Provider Attitudes toward Standardized Clinical Assessment and Management Plans (SCAMPs)

Introduction. Despite the growing importance of clinical guidelines, their adoption has encountered significant resistance among clinicians. We developed Standardized Clinical Assessment and Management Plans (SCAMPs) as an innovative, clinician‐led approach to building, implementing, and constantly improving flexible guidelines. We hypothesized that SCAMPs would fit well within the culture of medicine and that clinicians would therefore prefer SCAMPs over other guidelines. Methods. We implemented an anonymous, computer‐based survey to analyze provider attitudes toward SCAMPs at our institution. Results. Sixty‐nine providers completed the questionnaire (73% response rate). Most providers reported a positive opinion about SCAMPs along axes of overall familiarity (83%), trust (91–94%), utility (75–87%), and overall attitude (64%). Fewer providers felt familiar with the SCAMP improvement process (60% neutral to unfamiliar) or knew that they played a role in this process (62% said no or unsure). Sixty‐five percent reported experiencing an erosion in their autonomy with SCAMPs; when comparing this to other guidelines, 38% said other guidelines erode more, 26% felt SCAMPs erode more, and 36% were neutral. The plurality of providers chose SCAMPs as their preferred means to incorporate evidence‐based medicine into their practice (46% vs 29% for clinical practice guidelines, 25% for other guidelines). Conclusion. Providers look upon SCAMPs favorably and believe that SCAMPs successfully address numerous barriers to guideline adoption. Furthermore, SCAMPs are the preferred means to incorporate evidence‐based medicine into practice among providers surveyed. SCAMPs may represent an important step in building guidelines that fit into the culture of medicine, obtain clinician “buy‐in,” and better influence clinical decision making.     

Characterization of a whole,inactivated influenza (H5N1) vaccine

Objectives Effective vaccines against the highly pathogenic influenza A/H5N1 virus are being developed worldwide. In Japan, two adjuvanted, inactivated, whole‐virion influenza vaccines were recently developed and licensed as mock‐up, pre‐pandemic vaccine formulations by the Ministry of Health and Labor Welfare of Japan. During the vaccine design and development process, various obstacles were overcome and, in this report, we introduce the non clinical production, immunogenicity data in human and development process that was associated with egg‐derived adjuvanted, inactivated, whole‐virion influenza A (H5N1) vaccine. Design Pilot lots of H5N1 vaccine were produced using the avirulent H5N1 reference strain A/Vietnam/1194/2004 (H5N1) NIBRG‐14 and administered following adsorption with aluminum hydroxide as an adjuvant. Quality control and formulation stability tests were performed before clinical trials were initiated (phase I‐III).
The research foundation for microbial diseases of Osaka University (BIKEN) carried out vaccine production, quality control, stability testing and the phase I clinical trial in addition to overseeing the licensing of this vaccine. Mitsubishi Chemical Safety Institute Ltd. carried out the non clinical pharmacological toxicity and safety studies and the Japanese medical association carried out the phase II/III trials. Phase I‐III trials took place in 2006. Results The production processes were well controlled by established tests and validations. Vaccine quality was confirmed by quality control, stability and pre‐clinical tests, and the vaccine was approved as a mock‐up, pre‐pandemic vaccine by the Ministry of Health and Labor Welfare of Japan. Conclusions Numerous safety and efficacy procedures were carried out prior to the approval of the described vaccine formulation. Some of these procedures were of particular importance e.g., vaccine development, validation, and quality control tests that included strict monitoring of the hemagglutinin (HA) content of the vaccine formulations.
Improving vaccine productivity, shortening the production period and improving antigen yield of the avirulent vaccine strains were also considered important vaccine development criteria.     

(Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid protects rats from CCl(4) -induced liver injury

Background and Aim: (Z)2‐(5‐(4‐methoxybenzylidene)‐2, 4‐dioxothiazolidin‐3‐yl) acetic acid (MDA) is an aldose reductase (AR) inhibitor. Recent studies suggest that AR contributes to the pathogenesis of inflammation by affecting the nuclear factor κB (NF‐κB)‐dependent expression of cytokines and chemokines and therefore could be a novel therapeutic target for inflammatory pathology. The current study evaluated the in vivo role of MDA in protecting the liver against injury and fibrogenesis caused by CCl₄ in rats, and the underlying mechanisms. Methods: A single injection of CCl₄ induced acute hepatitis, and repeated injections were used to induce hepatic fibrosis in rats. Therapeutic efficacy was assessed by comparison of the severity of hepatic injury and fibrosis in MDA ‐ treated rats versus untreated controls. Results: MDA significantly protected the liver from injury by reducing the activity of serum alanine aminotransferase, and improving the histological architecture of the liver. MDA modulated NF‐κB‐dependent activation of inflammatory cytokines by reducing hepatic mRNA levels of tumor necrosis factor‐α, interleukin‐1β, inducible nitric oxide (NO) synthase and transforming growth factor‐β. In addition, MDA attenuated oxidative stress by increasing the content of hepatic glutathione. These favorable changes were associated with suppressed hepatic NF‐κB activation by MDA. MDA treatment improved liver fibrosis in rats that received repeated CCl₄ injections. In vitro, MDA attenuated phosphorylation of IκB and activation of NF‐κB, and thus prevented biosynthesis of NO in lipopolysaccharide‐activated RAW264.7 cells. Conclusions: The present study suggests that AR is a novel therapeutic anti‐inflammatory target for the treatment of hepatitis and liver fibrosis.     

Consensus on the diagnosis and treatment of hepatic fibrosis (2019)

Hepatic fibrosis is a reparative response of diffuse over‐deposition and abnormal distribution of extracellular matrix (collagen, glycoprotein and proteoglycans) after exposure to various kinds of liver injuries, and is a key step in the developmental process of various chronic liver diseases leading to cirrhosis. Recently, many advances in our understanding of hepatic fibrosis have been obtained through basic and clinical research. Therefore, this consensus summarizes and offers 15 evidence‐based recommendations on the diagnosis and evaluation of hepatic fibrosis, its treatment, drug development and applications.     

Neurophysiological profiles of replicate line 2 high-alcohol-drinking (HAD-2) and low-alcohol-drinking (LAD-2) rats

Rationale A select number of electrophysiological findings have been demonstrated to differentiate rat lines selectively bred for high and low ethanol preference. Objective In the present study, EEGs and event‐related potentials (ERPs) of high‐alcohol‐drinking (HAD) and low‐alcohol‐drinking (LAD) rats from replicate line 2 (HAD‐2 and LAD‐2) were assessed to determine if their neurophysiological profiles are similar to selected lines previously evaluated. Methods Rats obtained from Indiana University were implanted with cortical and amygdalar recording electrodes. Baseline EEG and ERPs were assessed in ethanol‐naïve HAD‐2 and LAD‐2 rats. Animals subsequently were trained to self‐administer ethanol by using a sucrose‐substitution procedure. Results Compared with LAD‐2 rats, HAD‐2 rats displayed greater parietal cortical power in the 6 to 32 Hz frequency range of the EEG. Greater parietal cortical peak frequency in the 2 to 4 Hz range and decreased frontal, parietal, and amygdalar peak frequencies in the 16 to 32 Hz frequency range were also seen. Compared with LAD‐2 rats, HAD‐2 rats had decreased P2 latency of ERPs recorded in the parietal cortex. HAD‐2 rats also had greater frontal, parietal, and amygdalar P2 amplitudes, greater frontal and parietal cortical P1 amplitudes, and greater parietal cortical P3 amplitudes compared with LAD‐2 rats. As anticipated, HAD‐2 rats consumed significantly greater levels of sucrose, sucrose‐ethanol, and ethanol over the course of the sucrose‐substitution procedure compared with LAD‐2 rats. Conclusions These data suggest that increased cortical power is associated with high ethanol preference in a number of selectively bred rat lines. However, unique electrophysiological characteristics may index alcohol preference in each line.     

Serum Th1 (CXCL10) and Th2 (CCL2) chemokine levels in children with newly diagnosed Type 1 diabetes: a longitudinal study

Aims Cell‐mediated immunity and pro‐inflammatory cytokines are implicated in the pathogenesis of Type 1 diabetes. The aim of this study was to investigate whether circulating chemokines involved in T‐helper 1 (CXCL10) and T‐helper 2 (CCL2) autoimmunity are increased in children with Type 1 diabetes at onset and follow‐up. Methods Serum CXCL10 and CCL2 were measured in 96 children with newly diagnosed Type 1 diabetes, 59 age‐matched first‐degree relatives of diabetic children and 40 age‐matched non‐diabetic children with no family history of diabetes. In the diabetic children, an additional serum sample was obtained a median of 16 months after diagnosis. Results Serum CXCL10 levels were significantly higher in Type 1 children than in relatives or control children (P < 0.001); 44.7% of patients had a serum CXCL10 level ≥ 2 standard deviation above the mean value of the control group vs. 3.4% of relatives (P < 0.0001). In contrast, serum CCL2 levels were similar in patients, relatives and control subjects. In the Type 1 diabetic patients at follow‐up, CXCL10 was significantly reduced vs. baseline (P = 0.01), while CCL2 did not change. Conclusions In children with newly diagnosed Type 1 diabetes, raised serum CXCL10 and normal CCL2 concentrations signal a predominant T‐helper 1‐driven autoimmune process, which shifts toward T‐helper 2 immunity over the first 1–2 years from diagnosis.     

Gem-(R)CHOP versus (R)CHOP: a randomized phase II study of gemcitabine combined with (R)CHOP in untreated aggressive non-Hodgkin's lymphoma--EORTC lymphoma group protocol 20021 (EudraCT number 2004-004635-54)

Background: Despite recent improvements, many patients with aggressive non‐Hodgkin’s lymphoma (NHL) ultimately succumb to their disease. Therefore, improvements in front‐line chemotherapy of aggressive NHL are needed. Gemcitabine is active in lymphoma. Methods: We performed a randomized phase II trial of the addition of gemcitabine to standard CHOP chemotherapy with or without rituximab [(R)CHOP]. The trial was also designed to determine the maximal tolerated dose (MTD) of gemcitabine in this combination. Patients with previously untreated aggressive NHL were randomized to receive either eight cycles of (R)CHOP given every 3 wk or (R)CHOP combined with gemcitabine [Gem‐(R)CHOP]. Results: Twenty‐five patients were enrolled in the trial before early closure. Twelve were randomized to Gem‐(R)CHOP and 13 to (R)CHOP. MTD of gemcitabine was 800 mg/m² given on days 1 and 8; dose‐limiting toxicity was hematologic. Five patients (42%) treated with Gem‐(R)CHOP achieved complete response in comparison with 10 (77%) treated with (R)CHOP. Median time to treatment failure was 1.5 yr for Gem‐(R)CHOP and 3.1 yr for (R)CHOP. Three patients receiving Gem‐(R)CHOP had serious pulmonary toxicity, when compared to none receiving (R)CHOP. One patient died of pneumonitis. Conclusions: In this group of patients, addition of gemcitabine did not seem to improve outcomes. Gem‐(R)CHOP in previously untreated patients with aggressive NHL occasionally results in severe, potentially fatal, pulmonary toxicity.     

Somatic hypermutation and V(H) gene usage in mantle cell lymphoma

Abstract: Mantle cell lymphoma (MCL) is considered to derive from naïve, pregerminal center (GC) CD5⁺ B‐cells. However, the cell of origin has been questioned in recent studies that showed somatic hypermutations in the immunoglobulin (Ig) variable heavy chain (V_H) genes in subsets of MCL. To clarify this issue, we analyzed the IgV_H genes for the presence of somatic hypermutations in 51 MCL cases. Twenty percent of the MCL cases displayed somatically mutated V_H genes (defined as >2% mutated), whereas 80% showed unmutated V_H genes. This finding suggests that MCL is a genetically heterogeneous disease, with the majority of cases originating from unmutated pre‐GC B‐cells and a subset deriving from more mature B‐cells which have been exposed to the GC environment and have undergone somatic hypermutation. A biased V_H gene usage has been demonstrated in several B‐cell malignancies; however, this has not yet been investigated in MCL, although V_H4‐34 overusage has been indicated by small studies. Interestingly, we found a restricted usage of three individual V_H genes in our MCL material; V_H4‐34 (22%), V_H3‐21 (16%) and V_H5‐51 (12%). This novel finding of preferential V_H gene usage in half of the MCL cases may suggest an antigen driven process occurring in B‐cells expressing specific V_H genes, thus implicating that Ig specificity could be involved in mantle cell lymphoma development.     

Enhanced high‐mobility group box 1 (HMGB1) modulates regulatory T cells (Treg)/T helper 17 (Th17) balance via toll‐like receptor (TLR)‐4‐interleukin (IL)‐6 pathway in patients with chronic hepatitis B

High‐mobility group box 1 (HMGB1) proteins are substantially up‐regulated in acute and chronic hepatitis. However, the immunopathogenic role of HMGB1 in patients with chronic hepatitis B (CHB) has not been elucidated. In this study, using a cohort of 36 CHB patients, we demonstrated a crucial role for HMGB1 to modulate balance between regulatory T (Treg) and T helper 17 (Th17) cells via the toll‐like receptor (TLR)‐4‐interleukin (IL)‐6 pathway. Serum HMGB1 levels were dramatically higher in CHB patients and increased along with liver injury, inflammation and fibrosis. Notably, HMGB1 increased along with decreased Treg/Th17 cells ratios in the periphery or intrahepatic microenvironment, which provides a clue for HMGB1 to favour Th17 responses whereas inhibit Treg responses. For in vitro studies, serum pools were constructed with serum from CHB patients at an advanced stage, whereas peripheral blood mononuclear cells (PBMC) pools were constructed with cells from those at an early stage. CHB‐serum significantly enhanced retinoic acid‐related orphan receptor‐γt (RORγt), whereas they inhibited forkhead box P3 (Foxp3) expression in CHB‐PBMC, which could be reversed by blocking of HMGB1, TLR4, or IL‐6. Besides, recombinant HMGB1 (rHMGB1) dose‐dependently up‐regulated RORγt whereas down‐regulated Foxp3 expression in CHB‐PBMC, and meanwhile, rHMGB1 enhanced TLR4 and IL‐6 expression in CHB‐PBMC. Moreover, the axis of HMGB1–TLR4‐IL‐6–Treg/Th17 required noncontact interactions between CD4 and non‐CD4 cells. In addition, rHMGB1 down‐regulated anti‐inflammatory proteins on CD4⁺CD25⁺ cells whereas up‐regulated pro‐inflammatory cytokines in CD4⁺CD25⁻ cells. In summary, enriched HMGB1 in CHB patients shifts Treg/Th17 balance to Th17 dominance via the TLR4‐IL‐6 pathway, which exacerbates liver injury and inflammation.     

Melatonin regulates PARP1 to control the senescence‐associated secretory phenotype (SASP) in human fetal lung fibroblast cells

Cellular senescence is an important tumor‐suppressive mechanism. However, acquisition of a senescence‐associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene‐induced senescence (OIS). Moreover, poly(ADP‐ribose) polymerase‐1 (PARP‐1), a sensor of DNA damage, was identified as a new melatonin‐dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat‐containing RNA (TERRA) and PARP‐1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP‐1 recruits CREB‐binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP‐1 in suppression of SASP gene expression in OIS‐induced senescent cells. Our studies identify melatonin as a novel anti‐SASP molecule, define PARP‐1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP‐1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.     

Incidence of atrial arrhythmias detected by permanent pacemakers (PPM) post-pulmonary vein antrum isolation (PVAI) for atrial fibrillation (AF): correlation with symptomatic recurrence

Background: Studies examining AF recurrences post‐PVAI base recurrence on patient reporting of symptoms. However, whether asymptomatic recurrences are common is not well known. Objective: To assess the incidence of atrial tachycardia/fibrillation post‐PVAI as detected by a PPM and whether these recurrences correlate to symptomatic recurrence. Methods: Eighty‐six consecutive patients with symptomatic AF and PPMs with programmable mode‐switch capability underwent PVAI. Mode switching was programmed post‐PVAI to occur at an atrial‐sensed rate of >170 bpm. Patients were followed with clinic visits, ECG, and PPM interrogation at 1, 3, 6, and 9 months post‐PVAI. The number and duration of mode‐switching episodes (MSEs) were recorded at each visit and is presented as median (interquartile range). Results: The patients (age 57 ± 8 years, EF 54 ± 10%) had paroxysmal (65%) and persistent (35%) AF pre‐PVAI. Sensing, pacing, and lead function were normal for all PPMs at follow‐up. Of the 86 patients, 20 (23%) had AF recurrence based on symptoms. All 20 of these patients had appropriate MSEs detected. Of the 66 patients without symptomatic recurrence, 21 (32%) had MSEs detected. In 19 of these patients, MSEs were few in number, compared with patients with symptomatic recurrence (16 [4–256] vs 401 [151–2,470], P < 0.01). The durations were all <60 seconds. All of these nonsustained MSEs occurred within the first 3 months post‐PVAI, gradually decreasing over time. The other 2 of 21 remaining patients had numerous (1,343 [857–1,390]) and sustained (18 ± 12 minutes) MSEs that also persisted beyond 3 months (1 beyond 6 months). Therefore, the incidence of numerous, sustained MSEs in asymptomatic patients post‐PVAI was 2 of 66 (3%). Conclusions: Detection of atrial tachyarrhythmias by a PPM occurred in 30% of patients without symptomatic AF recurrence. Most of these episodes were <60 seconds and waned within 3 months. Sustained, asymptomatic episodes were uncommon.     

Clarithromycin (Biaxin)‐lenalidomide‐low‐dose dexamethasone (BiRd) versus lenalidomide‐low‐dose dexamethasone (Rd) for newly diagnosed myeloma

The objective of this case‐matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low‐dose dexamethasone (BiRd) vs. lenalidomide/low‐dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital‐Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention‐to‐treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very‐good‐partial‐response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time‐to‐progression (median 48.3 vs. 27.5 months, P = 0.071), and progression‐free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3‐year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3–4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case‐matchedanalysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS‐4 (aggrecanase 1) or ADAMTS‐5 (aggrecanase 2)

Objective

To determine whether aggrecanase (ADAMTS) activities in articular cartilage can directly lead to the release of hyaluronan (HA) and hyaladherins (aggrecan G1 domain and link proteins), as may occur ex vivo during stimulation of cartilage explants with interleukin‐1 (IL‐1) or retinoic acid or in vivo in synovial joints during aging and joint pathology.

Methods

Bovine articular cartilage discs (live or freeze‐killed) were cultured in the presence of IL‐1 or were incubated in digestion buffer containing recombinant human ADAMTS‐4 (rHuADAMTS‐4; aggrecanase 1) or rHuADAMTS‐5 (aggrecanase 2). Culture media, digestion supernatants, and tissue extracts were assayed for sulfated glycosaminoglycan (sGAG) content and analyzed by Western blotting to detect aggrecanase‐generated G1 domain (using neoepitope monoclonal antibody AGG‐C1/anti‐NITEGE³⁷³) and link proteins (using monoclonal antibody 8‐A‐4), as well as by quantitative enzyme‐linked immunosorbent assays to detect aggrecanase‐generated G1 domain (G1‐NITEGE³⁷³) and HA.

Results

IL‐1 treatment of live cartilage explants induced a time‐dependent release of sGAG, aggrecanase‐generated G1 domain (G1‐NITEGE³⁷³), and HA into the culture media. Exposure of live or freeze‐killed articular cartilage discs to rHuADAMTS‐4 or rHuADAMTS‐5 resulted in a dose‐ and time‐dependent release of sGAG and hyaluronan from the tissue, accompanied by a concomitant release of functionally intact hyaladherins (aggrecan G1‐NITEGE³⁷³ and link proteins).

Conclusion

Coincident with aggrecanolysis, aggrecanase activities in articular cartilage may actuate the release of HA and associated hyaladherins, thereby further compromising the integrity of the cartilage matrix during degenerative joint diseases such as osteoarthritis.

     

The Bruton tyrosine kinase (BTK) inhibitor PCI‐32765 synergistically increases proteasome inhibitor activity in diffuse large‐B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib

Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI‐32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large‐B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co‐administration of PCI‐32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre‐ or activated B‐cell‐like‐DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)‐κB (NFKB1) inactivation, down‐regulation of Mcl‐1 (MCL1), Bcl‐xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib‐resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI‐32765/bortezomib regimens displayed minimal toxicity toward normal CD34⁺ bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF‐κB “super‐repressor” (IκBα_ser34/36) increased both PCI‐32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant‐negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI‐32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI‐32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies.     

Human papillomavirus (HPV) infection and the risk of esophageal squamous cell carcinoma

There is currently no consensus on the relationship between human papillomavirus (HPV) infection and the pathogenic process of esophageal squamous cell carcinoma (ESCC). Therefore, a retrospective study was performed to explore the association between HPV infection and ESCC, where 225 patients with diagnosed ESCC and 224 matched controls were enrolled in the study and stratified according to smoking and alcohol consumption. Enzyme‐linked immunosorbent assay was used to determine seropositivity to HPV by the detection of either IgG or IgM anti‐HPV antibodies. In the non‐smoking and non‐alcohol‐consuming subgroup, the incidence of ESCC of HPV seropositive subjects was similar with that of HPV seronegative subjects (P= 0.737, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.54–2.40). However, in the smoking subgroup, there was a significant difference in the incidence of ESCC between HPV seropositive subjects and HPV seronegative subjects (P= 0.009, OR 2.22, 95% CI 1.22–4.04). In addition, there was a significantly higher association of the development of ESCC in HPV seropositive patients that smoke and drink than those that do not (P < 0.001, OR 10.31, 95% CI 4.04–26.29). Therefore, HPV infection is not an independent risk factor for developing ESCC in the non‐smoking and non‐alcohol‐consuming group. For smokers, however, HPV infection increases the risk of the incidence of ESCC.     

Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection

The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross‐sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti‐HIV‐negative patients (71 males; median age 49.8 [21.7‐66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV‐DNA, HBcrAg, total anti‐HBc, HDV‐RNA, IgM and total anti‐HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti‐HBc/IgM anti‐HDV ratio (OR 0.990, 95% CI 0.981‐0.999, P = .038), whereas disease activity was associated with higher total anti‐HDV (OR 10.105, 95% CI 1.671‐61.107, P = .012) and HDV‐RNA levels (OR 2.366, 95% CI 1.456‐3.844, P = .001). HDV‐RNA serum levels showed a positive correlation with HBV‐DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV‐RNA, IgM anti‐HDV, total anti‐HDV, total anti‐HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.     

A randomized controlled trial comparing two vaso‐occlusive episode (VOE) protocols in sickle cell disease (SCD)

Limited evidence guides opioid dosing strategies for acute Sickle Cell (SCD) pain. We compared two National Heart, Lung and Blood (NHBLI) recommended opioid dosing strategies (weight‐based vs. patient‐specific) for ED treatment of acute vaso‐occlusive episodes (VOE). A prospective randomized controlled trial (RCT) was conducted in two ED's. Adults ≥ 21 years of age with SCD disease were eligible. Among the 155 eligible patients, 106 consented and 52 had eligible visits. Patients were pre‐enrolled in the outpatient setting and randomized to one of two opioid dosing strategies for a future ED visit. ED providers accessed protocols through the electronic medical record. Change in pain score (0‐100 mm VAS) from arrival to ED disposition, as well as side effects were assessed. 52 patients (median age was 27 years, 42% were female, and 89% black) had one or more ED visits for a VOE (total of 126 ED study visits, up to 5 visits/patient were included). Participants randomized to the patient‐specific protocol experienced a mean reduction in pain score that was 16.6 points greater than patients randomized to the weight‐based group (mean difference 95% CI = 11.3 to 21.9, P = 0.03). Naloxone was not required for either protocol and nausea and/or vomiting was observed less often in the patient‐specific protocol (25.8% vs 59.4%, P = 0.0001). The hospital admission rate for VOE was lower for patients in the patient‐specific protocol (40.3% vs 57.8% P = 0.05). NHLBI guideline‐based analgesia with patient‐specific opioid dosing resulted in greater improvements in the pain experience compared to a weight‐based strategy, without increased side effects.     

Comparative analysis of Bayer wide-range C-reactive protein (wr-CRP) and the Dade-Behring high sensitivity C-reactive protein (hs-CRP) in patients with inflammatory bowel disease

OBJECTIVE: The recently introduced Bayer wide‐range C‐reactive protein (wr‐CRP) assay might be relevant for the real‐time low‐cost and online determination of inflammatory bowel disease (IBD) activity. Our aim was to examine whether wr‐CRP can substitute for the Dade Behring high sensitivity C‐reactive protein (hs‐CRP) assay in IBD patients. METHODS: A total of 71 patients with IBD, of whom 48 had Crohn's disease CD and 23 had ulcerative colitis (UC) with various intensities of disease activity participated in the study. The CRP of patients who were under treatment at the Department of Gastroenterology and Liver Diseases were measured using both wr‐CRP and the hs‐CRP. RESULTS: A significant (r = 0.995; P < 0.001) correlation was noted between the hs‐CRP and wr‐CRP measurements for the whole sample as well as for the two diseases, CD (r = 0.994; P < 0.001) and UC (r = 0.997; P < 0.001), which were analyzed separately. CONCLUSION: The Bayer wr‐CRP assay might be a useful low‐cost and real‐time inflammation‐sensitive biomarker in patients with IBD.     

Chronic lymphocytic leukemia (CLL)—Then and now

The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO‐1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo‐immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kδ inhibitor) and novel anti‐CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT‐199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. Am. J. Hematol. 91:330–340, 2016. © 2015 Wiley Periodicals, Inc.