Short- and long-term outcomes of neutropenic cancer patients in intensive care according to requirement for invasive ventilation.

BACKGROUND: Neutropenic fever is a frequently encountered complication when caring for cancer patients and can lead to intensive care admission, with high mortality rates in those patients who require invasive mechanical ventilation (IMV). Although hospital survival in this population has improved, long-term outcomes of critically ill neutropenic cancer patients have not been well defined. AIMS: To evaluate short- and long-term outcomes of neutropenic cancer patients admitted to intensive care, according to requirement for invasive ventilation. Additionally, we aimed to determine predictors of poor clinical outcomes in this group. METHODS: A retrospective cohort study of neutropenic cancer patients admitted to our intensive care unit (ICU) from 2008 to 2016. RESULTS: We included 192 cancer patients of whom 100 (52.1%) required IMV. Overall ICU mortality was 29.7% and 12-month post-ICU mortality was 61.5%. Patients requiring IMV had significantly higher short- and long-term mortality (P < 0.001). Multivariate analysis determined three variables to be predictors of mortality at ICU discharge in the whole cohort: IMV (OR 13.52), renal replacement therapy (RRT, OR 2.37) and higher APACHE II scores (OR 1.1 for each unit increase). These variables were identical in the subgroup requiring invasive ventilation, with RRT (OR 2.76) and APACHE II scores (OR 1.1 for each unit increase) predicting short-term mortality. CONCLUSION: Neutropenic cancer patients admitted to ICU have lower short-term mortality than previously reported in cohort studies, however their mortality rises significantly following discharge from ICU. Those patients who require IMV are at significantly increased risk of both short- and long-term mortality.

Novel role for matricellular proteins in the regulation of islet ß cell survival: the effect of SPARC on survival, proliferation, and signaling.

Understanding the mechanisms regulating islet growth and survival is critical for developing novel approaches to increasing or sustaining ß cell mass in both type 1 and type 2 diabetes patients. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that is important for the regulation of cell growth and adhesion. Increased SPARC can be detected in the serum of type 2 diabetes patients. The aim of this study was to investigate the role of SPARC in the regulation of ß cell growth and survival. We show using immunohistochemistry that SPARC is expressed by stromal cells within islets and can be detected in primary mouse islets by Western blot. SPARC is secreted at high levels by pancreatic stellate cells and is regulated by metabolic parameters in these cells, but SPARC expression was not detectable in ß cells. In islets, SPARC expression is highest in young mice, and is also elevated in the islets of non-obese diabetic (NOD) mice compared with controls. Purified SPARC inhibits growth factor-induced signaling in both INS-1 ß cells and primary mouse islets, and inhibits IGF-1-induced proliferation of INS-1 ß cells. Similarly, exogenous SPARC prevents IGF-1-induced survival of primary mouse islet cells. This study identifies the stromal-derived matricellular protein SPARC as a novel regulator of islet survival and ß cell growth.

Demise of the LCP: villain or scapegoat?

The winding down and withdrawal of the Liverpool Care Pathway (LCP) following the Neuberger Report has been met with mixed reviews. It appears that responsibility for failures of clinical care has been laid at the feet of a care pathway rather than the practitioners who used it, a rather curious outcome given that the LCP was primarily a system of documentation, a tool with no intrinsic therapeutic properties. The Neuberger inquiry was the result of persistent and repeated reports of poor-quality end-of-life care associated with the use of the LCP. There were indeed problems with the LCP regarding the process of diagnosing dying and its approach to supportive care, particularly artificial nutrition and hydration. Some of the problems were the product of personal or professional ideology influencing goals of care rather than patient-centred considerations. These problems were not insurmountable, however, and were being addressed by the organisation responsible for the LCP. With the removal of the LCP, we are left with no bench mark for end-of-life care, only aspirational goals for individualised care plans. It seems unlikely that practitioners who could not provide appropriate care with the LCP will do so without it.

Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells.

BACKGROUND: Aberrant expression and activation of the IGF-IR have been reported in a variety of human cancers and have been associated with resistance to HER targeted therapy. In this study, we investigated the effect of simultaneous targeting of IGF-IR and HER (erbB) family, with NVP-AEW541 and afatinib, on proliferation of pancreatic cancer cells. METHODS: The sensitivity of a panel of human pancreatic cancer cell lines to treatment with NVP-AEW541 used alone or in combination with afatinib, anti-EGFR antibody ICR62, and cytotoxic agents was determined using the Sulforhodamine B colorimetric assay. Growth factor receptor expression, cell-cycle distribution and cell signalling were determined using flow cytometry and western blot analysis. RESULTS: All pancreatic cancer cell lines were found to be IGF-IR positive and NVP-AEW541 treatment inhibited the growth of the pancreatic cancer cell lines with IC50 values ranging from 342 nM (FA6) to 2.73 µM (PT45). Interestingly, of the various combinations examined, treatment with a combination of NVP-AEW541 and afatinib was superior in inducing synergistic growth inhibition of the majority of pancreatic cancer cells. CONCLUSION: Our results indicate that co-targeting of the erbB (HER) family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and encourages further investigation in vivo on their therapeutic potential in IGF-IR and HER positive pancreatic cancers.

Spreading by snail (Lymnaea stagnalis) defence cells is regulated through integrated PKC, FAK and Src signalling.

Cell adhesion and spreading are vital to immune function. In molluscs, haemocytes (circulating phagocytes) are sentinels and effectors of the internal defence system; however, molecular mechanisms that regulate integrin-mediated spreading by haemocytes have not been characterised in detail. Visualisation of Lymnaea stagnalis haemocytes by scanning electron microscopy revealed membrane ruffling, formation of lamellipodia and extensive filopodia during early stages of cell adhesion and spreading. These events correlated with increased phosphorylation (activation) of protein kinase C (PKC) and focal adhesion kinase (FAK), sustained for 60 min. Treatment of haemocytes with the PKC inhibitors GF109203X or Gö 6976, or the Src/tyrosine kinase inhibitors SrcI or herbimycin A, attenuated haemocyte spread by 64, 46, 32 and 35%, respectively (P

Immune checkpoint inhibitor use in antisynthetase syndrome.

We report on the unique case of a patient with antisynthetase syndrome and metastatic non-small cell lung cancer undergoing therapy with the PD-1 checkpoint inhibitor, nivolumab. Despite adequate autoimmune disease control over a period of 12 months, the patient rapidly experienced a flare of interstitial lung disease following initial nivolumab administration, which ultimately proved fatal. The use of immune checkpoint inhibitors in patients with autoimmune disease is becoming more commonplace, however this is the first reported case of the use of these agents in a patient with antisynthetase syndrome. Additionally, the patient's initial clinical presentation with antisynthetase syndrome and simultaneous primary lung cancer, a rare association of which there are few case reports, makes this case interesting and unusual.

A novel medium devoid of ruminant peptone for high yield growth of Mycoplasma ovipneumoniae.

Mycoplasma ovipneumoniae is considered an emerging veterinary pathogen causing pneumonia in sheep and goats worldwide. Currently it has not been possible to define a growth medium that yields the maximum growth of M. ovipneumoniae within a short incubation period. Growth yields of M. ovipneumoniae in Eaton's medium are variable and not as consistently high as those seen with other Mycoplasma spp. This study investigated the ability of different M. ovipneumoniae field strains to grow in various media formulations, where PPLO broth was replaced by a vegetable protein source, and comparisons were made in terms of strain viability in Eaton's medium. Studies were also conducted to determine the optimal carbohydrate source for use in the M. ovipneumoniae medium. Generally, it was found that different strains showed good growth in all media tested, with growth yields at 24h in TSB-1 medium higher than those observed with Eaton's medium. Growth yields reached 10(8) to 10(9)cfu ml(-1) within 24h for particular field strains, with all strains achieving this growth level within 48-72h.

Olanzapine induced delirium-a "probable" adverse drug reaction.

Olanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and known to be effective in the management of delirium. In addition to its use for these indications olanzapine has also been used in the management of chemotherapy induced nausea and vomiting and otherwise difficult to control nausea and vomiting in palliative care settings. Although considered to be well tolerated with a lower incidence of extrapyramidal effects than first generation antipsychotics there are a small number of reports of olanzapine inducing delirium. Reported here are two cases of "probable" acute cognitive impairment following treatment of nausea with olanzapine. The cognitive impairment associated with olanzapine is probably mediated through its activity at cholinergic receptors a known risk factor for delirium particularly in the elderly.

Olanzapine in the Management of Difficult to Control Nausea and Vomiting in a Palliative Care Population: A Case Series.

BACKGROUND: Nausea and vomiting are distressing and relatively common symptoms in palliative care populations. Adequate control may be difficult to achieve, requiring multiple agents. Although a growing literature supports the use of olanzapine in management of chemotherapy induced nausea and vomiting, the published literature in palliative care populations is less extensive. OBJECTIVE: The study objective was to assess the efficacy of olanzapine in the management of difficult to control nausea and vomiting in a palliative care patient population. METHODS: Patients whose nausea and vomiting had not responded adequately to other antiemetics were treated with olanzapine 5mg as a single dose at night. Treatment was considered to be successful if the patient reported an adequate improvement in their symptoms. Duration of observed treatment ranged from three days to five months. RESULTS: Sixteen patients were treated with an evaluable outcome in 14. Of these, 13 reported a self-evaluated adequate ongoing improvement in their symptoms. One patient experienced no relief and one other experienced a return of nausea after two weeks; this patient requested a change of treatment due to unacceptable sedative effects. There were no other reports of significant adverse events. CONCLUSIONS: Olanzapine provided adequate, ongoing relief of nausea and vomiting with an acceptable adverse effect profile in 13 of 14 evaluable patients. Particularly in comparison with metoclopramide and haloperidol, olanzapine should be considered for first-line therapy for nausea and vomiting in this population. Further evaluation of dose ranging and safety is required.

Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition.

Drug-resistance is a major contributing factor for the poor prognosis in patients with pancreatic cancer. We have shown previously that the irreversible ErbB family blocker afatinib, is more effective than the reversible EGFR tyrosine kinase inhibitor erlotinib in inhibiting the growth of human pancreatic cancer cells. The aim of this study was to develop human pancreatic cancer cell (BxPc3) variants with acquired resistance to treatment with gemcitabine, afatinib, or erlotinib, and to investigate the molecular changes that accompany the acquisition of a drug-resistant phenotype. We also investigated the therapeutic potential of various agents in the treatment of such drug-resistant variants. Three variant forms of BxPc3 cells with acquired resistance to gemcitabine (BxPc3GEM), afatinib (BxPc3AFR) or erlotinib (BxPc3OSIR) were developed following treatment with increasing doses of such drugs. The expression level, mutational and phosphorylation status of various growth factor receptors and downstream cell signaling molecules were determined by FACS, human phopsho-RTK array, and western blot analysis while the sulforhodamine B assay was used for determining the effect of various agents on the growth of such tumours. We found that all three BxPc3 variants with acquired resistance to gemcitabine (BxPc3GEM), afatinib (BxPc3AFR) or erlotinib (BxPc3OSIR) also become less sensitive to treatment with the two other agents. Acquisition of resistance to these agents was accompanied by upregulation of p-c-MET, p-STAT3, CD44, increased autocrine production of EGFR ligand amphiregulin and differential activation status of EGFR tyrosine residues as well as downregulation of total and p-SRC. Of all therapeutic interventions examined, including the addition of an anti-EGFR antibody ICR62, an anti-CD44 monoclonal antibody, and of STAT3 or c-MET inhibitors, only treatment with the STAT3 inhibitor Stattic produced a higher growth inhibitory effect in all three drug-resistant variants. In addition, treatment with a combination of afatinib with either c-MET inhibitor Crizotinib or Stattic resulted in an additive or synergistic growth inhibition in all three variants. Our results suggest that activation of STAT3 may play an important role in the acquisition of resistance to gemcitabine and HER inhibitors in pancreatic cancer and warrant further studies on the therapeutic potential of STAT3 inhibitors in such a setting.

Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer.

Pancreatic cancer is still one of the most aggressive and fatal types of human cancer . Survival rates for patients with pancreatic cancer are extremely poor and one major contributing factor is the lack of specific marker(s) for the early detection of pancreatic cancer. Indeed, the great majority of pancreatic cancer cases are diagnosed at an advanced stage of the disease and these patients often have a poor response to treatment with conventional forms of therapy. In this article, we conduct a comprehensive review of the literature on the expression pattern, prognostic significance and predictive value of EGFR family members, IGF-IR and their ligands in pancreatic cancer. We also discuss recent advances in pancreatic cancer treatments and highlight the remaining challenges as well as future opportunities for more effective targeting of such receptors using a combination of growth factor receptor specific monoclonal antibodies, small molecule tyrosine kinase inhibitors and other therapeutic strategies. Such strategies could ultimately help to overcome the development of drug resistance and improve the overall survival rates for patients with pancreatic cancer.

Alcohol pharmacokinetics, decision making and folk wisdom: a reply to Moxnes and Jensen (2009).

Moxnes and Jensen (2009) present a study of decision making under conditions of uncertainty using a computerised simulation of alcohol pharmacokinetics. In their article, they conclude that their findings challenge the 'folk wisdom' that advises against drinking on an empty stomach. We contend that this is a problematic conclusion for three reasons: (1) the study and findings presented in their paper are simply not sufficient to allow one to, even tentatively, draw such a conclusion; (2) the conclusion is contrary to basic pharmacological knowledge concerning alcohol absorption, metabolism and the implications for peak blood alcohol concentration; and (3) the implications for understanding the process of decision making while alcohol intoxicated are not considered in the study. The Moxnes and Jensen (2009) study did not involve alcohol administration and is therefore an examination of decision making in situations of uncertainty rather than a specific exploration of drinking-related decision making. Recent formulations of the effects of alcohol on cognitive processing would lead to different conclusions than those presented by Moxnes and Jensen (2009). We conclude by suggesting our understanding of the implications of the study.

Beta-1, 3-glucan modulates PKC signalling in Lymnaea stagnalis defence cells: a role for PKC in H2O2 production and downstream ERK activation.

Haemocytes from the gastropod snail Lymnaea stagnalis (Linnaeus) were used as a model to characterize protein kinase C (PKC) signalling events in molluscan defence cells. Challenge of freshly collected haemocytes with the beta-1, 3-glucan laminarin resulted in a transient increase in the phosphorylation of haemocyte PKC, with maximal phosphorylation (represented by a 3.5-fold increase) occurring at 10 min; this effect was blocked by the PKC inhibitor, GF109203X. Moreover, extracellular signal-regulated kinase (ERK) was found to be a downstream target of molluscan PKC, operating via a MAPK/ERK kinase (MEK)-dependent mechanism. Pharmacological inhibition of PKC phosphorylation by U-73122 and ET-18-OCH(3) suggested that laminarin-dependent PKC signalling was modulated via phospholipase C (PLC); however, a role for phosphatidylinositol-3-kinase (PI-3-K) is unlikely since the PI-3-K inhibitor LY294002 was without effect. Generation of H(2)O(2) by haemocytes in response to laminarin was also investigated. H(2)O(2) output increased in a dose- and time-dependent manner, with 10 mg ml(-1) laminarin eliciting a 9.5-fold increase in H(2)O(2) production after 30 min. H(2)O(2) production was significantly attenuated by the PKC inhibitors, GF109203X and Gö 6976, and by the NADPH-oxidase inhibitor, apocynin. In conclusion, these data further our understanding of PKC signalling events in molluscan haemocytes and for the first time define a role for PKC in H(2)O(2) production by these defence cells. Given that H(2)O(2) is an important anti-pathogen molecule, and that haemocytes play a crucial role in the elimination of invading organisms, PKC signalling in these cells is likely to be crucial to the molluscan innate defence response.

Mitogenic activity of insulin in the culture of a trypanosome: duration and dose response.

The effects of insulin on the in vitro growth characteristics of Trypanosoma granulosum were investigated. The insulin growth stimulus had a rapid onset with little or no lag phase but was relatively short lived, growth peaking typically on day 3 or 4 of culture. This contrasted with medium containing 10% foetal calf serum, normally used for in vitro culture of this trypanosome, which after a 3 day lag stimulated sustained log-phase growth. Insulin demonstrated a biphasic dose response with maximum growth typically occurring at 3-10 microg/ml and a much reduced effect at higher concentrations. These findings suggest a possible role for host insulin and/or trypanosomal insulin-like molecules in regulating parasite growth in vivo.