve patients (40%) had bulky disease. None of them expressed CD5. Two patients expressed cyclin D2. Gene expression profiling indicated that 17 tumors were of the germinal center type, and 13 were of the activated B-cell type. Genetic aberrations of B-cell leukemia/lymphoma 2 ( BCL2), BCL6, v-myc avian myelocytomatosis viral oncogene homolog ( MYC), mouse double minute 2 oncogene E3 ubiquitin protein ligase ( MDM2), MDM4, and tumor protein 53 ( TP53) were rare or absent. Gene expression profiling did not reveal any striking differences with respect to cyclin D1 in DLBCL. CONCLUSIONS Compared with patients who had cyclin D1-negative DLBCL, men were more commonly affected with cyclin D1-positive DLBCL, and they were significantly younger. There were no other significant differences in clinical presentation, pathologic features, overall survival, or progression-free survival between these two subgroups of patients with DLBCL. Cancer 2014;120:1818-1829. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which describes the expression of BCL7A protein in normal and malignant lymphoid tissues through the use of immunohistochemistry technique.

Heterogeneity and small-study effects are major concerns for the validity of meta-analysis. Although random effects meta-analysis provides a partial solution to heterogeneity, neither takes into account the presence of small-study effects, although they can rarely be ruled out with certainty. In this paper, we facilitate a better understanding of the properties of a recently described regression-based approach to deriving a meta-analysis estimator robust to small-study effects and unexplainable heterogeneity. The weightings of studies in the meta-analysis are derived algebraically for the regression model and compared with the weightings allocated to studies by fixed and random effects models. These weightings are compared in case studies with and without small-study effects. The presence of small-study effects causes pooled estimates from fixed and random effects meta-analyses to differ, potentially markedly, as a result of the different weights allocated to individual studies. Because random effects meta-analysis gives more weight to smaller studies, it becomes more vulnerable to the small-study effects. The regression approach gives heavier weight to the larger studies than either the fixed or random effects models, leading to its dominance in the estimated pooled effect. The weighting properties of the proposed regression-derived meta-analysis estimator are presented and compared with those of the standard meta-analytic estimators. We propose that there is much to recommend the routine use of this model as a reliable way to derive a pooled meta-analysis estimate that is robust to potential small-study effects, while still accommodating heterogeneity, even though uncertainty will often be considerably larger than for standard estimators. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Rodríguez-Pinilla S M, Barrionuevo C, García J, de los Ángeles M, Pajares R, Casavilca S, Montes J, Martínez A, Montes-Moreno S, Sánchez L & Piris M Á (2011) Histopathology 59, 1183-1193 Epstein-Barr virus-positive systemic NK/T-cell lymphomas in children: report of six cases Aims: The World Health Organization lymphoma classification recognizes two different Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders of childhood: systemic EBV-positive T-cell lymphoproliferative disease of childhood, and hydroa vacciniforme-like lymphoma, which is more prevalent in Asia and Latin America. The aim of this study was to characterize six cases of paediatric EBV-positive peripheral T-cell lymphoma with distinct features. Methods and results: All cases were male, with a median patient age of 9 years (range: 5-17 years). Most of them presented suddenly with fever, weight loss, hepatosplenomegaly, peripheral lymphadenopathy, and high lactate dehydrogenase (LDH) levels. Moreover, gut, lung or soft tissues of the abdominal wall were also affected in four cases. Partial to total replacement of the lymph node by pleomorphic infiltration of atypical neoplastic cells was found in all cases. Vasculitis and geographical areas of necrosis were seen in three and four cases, respectively. Neoplastic cells showed expression of EBV-encoded RNA, T-cell markers (CD2 and CD3), and cytotoxic markers (TIA1, granzyme-B, and perforin). CD56 and T-cell receptor -γ were expressed in one case each. TCR-BF1, CD4, CD8 and anaplastic lymphoma kinase were negative. In all cases, the disease progressed rapidly, causing death of the patient, with a median survival of 7.1 months (range: 1-13 months). Conclusions: These cases probably represent a solid form of systemic EBV-positive T-cell lymphoproliferative disease of childhood, which requires identification and the development of appropriate therapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting," by J. I. Cohen and colleagues in the 2009 issue.

To characterize diffuse large B-cell lymphoma (DLBCL) with chromosome 7 gains, we combined clinical data with genomic, RNA and miRNA profiling. Gains were associated with age >60 years, female gender, a trend for higher complete response rate, lower death rate, and better overall survival in patients treated with R-CHOP. Lesions were inversely associated with bone marrow involvement and number of extra-nodal sites. Differentially expressed transcripts were enriched of genes belonging to specific pathways and miRNAs targets. MIR96, MIR182, MIR589, MIR25 were shown significantly up-regulated in 7q+ DLBCL by real-time PCR . [ABSTRACT FROM AUTHOR]

Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 d). 166 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the comparison between nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and T cell/hystiocyte-rich large B cell lymphoma (T/HRBCL) in the previous issue.

Richter's syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma and is mostly represented by diffuse large B-cell lymphoma (DLBCL), with a post-germinal centre (GC) phenotype, clonally related to the pre-existing CLL. RS has a very poor prognosis and its pathogenetic mechanisms are poorly understood. In order to gain additional hints in RS pathogenesis, we performed a genome-wide DNA profiling study of 13 RS phases and eight matched CLL phases using the Affymetrix Human Mapping 250K NspI SNP arrays. Individual genomic profiles were heterogeneous, with no individual lesions occurring in more than half of the cases. However, several observations suggest that MYC pathway might be involved in RS. The 13q13.3-qter region containing MIRHG1 (MIR-17-92), a cluster of microRNA interacting with c-MYC, was acquired at the time of transformation. The 13q gain was coupled with the gain of c-MYC and loss of TP53. Translocation of c-MYC was acquired at transformation in a fraction of cases and this event appeared mutually exclusive with gain of MIRHG1. MYCN, a c-MYC homologue, was also recurrently gained. By comparing RS with 48 de novo DLBCL, RS presented a significantly lower prevalence of deletions affecting the PRDM1 and TNFAIP3, genes on 6q, known to be associated with a post-GC phenotype. In conclusion, the genomic profile of RS seems to differ from what observed in de novo DLBCL and in other transformed DLBCL. Genomic lesions occurring in RS are heterogeneous suggesting the existence of different RS subsets, possibly due to different transforming mechanisms. A deregulation of MYC pathway might represent one of the main transformation events in the pathogenesis of a subset of RS clonally related to the previous CLL. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorders (PTLD) are complications of solid organ transplantation associated with severe morbidity and mortality. Diffuse large B-cell lymphoma (DLBCL) represents the most common form of monomorphic PTLD. We studied 44 cases of post-transplant DLBCL (PT-DLBCL) with high-density genome wide single nucleotide polymorphism-based arrays, and compared them with 105 cases of immunocompetent DLBCL (IC-DLBCL) and 28 cases of Human Immunodeficiency Virus-associated DLBCL (HIV-DLBCL). PT-DLBCL showed a genomic profile with specific features, although their genomic complexity was overall similar to that observed in IC- and HIV-DLBCL. Among the loci more frequently deleted in PT-DLBCL there were small interstitial deletions targeting known fragile sites, such as FRA1B, FRA2E and FRA3B. Deletions at 2p16.1 (FRA2E) were the most common lesions in PT-DLBCL, occurring at a frequency that was significantly higher than in IC-DLBCL. Genetic lesions that characterized post-germinal center IC-DLBCL were under-represented in our series of PT-DLBCL. Two other differences between IC-DLBCL and PT-DLBCL were the lack of del(13q14.3) ( MIR15/MIR16) and of copy neutral LOH affecting 6p [major histocompatibility complex (MHC) locus] in the latter group. In conclusion, PT-DLBCL presented unique features when compared with IC-DLBCL. Changes in PT-DLBCL were partially different to those in HIV-DLBCL, suggesting different pathogenetic mechanisms in the two conditions linked to immunodeficiency. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article"Intrafollicular neoplasia/in situ follicular lymphoma: review of a series of 13 cases" published in previous issues of the journal.

Non-Hodgkin lymphomas (NHL) represent a frequent complication of human immunodeficiency virus (HIV) infection. To elucidate HIV-NHL pathogenesis, we performed a genome-wide DNA profiling based on a single nucleotide polymorphism-based microarray comparative genomic hybridization in 57 HIV-lymphomas and, for comparison, in 105 immunocompetent diffuse large B-cell lymphomas (IC-DLBCL). Genomic complexity varied across HIV-NHL subtypes. HIV-Burkitt lymphoma showed a significantly lower number of lesions than HIV-DLBCL ( P = 0·032), whereas the median number of copy number changes was significantly higher in Epstein–Barr virus negative (EBV-) HIV-DLBCL (42·5, range 8–153) compared to EBV+ cases (22; range 3–41; P = 0·029). Compared to IC-DLBCL, HIV-DLBCL displayed a distinct genomic profile with no gains of 18q and specific genetic lesions. Fragile sites-associated genes, including FHIT (FRA3B), WWOX (FRA16D), DCC (FRA18B) and PARK2 (FRA6E) were frequently inactivated in HIV-NHL by interstitial deletions, and a significantly higher prevalence of FHIT alterations was observed in HIV-DLBCL compared to IC-DLBCL. The same genes involved by fragile site deletions were also frequently affected by aberrant methylation of regulative regions. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions We assessed the opinions of physicians caring for people with HIV (PWH) from the multicentre Spanish CoRIS cohort regarding the assessment of health‐related quality of life (HRQoL).We designed an online self‐administered questionnaire comprising 27 structured questions across four domains: (i) sociodemographic and clinical data; (ii) usefulness of measuring HRQoL; (iii) information, training and resource needed; and (iv) whether and how HRQoL should be measured. Physicians completed the questionnaire between April and June 2023.Of 131 physicians surveyed [53.8% men, median age 52 years (interquartile range: 42–60)], 90.9% and 88.6% agreed that measuring HRQoL is useful for both PWH and medical decision‐making, respectively. However, 67.2% needed training on what HRQoL is and how to measure it, 79.4% required information on validated tools, and 80.9% felt that clinical guidelines are needed. Overall, 90.1% of physicians agreed that HRQoL should be measured among PWH. Most physicians (82.8%) supported using specific scales for PWH, with 74.1% recommending annual measurement, 49.1% suggesting that nurses from HIV units conduct the assessments, and 43.1% favouring personal interviews during medical visits. At the time of the survey, 55.3% of physicians did not measure HRQoL in any patients due to time or resource constraints (75.8%).Despite the recognized importance of HRQoL measurement in PWH, Spanish physicians encounter barriers such as time constraints and limited resources. Developing clear guidelines, using tailored scales, and integrating digital tools along with multidisciplinary support could enhance routine HRQoL assessments and improve patient‐centred care. [ABSTRACT FROM AUTHOR]

The article focuses on the benefits of MYC oncogene in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) chemoimmunotherapy. It relates two studies that show the association of MYC translocations with worse survival of patients with DLBCL. It mentions that MYC gene status has a potential benefit for diagnosing DLBCL patients.

A letter to the editor, in context with a case of sarcoma-like inflammatory pseudotumour of the lymph node, is presented.

A letter to the editor on a case of follicular T-cell lymphoma with a pure follicular pattern, paratrabecular bone marrow infiltration and a T follicular-helper (TFH) immunophenotype, is presented.

Introduction EuroSIDA has previously reported a poorer clinical prognosis for HIV-positive individuals in Eastern Europe (EE) as compared with patients from other parts of Europe, not solely explained by differences in patient characteristics. We explored regional variability in self-reported HIV management at individual EuroSIDA clinics, with a goal of identifying opportunities to reduce the apparent inequalities in health. Methods A survey () on HIV management was conducted in early 2014 in all currently active EuroSIDA clinics. Responders in EE were compared with clinics in all other EuroSIDA regions combined (non-EE). Characteristics were compared between regions using Fishers exact test. Results A total of 80/97 clinics responded (82.5%, 12/15 in EE, 68/82 in non-EE). Participating clinics reported seeing a total of 133,532 patients [a median of 1300 per clinic (IQR 700-2399)]. The majority of clinics requested viral load and CD4 measurements at least every six months for patients on as well as off ART (EE 66.7%, non-EE 75%, p=0,72). Significantly fewer EE clinics performed resistance tests before ART as well as upon treatment failure (Figure 1). Half of the EE clinics indicated following WHO guidelines (EE 50%, non-EE 7.4%, p<0.0001), whereas most non-EE clinics followed EACS guidelines (non-EE 76.5%, EE 41.7%, p=0.017). The majority of EE clinics and ¼ non-EE clinics indicated deferral of ART initiation in asymptomatic individuals until CD4 ≤350 cells/mm3 (Figure 1). There were no significant regional differences in screening haematology, liver or renal function, which the majority of clinics reported to do routinely. However, EE clinics reported screening significantly less for cardiovascular disease (CVD), and only about half screened for tobacco use, alcohol consumption and drug use (Figure 1). Screening for cervical cancer and for anorectal cancer was low in both regions (Figure 1). Conclusions We found significant regional variability in self-reported HIV management across Europe, with less resistance testing, screening for CVD and substance use in EE. EE clinics indicated deferral of ART initiation for longer than non-EE clinics. Adherence to international guidelines for cervical cancer screening was poor in both regions. Whether differences in HIV management are reflected in clinical outcomes deserves further investigation. [ABSTRACT FROM AUTHOR]

This document provides summaries of research studies on the use of extracellular vesicles (EVs) as biomarkers, therapeutic agents, and drug delivery vehicles. The studies cover a wide range of diseases and conditions, including cancer, neurological disorders, diabetes, and osteoarthritis. The findings suggest that EVs have potential applications in diagnostics, regenerative medicine, targeted drug delivery, and immune modulation. However, further research is needed to fully understand the mechanisms and optimize the use of EVs in clinical settings. [Extracted from the article]

The author comments on a paper by Xuan J. Wang et al. on a study of the clinicopathological features of a retrospective series of 98 patients diagnosed as de novo EBV-negative Diffuse Large B-cell Lymphoma (DLBCL). He notes that CD30 expression in large B-cell lymphomas can be found in multiple B-cell lymphoma entities with variable prevalence and concludes that the availability of new drugs against CD30 molecule should foster the development of clinical trials to test its efficacy.

Introduction Etravirine has become an alternative in HIV/HCV coinfected patients because of safety and lack of interactions with anti-HCV drugs. The aim of this study was to establish the risk of liver toxicity in HIV/HCV coinfected patients receiving etravirine in the clinical setting, according to the degree of liver fibrosis and different accompanying drugs. Material and Methods Cohort study of 211 patients initiating etravirine as part of their antiretroviral regimen. HCV coinfection was defined as a positive RNA-HCV, whereas baseline liver fibrosis was assessed by transient elastography at baseline. Hepatotoxicity was defined as an increased AST/ALT, 5-fold higher over upper, normal limits for patients with normal baseline values, or 3.5-fold if altered at baseline. Results HCV coinfection was observed in 145 patients (69%) with a longer time of HIV infection and time on HAART than mono-infected patients, and a lower nadir (182 vs 227 cells/mL; p=0.02) and baseline CD4+ count (446 vs 552 cells/mL; p=0.02). Etravirine was used with two nucleoside analogues in 62%, with boosted darunavir in 17%, with raltegravir in 10%, and with darunavir plus raltegravir or maraviroc in 10% of patients without differences according to HCV serostatus. Transient elastography in 117 patients performed at etravirine initiation (median, 33 days) showed fibrosis 1 and fibrosis 4 in 37% and 24% of cases, and median stiffness value was 8.25 kPa (3.5-69). During an accumulated follow-up of 449.3 patient-years (median, 611 days), only one coinfected patient with fibrosis 4 (stiffness value, 50.1 kPa), receiving a rescue regimen including darunavir/r plus maraviroc plus two nucleoside analogues, developed a grade 3-4 of liver toxicity (0.5%). There were no other episodes of liver toxicity, as defined, and only 6 (3%) and 9 patients (4%) had a grade 1 and 2 of toxicity, respectively, in most cases related to HCV coinfection (6 and 6 cases). Moreover, HCV coinfection or advanced fibrosis was not associated to a higher risk of etravirine discontinuation (26% vs 21%; p=0.27, log-rank test) or virologic failure (9% vs 11%, p=0.56). CD4+ cell count increase was lower in HCV patients (+23 vs +86 at 6 month; p=0.02). Conclusions Etravirine is safe in HIV/HCV coinfected patients, even in presence of moderate and advanced liver fibrosis and as part of different antiretroviral regimens. [ABSTRACT FROM AUTHOR]

Introduction Concomitant use of combination antiretroviral regimen (cART) and cancer chemotherapy is difficult due to complex interactions and increased toxicity. Raltegravir could be an adequate option through its favourable drug-drug interaction profile. Methods Prospective longitudinal study of HIV patients with cancer, AIDS related or not, undergoing chemotherapy. Patients without resistance or previous failure were switched or initiated raltegravir plus two nucleoside analogues. Plasma trough levels of raltegravir were measured. Results Overall, 28 patients receiving a raltegravir-based regimen (4 naive) with tenofovir-emtricitabine (18 cases) or abacavir-lamivudine (10 cases) were included. Mean age was 46.2 years (IQR, 39-52.7), and 79% were male. Median time of HIV was 201.7 months, CD4+ nadir was 268 cells/mm3, and 75% had previous AIDS. At the diagnosis of neoplasia, 17 were on protease inhibitors and 4 with efavirenz. Ten patients had a non-HIV-related cancer (three breast, two pancreatic, one Ewing sarcoma, one myeloblastic leukemia, one melanoma, one parotid adenocarcinoma, one lung), and 18 had an HIV-related cancer (nine non-Hodgkin lymphoma, seven Hodgkin disease, two anal). Overall, 43% of patients received more than one line of chemotherapy, including antimetabolites in 12 patients (5-FU, capecitabine, methotrexate, gemcitabine), alkylating agents in 12 cases (ciclophosphamide, iphosphamide), vinca alkaloids in 20 patients (vincristine, vinblastine, vindesine), antitumor antibiotics in 16 cases (adriamycin), cisplatin o carboplatin in six and monoclonal antibodies in six patients (rituximab, trastuzumab, cetuximab). Six patients modified the doses of antineoplastic agents due to toxicity (four neutropenia), not related to raltegravir. During a median follow up of 12.7 patients-year in concomitant therapy, there was only 1 case of virological failure and no patient discontinued raltegravir. Plasma concentrations of raltegravir in eight patients showed a median concentration of 143 ng/mL (79-455). Four patients (14%) died during the study, not related to AIDS progression. Raltegravir was continued after chemotherapy in all the cases. Conclusions A raltegravir-based therapy is safe and effective in HIV patients undergoing antineoplastic chemotherapy, regardless of the type of tumour, and type and duration of chemotherapy. Pharmacokinetic data show adequate raltegravir levels. [ABSTRACT FROM AUTHOR]

Introduction The combination of lamivudine plus a protease inhibitor boosted with ritonavir (PI/r) has become an alternative as simplification strategy in HIV-infected patients with toxicity/intolerance to other nucleoside analogues (NA). Lamivudine plus darunavir/r (DRV/r) could be an adequate once daily option. Materials and Methods Prospective cohort study of 48 HIV-infected patients on suppressive triple therapy-based HAART, HBV negative, who switched to lamivudine 300 mg plus DRV/r 800/100 mg once daily. Results Mean age was 50 yrs (35-74), and 65% were male. Thirty patients (63%) had HCV co-infection (fibrosis 4 in 7 cases, 23%). Median time of HIV infection was 19.1 years, and CD4+ count nadir was 220 cells/µL (2-604). They had received a mean of three regimens before (2-20), and 20 (42%) had a previous AIDS diagnosis. In eight cases, a previous resistance test showed two to seven secondary mutations in the protease gene, without resistance to DRV/r (one patient with the I84V mutation). At baseline, patients had viral suppression (<50 copies/mL) for a median time of 1263 days (341-1884), and they were receiving predominantly a PI based regimen (ATV in four, FPV in four, LPV in three, DRV in six) or an efavirenz-based regimen (seven). The main reason to switching to this dual therapy was toxicity (35 patients, 75%), mainly renal toxicity attributed to tenofovir (24 cases). During 104.3 patients-year of follow-up (median 912 days), only two patients (4%) failed at 27 and 505 days, due to non-adherence and lost to follow up, respectively. Total cholesterol and triglycerides increased significantly during the first six months after initiation (TC, from 185 to 269 mg/dL; p=0.01, TG from 118 to 185 mg/dL; p=0.03, TC/HDL ratio, from 4.09 to 4.66) and decreased after. Median estimated glomerular filtration rate (eGFR) improved during follow up (from 86 to 96.1 mL/min; p=0.13). In patients with renal toxicity as cause of switch there was a mild, no significant improvement during the first year (from 63.3 to 68.7 mL/min), although an improvement in protein-uria levels (protein/creatinine ratio, from 171 to 126 mg/g; p=0.04) was observed soon after initiation. Conclusions Dual therapy with lamivudine plus darunavir boosted with ritonavir once daily is safe and effective as simplification strategy in HIV-infected patients. [ABSTRACT FROM AUTHOR]