Has the time come to leave the watch-and-wait strategy in newly diagnosed asymptomatic follicular lymphoma patients?

ABSTRACT: BACKGROUND: Historically, the median overall survival for follicular lymphoma (FL) has been considered to be 9-10 years, and no treatment had ever prolonged this time period. Studies conducted more than 20 years ago demonstrated that treating patients with asymptomatic FL at the onset of the disease did not increase their survival, and that almost 20% of these patients did not need any treatment in the first 10 years of follow-up. Based on these facts, most clinical practice guidelines recommend active surveillance policies for patients with asymptomatic FL. DISCUSSION: The introduction of antiCD-20 monoclonal antibodies, over the last 15 years, has significantly increased the median survival rate to above 14 years. This improvement was achieved before the combination of rituximab and chemotherapy regimens became extensively used in patients with symptomatic disease. Therefore, this increase in survival may currently be more significant. At present, several clinical trials have evaluated low-toxicity therapies that prolong progression-free periods, among which rituximab monotherapy, radioimmunotherapy or the combination of rituximab with bendamustine are the most relevant. Unfortunately, these clinical trials have included only patients with symptomatic FL. The results of a recently reported clinical trial show that treatment with single-agent rituximab prolongs progression-free survival rates, time to new treatment and the quality of life of asymptomatic patients, as compared with the active surveillance strategy. Longer follow-up of these results and data regarding overall survival are awaited before this treatment can be recommended as the standard initial therapy. SUMMARY: There are different therapeutic possibilities for asymptomatic FL patients, but no data are currently available to indicate which option is the best. Patients need to understand the risks and benefits of observation versus treatment before a final decision can be made. For patients who want active treatment the administration of four weekly rituximab doses should be considered.     

Differences in the causes of death of HIV-positive patients in a cohort study by data sources and coding algorithms

OBJECTIVES:: To compare causes of death (CoDs) from two independent sources: National Basic Death File (NBDF) and deaths reported to the Spanish HIV Research cohort [Cohort de adultos con infección por VIH de la Red de Investigación en SIDA CoRIS)] and compare the two coding algorithms: International Classification of Diseases, 10th revision (ICD-10) and revised version of Coding Causes of Death in HIV (revised CoDe). METHODS:: Between 2004 and 2008, CoDs were obtained from the cohort records (free text, multiple causes) and also from NBDF (ICD-10). CoDs from CoRIS were coded according to ICD-10 and revised CoDe by a panel. Deaths were compared by 13 disease groups: HIV/AIDS, liver diseases, malignancies, infections, cardiovascular, blood disorders, pulmonary, central nervous system, drug use, external, suicide, other causes and ill defined. RESULTS:: There were 160 deaths. Concordance for the 13 groups was observed in 111 (69%) cases for the two sources and in 115 (72%) cases for the two coding algorithms. According to revised CoDe, the commonest CoDs were HIV/AIDS (53%), non-AIDS malignancies (11%) and liver related (9%), these percentages were similar, 57, 10 and 8%, respectively, for NBDF (coded as ICD-10). When using ICD-10 to code deaths in CoRIS, wherein HIV infection was known in everyone, the proportion of non-AIDS malignancies was 13%, liver-related accounted for 3%, while HIV/AIDS reached 70% due to liver-related, infections and ill-defined causes being coded as HIV/AIDS. CONCLUSION:: There is substantial variation in CoDs in HIV-infected persons according to sources and algorithms. ICD-10 in patients known to be HIV-positive overestimates HIV/AIDS-related deaths at the expense of underestimating liver-related diseases, infections and ill defined causes. CoDe seems as the best option for cohort studies.     

Carbonic anhydrase is aberrantly and constitutively expressed in both human and murine erythroleukemia cells.

The levels of the erythrocyte proteins carbonic anhydrase (CA) and hemoglobin (Hb) change coordinately during human ontogeny. To further probe the coordinate gene expression of these two proteins in vitro, we used an immunoblotting technique to measure their levels during erythroid differentiation in normal human and murine erythroid progenitors, in human and murine erythroleukemia cells, and in normal murine erythroid progenitors infected with Friend virus. Levels of CA and Hb seem to gradually increase in normal differentiating stem cells. In contrast, both human and murine erythroleukemia cells show high levels of CA, but not of Hb, prior to induction of differentiation. Friend virus infection of normal murine progenitors appears to stimulate CA synthesis as an initial and integral step in transformation. In addition, both the erythroleukemia cells and the erythroid progenitors transformed with Friend virus seem to contain much higher levels of CA than Hb during the early stages of differentiation. This relationship is in marked contrast to normal erythroid differentiation, in which Hb levels are always higher than CA levels. Thus, neoplastic transformation seems to be associated with aberrant production of CA that does not correspond to a maturation arrest of the normal differentiation sequence.     

Sequential activation of microglia and astrocyte cytokine expression precedes increased iba‐1 or GFAP immunoreactivity following systemic immune challenge

Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2–12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2‐4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba‐1⁺) and astrocytes (GFAP⁺), however, were undetected during this 2–12 h timeframe. Increased Iba‐1 immunoreactivity and de‐ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba‐1 or GFAP immunoreactivity after LPS challenge. GLIA 2016;64:300–316     

Predictive value of peripheral blood lymphocyte count in breast cancer patients treated with primary chemotherapy

Peripheral blood lymphocyte (PBL) count may reflect the immune status of cancer patients. We retrospectively analyzed the predictive and prognostic impact of baseline and post-chemotherapy PBL counts in a homogeneous group of 103 breast cancer patients treated with neoadjuvant chemotherapy (anthracyclines and taxanes). In univariate analysis, baseline PBL under 1500 × 10(6)/L (p = 0.013; hazard ratio [HR]: 2.80, 95%CI 1.24-6.61), and PBL decrease >200 × 10(6)/L after the first cycle of chemotherapy (p = 0.047; HR: 2.82, 95%CI 1.01-7.86) were significantly related to disease free survival. In multivariate analysis, both baseline PBL count less than 1500 × 10(6)/L (p = 0.034; HR: 3.32, 95%CI 1.09-10.02) and PBL decrease >200 × 10(6)/L after first cycle (p = 0.032; HR: 3.25, 95%CI 1.10-9.56) showed independent prognostic value for worse disease free survival. No effect was observed for overall survival. Our data support the relevance of pre- and post-chemotherapy PBL for breast cancer recurrence after neoadjuvant chemotherapy.     

25 hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis

It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis.MethodsWe included 120 postmenopausal osteoporotic women (aged 68 ± 8 years) receiving BP (alendronate or risedronate) at their annual follow-up, performing complete anamnesis, including treatment adherence, use of vitamin D supplements, and previous falls and fractures during the last year. We analyzed the evolution of bone mineral density (BMD) during this period and serum PTH and 25 hydroxyvitamin D (25(OH)D) and urinary NTx levels. Patients were classified as inadequate responders to antiosteoporotic treatment based on BMD loss > 2% and/or the presence of fragility fractures during the last year.ResultsThirty percent of patients showed inadequate response to BP treatment, with significantly lower levels of 25(OH)D (22.4 ± 1.3 vs. 26.6 ± 0.3 ng/ml, p = 0.01), a higher frequency of 25(OH)D levels < 30 ng/ml (91% vs. 69%, p = 0.019) and higher urinary NTx values (42.2 ± 3.9 vs. 30.9 ± 2.3 nM/mM, p = 0.01). Patients with 25(OH)D > 30 ng/ml had a greater significant increase in lumbar BMD than women with values < 30 ng/ml (3.6% vs. 0.8%, p < 0.05). The probability of inadequate response was 4-fold higher in patients with 25(OH)D < 30 (OR, 4.42; 95% CI, 1.22–15.97, p = 0.02).ConclusionsInadequate response to BP treatment is frequent in postmenopausal women with osteoporosis as is vitamin D insufficiency, despite vitamin D supplementation. Maintenance of 25(OH)D levels > 30 ng/ml is especially indicated for adequate response to BP treatment.     

Diffuse Axonal Injury (DAI) is not Associated with Elevated Intracranial Pressure (ICP)

Summary Objective. Traditionally, intracranial pressure (ICP) monitoring has been utilized in all patients with severe head injury (Glasgow coma score of 3–8). Ventriculostomy placement, however, does carry a 4 to 10 percent complication rate consisting mostly of hematoma and infection. The authors propose that a subgroup of patients presenting with severe head trauma and diffuse axonal injury without associated mass lesion, do not need ICP monitoring. Additionally, the monitoring data from ICP, MAP, and CPP for a comparison severe head injury group, and subgroups of DAI would be presented. Materials and methods. Thirty-six patients sustaining blunt head trauma and fitting our strict clinical and radiographic diagnosis of DAI were enrolled in our study. Inclusion criteria were severe head injury patients who did not regain consciousness after the initial impact, and whose CT scan demonstrated characteristic punctate hemorrhages of <10 mm diameter at the greywhite junction, basal ganglia, corpus callosum, upper brainstem, or a combination of the above. Patients with significant mass lesions and documented anoxia were excluded. Their intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were compared to a control group of 36 consecutive patients with severe non-penetrating non-operative head injury, using the Analysis for Variance method. Results. Eighteen (50.0%), six (16.7%), and twelve (33.3%) patients had types I, II, and III DAI, respectively. The admission Glasgow Coma Score (GCS) was higher for types I and II than for type III DAI. ICP was monitored from 23 to 165 hours, with a mean ICP for 36 patients of 11.70 mmHg (SEM=75) and a range from 4.3 to 17.3 mmHg. Of all ICP recordings, of which 89.7% (2421/2698) were ≤20 mmHg. Average mean arterial pressure (MAP) was 96.08 mmHg (SEM=1.69), and 94.6% (2038/2154) of all MAP readings were greater than 80 mmHg. Average cerebral perfusion pressure (CPP) was 85.16 mmHg (SEM=1.68), and 90.1% (1941/2154) of all CPP readings were greater than 70 mmHg. This is compared to the control group mean ICP, MAP, and CPP of 16.84 mmHg (p=0.000021), 92.80 mmHg (p=0.18), and 76.49 mmHg (p=0.0012). No treatment for sustained elevated ICP>20 mmHg was needed for DAI patients except in two; one with extensive intraventricular and subarachnoid hemorrhage who developed communicating hydrocephalus, and another with ventriculitis requiring intrathecal and intravenous antibiotic treatments. Two complications, one from a catheter tract hematoma, and another with Staph epidermidis ventriculitis, were encountered. All patients, except type III DAI, generally demonstrated marked clinical improvement with time. The outcome, as measured by Glasgow Coma Score (GCS) and Glasgow Outcome Score (GOS) was similarly better with types I and II than type III DAI. Conclusion. The authors conclude that ICP elevation in DAI patients without associated mass lesions is not as prevalent as other severe head injured patients, therefore ICP monitoring may not be as critical. The presence of an ICP monitoring device may contribute to increased morbidity. Of key importance, however, is an accurate clinical history and interpretation of the CT scan.     

Treatment of Bowen's disease of the penis with imiquimod 5% cream

We present an alternative treatment of the intraepithelial neoplasms of penis (Bowen's disease), the topical application of imiquimod 5% cream. It was applied 3 times weekly for 5 weeks. Imiquimod is an imidazoquinolone immune response modifier that has been shown to have indirect antiviral and antitumor effects with few adverse effects. Imiquimod 5% cream may represent an alternative treatment option for Bowen's disease.