What the HEC? Clinician Adherence to Evidence-Based Antiemetic Prophylaxis for Highly Emetogenic Chemotherapy.

BACKGROUND: Clinician adherence to antiemetic guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) caused by highly emetogenic chemotherapy (HEC) remains poorly characterized. The primary aim of this study was to evaluate individual clinician adherence to HEC antiemetic guidelines. PATIENTS AND METHODS: A retrospective analysis of patients receiving HEC was conducted using the IBM Watson Explorys Electronic Health Record Database (2012-2018). HEC antiemetic guideline adherence was defined as prescription of triple prophylaxis (neurokinin-1 receptor antagonist [NK1 RA], serotonin type-3 receptor antagonist, dexamethasone) at initiation of cisplatin or anthracycline + cyclophosphamide (AC). Clinicians who prescribed ≥5 HEC courses were included and individual guideline adherence was assessed, noting the number of prescribing clinicians with >90% adherence. RESULTS: A total of 217 clinicians were identified who prescribed 2,543 cisplatin and 1,490 AC courses. Patients (N=4,033) were primarily women (63.3%) and chemotherapy-naïve (92%) with a mean age of 58.6 years. Breast (36%) and thoracic (19%) cancers were the most common tumor types. Guideline adherence rates of >90% were achieved by 35% and 58% of clinicians using cisplatin or AC, respectively. Omission of an NK1 RA was the most common practice of nonadherence. Variation in prophylaxis guideline adherence was considerable for cisplatin (mean, 71%; SD, 29%; coefficient of variation [CV], 0.40) and AC (mean, 84%; SD, 26%; CV, 0.31). CONCLUSIONS: Findings showed substantial gaps in clinician adherence to HEC CINV guidelines, including a high variability across clinicians. Clinicians should review their individual clinical practices and ensure adherence to evidence-based CINV guidelines to optimize patient care.

Palonosetron plus single-dose dexamethasone for the prevention of nausea and vomiting in women receiving anthracycline/cyclophosphamide-containing chemotherapy: meta-analysis of individual patient data examining the effect of age on outcome in two phase III trials.

PURPOSE: Data from two randomized trials, evaluating a single-day regimen of palonosetron plus dexamethasone against emesis due to moderately emetogenic chemotherapy, were assessed for the impact of age on outcome in a pooled sample of women receiving anthracycline and/or cyclophosphamide (AC)-containing chemotherapy. METHODS: Chemo-naïve breast cancer patients randomized to receive palonosetron (0.25 mg) plus dexamethasone (8 mg IV) on day 1 of chemotherapy (n = 200), or the same regimen followed by oral dexamethasone (8 mg) on days 2 and 3 (n = 205), were included in the analysis. The primary endpoint was complete response (CR: no vomiting and no rescue anti-emetics) in the 5-day study period. The effect of the 1-day regimen and age (<50 and ≥ 50 years) was investigated by a meta-analysis of individual patient data. RESULTS: Younger patients comprised 43 % and 49 % of the 1-day and 3-day regimen groups, respectively; 94 % of the pooled sample received the AC combination. There were no between-treatment differences in CR rate according to age during all observation periods. In the 1-day regimen group, 55.2 % of younger patients achieved overall CR compared with 54 % of older patients. In the 3-day regimen group, 51.5 % of younger patients achieved overall CR compared with 58.7 % of older patients. In the adjusted analysis, younger age was not associated with overall CR to treatment (risk difference, -3.1 %; 95 % CI, -13.0 to 6.7 %; P = 0.533). CONCLUSIONS: These results provide evidence that, irrespective of age, the dexamethasone-sparing regimen is not associated with a significant loss in overall anti-emetic protection in women undergoing AC-containing chemotherapy.

"No distinction of Black or Fair": The Natural History of Race in Adam Ferguson's Lectures on Moral Philosophy.

Recent scholarship on the Scottish Enlightenment has emphasized the increasing importance, in the last decades of the eighteenth century, of the concept of race. Yet race was a conceptual, moral, and taxonomic puzzle for Scots intellectuals such as Adam Ferguson (1723-1816). While the influence of Ferguson's published works has received wide scholarly attention, the content of his teaching has not. His surviving moral philosophy lecture notes offer us a window into the development of thought on race at the disciplinary intersections of moral philosophy and natural history, and the crossroads of Edinburgh's curricula and Britain's Empire.

Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming.

Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7-/- DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor necrosis factor that conditioned the tissue for increased DC migration. These results indicate that DC number and tissue inflammation are critical parameters for DC-based vaccination.

The antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses in vitro and in vivo.

Palonosetron is the only 5-HT(3) receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT(3) cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT(3) receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.

Transforming Breast Cancer Together: European elections manifesto 2019 seizing the opportunities for breast cancer patients.

With the European Parliament elections having taken place in May 2019 and a new European Commission (EC) taking office in November 2019, this year is critical for European policymakers, as goals and priorities of the European Union (EU) for the next five years will be discussed and agreed upon. This Manifesto issued by the Transforming Breast Cancer Together initiative calls upon policymakers to improve services for patients in an area still of high unmet need and reduce the societal impact of breast cancer by elevating it as a health policy priority to improve breast cancer prevention, diagnosis and care across Europe.

Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor.

BACKGROUND: Palonosetron is a 5-HT(3)-receptor antagonist (5-HT(3)-RA) that has been shown to be superior to other 5-HT(3)-RAs in phase III clinical trials for the prevention of acute, delayed, and overall chemotherapy-induced nausea and vomiting. The improved clinical efficacy of palonosetron may be due, in part, to its more potent binding and longer half-life. However, these attributes alone are not sufficient to explain the results with palonosetron. We sought to elucidate additional differences among 5-HT(3)-RAs that could help explain the observations in the clinic. METHODS: Receptor site saturation binding experiments were performed with [3H] palonosetron, [3H] granisetron, and [3H] ondansetron to obtain the corresponding Scatchard analyses and Hill coefficients. Diagnostic equilibrium binding experiments and kinetic dissociation experiments were conducted to examine competitive versus potential allosteric interactions between ondansetron, granisetron and palonosetron and the 5-HT(3) receptor. Finally, the long-term effect of the three antagonists on receptor function as measured by Ca2+ influx in HEK 293 cells expressing the 5-HT(3)-receptor was compared. RESULTS: Analyses of binding isotherms using both Scatchard and Hill plots suggested positive cooperativity for palonosetron and simple bimolecular binding for both granisetron and ondansetron. Equilibrium diagnostic tests discriminated differential effects of palonosetron on [3H] ligand binding indicating that palonosetron was an allosteric antagonist whereas granisetron and ondansetron were competitive antagonists. Using dissociation rate strategies, palonosetron was shown to be an allosteric modifier that accelerated the rate of dissociation from the receptor of both granisetron and ondansetron. Differences in the binding mode of palonosetron to the 5-HT(3) receptor were shown to have an impact on receptor function. In these experiments, cells were incubated with each antagonist, followed by infinite dilutions and dissociation for 2.5 h; cells previously incubated with either granisetron or ondansetron showed calcium-ion influx similar to control cells that had not been exposed to a 5-HT(3) receptor antagonist. In contrast, substantial inhibition of calcium-ion influx was observed in cells that had been incubated with palonosetron. CONCLUSIONS: Palonosetron exhibited allosteric binding and positive cooperativity when binding to the 5-HT(3) receptor. Palonosetron also triggered functional effects that persisted beyond its binding to the 5-HT(3) receptor at the cell surface. Differences in binding and effects on receptor function may be relevant to the unique beneficial actions of palonosetron. To our knowledge, this is the first report showing palonosetron's interaction with the 5-HT(3) receptor at the molecular level, clearly differentiating it from other 5-HT(3)-RAs.

Nickel-specific CD4(+) and CD8(+) T cells display distinct migratory responses to chemokines produced during allergic contact dermatitis.

Development of allergic contact dermatitis to haptens depends upon a balance between CD8(+) T lymphocytes with pathogenic activity and CD4(+) T cells, which comprise both effector and regulatory cells. Thus, differential recruitment of CD8(+) and CD4(+) lymphocytes to sites of hapten challenge may have considerable impact on disease expression. Here the migration of cutaneous lymphocyte-associated antigen+, nickel-specific CD8(+) and CD4(+) T cell lines were compared with a panel of chemokines produced in the skin during allergic contact dermatitis. CCL17/TARC and CCL22/MDC induced a 3-fold higher migration of CD4(+) compared with CD8(+) lymphocytes. In contrast, CXCL10/IP-10 was 2-fold more potent in attracting CD8(+) cells. These findings were consistent with the higher expression of CCR4 and CXCR3 on CD4(+) and CD8(+) T cell lines, respectively. Moreover, CCR4 expression was high on nickel-specific T helper 2, intermediate on T helper 1 and T cytotoxic 2, and almost undetectable on T cytotoxic 1 clones. On the contrary, CXCR3 was expressed by T cytotoxic 1 and 2 and T helper 1, but not T helper 2 clones. Reverse transcription-polymerase chain reaction analysis of the skin before and after hapten challenge revealed the constitutive presence of TARC, and the early appearance of CCL2/MCP-1, followed by IP-10, CCL4/MIP-1beta, and MDC mRNA. Supernatants from activated keratinocytes induced a strong migration of CD8(+) lymphocytes, which was blocked by neutralization of IP-10. Conversely, supernatants from immature and mature dendritic cells attracted mostly CD4(+) lymphocytes in a TARC- and MDC-dependent manner. Our data indicate that distinct chemokines and cell types control the accumulation of CD8(+) and CD4(+) T cells within inflamed skin.

Activation of nickel-specific CD4+ T lymphocytes in the absence of professional antigen-presenting cells.

Allergic contact dermatitis ensues from exaggerated T cell responses to haptens. Dendritic cells are required for the initiation of hapten sensitization, but they may not be necessary for disease expression. Here we investigated the antigen-presenting cell requirement of nickel-specific CD4+ lymphocytes isolated from the blood of six allergic individuals. A significant proportion (42 out of 121; 35%) of the T cell clones proliferated in vitro to nickel also in the absence of professional antigen-presenting cells, suggesting a direct T-T hapten presentation. Antigen-presenting-cell-independent T cells showed a predominant T helper 1 phenotype. Nickel recognition by these T cells was major histocompatibility complex class II restricted, not influenced by CD28 triggering, independent from their state of activation, and did not require processing. The capacity of this T cell subset to be directly stimulated by nickel was not due to unique antigen-presenting properties, as both antigen-presenting-cell-dependent and antigen-presenting-cell-independent clones displayed comparable levels of HLA-DR, CD80, and CD86, and were equally capable of presenting nickel to antigen-presenting-cell-independent clones. In contrast, neither T cell types activated antigen-presenting-cell-dependent T lymphocytes. T-T presentation induced T cell receptor downregulation, CD25, CD80, CD86, and HLA-DR upregulation, and interferon-gamma release, although to a lesser extent compared to those induced by dendritic cell-T presentation. Following T-T presentation, the clones did not undergo unresponsiveness and maintained the capacity to respond to dendritic cells pulsed with antigen. In aggregate, our data suggest that antigen-presenting-cell-independent T cell activation can effectively amplify hapten- specific immune responses.

Immunoregulation of hapten and drug induced immune reactions.

PURPOSE OF REVIEW: Unbalanced immune responses to haptens lead to a variety of diseases, including allergic contact dermatitis to skin sensitizers and drug induced immune reactions. The occurrence, magnitude and persistence of immune responses are modulated by specialized T cell subsets with regulatory function. The purpose of this brief review is to summarize the recent data on the role of regulatory T cells in the control of hapten mediated diseases. RECENT FINDINGS: Several subsets of regulatory T cells, including T regulatory cell 1-like lymphocytes, and cutaneous lymphocyte associated antigen+ CD4+CD25+ regulatory T cells have been isolated from the skin at sites of hapten challenge. Both cell types suppress specific T cell responses to cutaneous sensitizers, such as nickel. SUMMARY: Although data concerning the regulation of drug hypersensitivity are lacking, several reports indicate the role of regulatory T cell subsets in allergic contact dermatitis to haptens. The understanding of their role in hapten diseases and the requirement for their in-vivo and in-vitro expansion appears as a critical step for the development of specific desensitization protocols.

The role of chemokines in allergic contact dermatitis.

Chemokines are important mediators of immune-mediated skin diseases. Allergic contact dermatitis (ACD) is the most thoroughly investigated T cell-mediated disorder because of the ability to easily reproduce the lesions in humans and the availability of an excellent mouse model. Migration of dendritic cells from the skin to lymph nodes is absolutely required for induction of hapten sensitization, and depends upon expression of CCR7 by mature dendritic cells and SLC in the lymph nodes. During expression of ACD, recruitment of T lymphocytes is driven by chemokines exposed on the surface of endothelial cells or released by activated resident skin cells such as mast cells, fibroblasts and keratinocytes. Chemokines are produced in a coordinated and sequential manner, with IL-8 and RANTES induced by TNF-alpha during early stages, and MCP-1, IP-10, Mig, I-TAC, I-309 and MDC induced by IFN-gamma during later stages. Infiltrating monocytes, dendritic cells and T cells are additional sources of chemokines for further leukocyte accumulation. Distinct T cell subsets express different chemokine receptors, with type 2 cells mostly attracted by eotaxin, MDC, TARC and I-309, and type 1 cells sensitive to IP-10, Mig, I-TAC, RANTES and MIP-1beta. MCP-1 is effective on both subsets. T regulatory cells, which inhibit dendritic cell function and are probably involved in the termination of ACD, are sensitive to MCP-1, MIPs and TARC, but express high levels of CCR8 and are more specifically attracted by I-309. Targeting chemokines and chemokine receptors may offer new opportunities for therapeutic interventions in ACD and other chronic inflammatory skin diseases.

Palonosetron triggers 5-HT(3) receptor internalization and causes prolonged inhibition of receptor function.

Palonosetron is a 5-HT(3) receptor antagonist that has demonstrated superiority in preventing both acute and delayed emesis when compared to older first generation 5-HT(3) receptor antagonists. The objective of this work was to determine if palonosetron exhibits unique molecular interactions with the 5-HT(3) receptor that could provide a scientific rationale for observed clinical efficacy differences. Previously, we showed that palonosetron exhibits allosteric binding and positive cooperativity to the 5-HT(3) receptor in contrast to ondansetron and granisetron which exhibit simple bimolecular binding. The present work shows, through several independent experiments, that palonosetron uniquely triggers 5-HT(3) receptor internalization and induces prolonged inhibition of receptor function. After 24h incubation followed by dissociation conditions, [(3)H]palonosetron remained associated with whole cells but not to cell-free membranes (P<0.001). [(3)H]Palonosetron's binding to cells was resistant to both protease and acid treatments designed to denature cell surface proteins suggesting that the receptor complex was inside the cells rather than at the surface. Cells pretreated with unlabeled palonosetron subsequently exhibited reduced cell surface 5-HT(3) receptor binding. Palonosetron-triggered receptor internalization was visualized by confocal fluorescence microscopy using cells transfected with 5-HT(3) receptor fused to enhanced cyan fluorescent protein. In contrast, granisetron and ondansetron showed minimal to no effect on receptor internalization or prolonged inhibition of receptor function. These experiments may provide a pharmacological basis for differences noted in published clinical trials comparing palonosetron to other 5-HT(3) receptor antagonists.

CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first beta-strand of chemokine.

In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first beta-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4(+) T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines.

A pre-tRNA carrying intron features typical of Archaea is spliced in yeast.

Archaeal pre-tRNAs are characterized by the presence of the bulge-helix-bulge (BHB) structure in the intron stem-and-loop region. A chimeric pre-tRNA was constructed bearing an intron of the archaeal type and the mature domain of the Saccharomyces cerevisiae suppressor SUP4 tRNA(Tyr). This pre-tRNA(ArchEuka) is correctly cleaved in several cell-free extracts and by purified splicing endonucleases. It is also cleaved and ligated in S. cerevisiae cells, providing efficient suppression of nonsense mutations in various genes.

A rich chemokine environment strongly enhances leukocyte migration and activities.

The migration of leukocytes in immune surveillance and inflammation is largely determined by their response to chemokines. While the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how leukocytes integrate the messages provided by different chemokines that are concomitantly produced in physiologic or pathologic situations in vivo. We present evidence for a novel regulatory mechanism of leukocyte trafficking. Our data are consistent with a mode of action where CC-chemokine receptor 7 (CCR7) agonists and unrelated, nonagonist chemokines first form a heteromeric complex, in the presence of which the triggering of CCR7 can occur at a much lower agonist concentration. The increase is synergistic and can be evoked by many but not all chemokines. Chemokine-induced synergism might provide an amplification system in "chemokine-rich" tissues, rendering leukocytes more competent to respond to migratory cues.

Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals.

We investigated the capacity of CD25(+) T regulatory cells (Treg) to modulate T cell responses to nickel, a common cause of allergic contact dermatitis. CD4(+) T cells isolated from the peripheral blood of six healthy, nonallergic individuals showed a limited capacity to proliferate in response to nickel in vitro, but responsiveness was strongly augmented (mean increment +/- SD, 240 +/- 60%) when cells were depleted of CD25(+) Treg. Although CD25(+) Treg were anergic to nickel, a small percentage up-regulated membrane CTLA-4 upon nickel exposure. CD25(+) Treg strongly and dose-dependently inhibited nickel-specific activation of CD25(-) T lymphocytes in coculture experiments in a cytokine-independent, but cell-to-cell contact-dependent, manner. Approximately 30% of circulating CD25(+) Treg expressed the cutaneous lymphocyte-associated Ag (CLA), and CLA(+)CD25(+) Treg were more efficient than CLA(-)CD25(+) cells in suppressing nickel responsiveness of CD25(-) T cells. The site of a negative patch test in response to nickel showed an infiltrate of CD4(+)CLA(+) cells and CD25(+) cells, which accounted for approximately 20% of the total T cells isolated from the tissue. Skin-derived T cells suppressed nickel-specific responses of peripheral blood CD25(-) T cells. In addition, 60 +/- 14% of peripheral blood CD25(+) Treg expressed the chemokine receptor CCR7 and strongly inhibited naive T cell activation in response to nickel. Finally, CD25(+) T cells isolated from peripheral blood of nickel-allergic patients showed a limited or absent capacity to suppress metal-specific CD4(+) and CD8(+) T cell responses. The results indicates that in healthy individuals CD25(+) Treg can control the activation of both naive and effector nickel-specific T cells.

Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes.

We previously reported that chronic stimulation with low, noncytotoxic doses of extracellular adenosine triphosphate (ATP) induced a distorted maturation of dendritic cells (DCs) and impaired their capacity to initiate T-helper (Th) 1 responses in vitro. Here, we examined the effects of ATP on chemokine-receptor expression and chemokine production by DCs. ATP strongly induced expression of CXC chemokine receptor 4 on both immature and lipopolysaccharide (LPS)-stimulated DCs and slightly up-regulated CC chemokine receptor (CCR) 7 on both DC types. In contrast, ATP reduced CCR5 expression on immature DCs. These effects were confirmed at both the messenger RNA and protein levels and were not produced by uridine triphosphate (UTP). Consistent with the changed receptor expression, ATP increased migration and intracellular calcium of immature and mature DCs to stromal-derived factor 1 (CXC ligand [CXCL] 12) and macrophage inflammatory protein [MIP] 3 beta (CC ligand [CCL] 19), whereas responses to MIP-1 beta (CCL4) were reduced. DCs are an important source of chemokines influencing recruitment of distinct T-lymphocyte subsets. ATP, but not UTP, significantly reduced LPS-induced production of interferon-inducible protein 10 (CXCL10) and regulated upon activation, normal T-cell expressed and secreted chemokine (CCL5); increased secretion of macrophage-derived chemokine (CCL22); and did not change production of thymus and activation-regulated chemokine (CCL17). Consistent with these findings, supernatants from ATP-treated mature DCs attracted Th1 and T-cytotoxic 1 cells less efficiently, whereas migration of Th2 and T cytotoxic 2 cells was not affected. Our data suggest that ATP provides a signal for enhanced lymph node localization of DCs but that it may, at the same time, diminish the capacity of DCs to amplify type 1 immune responses.