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A phase I study of high dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies

A phase I study of high dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies

showed significant statin-induced apoptosis in  vitro, disease stabilization of greater than 3 months in 23 % of patients was observed [26]. In this study, in a non-selected patient population that included a single SCC patient, similar rates but more pronounced disease stabilization (greater than 6  months for 4/16 patients in the concur- rent treatment regimens) was observed. This included 2/4 NSCLC, 1/2 pancreatic cancer (responder; neuroen- docrine tumour) and a single SCC (vaginal carcinoma) patient. In a recent study conducted by Han et al. [42], the hypercholesterolemia dose of simvastatin was employed in a daily regimen with the standard dose of gefitinib in NSCLC patients. In particular, SCC patients displayed higher response rates and longer PFS compared to gefi- tinib alone. This study was based on our work that showed in vitro synergy of this approach as well as the ability of statins to inhibit EGFR function [27, 29, 42, 43]. Taken together, these results suggest that high-dose statin ther- apy in combination with EGFR-TKIs may be beneficial in a subgroup of patients with advanced solid cancers.
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Bench to bedside review: Diaphragm muscle function in disuse and acute high dose corticosteroid treatment

Bench to bedside review: Diaphragm muscle function in disuse and acute high dose corticosteroid treatment

Critically ill patients may require mechanical ventilatory support and short-term high-dose corticosteroid to treat some specific under- lying disease processes. Diaphragm muscle inactivity induced by controlled mechanical ventilation produces dramatic alterations in diaphragm muscle structure and significant losses in function. Although the exact mechanisms responsible for losses in dia- phragm muscle function are still unknown, recent studies have highlighted the importance of proteolysis and oxidative stress. In experimental animals, short-term strategies that maintain partial diaphragm muscle neuromechanical activation mitigate diaphrag- matic force loss. In animal models, studies on the influence of combined controlled mechanical ventilation and short-term high- dose methylprednisolone have given inconsistent results in regard to the effects on diaphragm muscle function. In the critically ill patient, further research is needed to establish the prevalence and mechanisms of ventilator-induced diaphragm muscle dysfunction, and the possible interaction between mechanical ventilation and the administration of high-dose corticosteroid. Until then, in caring for these patients, it is imperative to allow partial activation of the diaphragm, and to administer the lowest dose of corticosteroid for the shortest duration possible.
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Intravenous non-high-dose pantoprazole is equally effective as high-dose pantoprazole in preventing rebleeding among low risk patients with a bleeding peptic ulcer after initial endoscopic hemostasis

Intravenous non-high-dose pantoprazole is equally effective as high-dose pantoprazole in preventing rebleeding among low risk patients with a bleeding peptic ulcer after initial endoscopic hemostasis

Acute, non-variceal upper gastrointestinal bleeding is a common cause of hospitalization and mortality has remained at 6% to 8% despite recent advances in both pharmacological and endoscopic therapy [1,2]. The risk of recurrent bleeding is increased in patients with high- risk stigmata found by endoscopy. Endoscopic hemosta- sis is able to control bleeding and reduce the rebleeding rate, morbidity and even mortality of this disease [3,4]. The success of hemostasis, however, is highly dependent on the intragastric pH and studies have shown that, when the intra-gastric pH is low, platelet function is impaired and pepsin is activated, which disaggregates platelet plugs [5,6]. The maintenance of an intragastric pH above 6.0 allows stabilization of the clot, which stops peptic ulcer (PU) bleeding and prevents rebleeding [7,8]. Interestingly, in Hung ’ s study [9], the time during which a intragastric pH above 6 was maintained was similar for both a non-high dose PPI group and a high dose group (49%, 59%, p = 0.182). This poses the ques- tion as to what is the optimal dose of PPI that is able to achieve the required therapeutic goal, This continues to be a controversial issue in clinical practice. Both the Vienna and Asia-Pacific consensus recommend intrave- nous high-dose PPI therapy after successful endoscopic hemostasis; however, the evidence related to the use of low-dose PPIs is limited [10,11]. Many studies have shown that high-dose PPIs do not further reduce the rate of rebleeding compared to non-high-dose PPIs [12-14]. Nevertheless, we do not know whether the effect of intravenous non-high-dose PPIs is able to reduce the rebleeding rate among patients at low risk (Rockall score ≤ 6) or among those at high risk, both compared to high-dose PPIs. We can assume that intra- venous high-dose PPI therapy is no doubt beneficial after successful endoscopic hemostasis but non-high dose treatment may be equally effective among certain subgroup of patients. If this is true, a change in strategy with respect to the use of PPIs may be both beneficial and cost-effective. The aim of this retrospective case- controlled study was to identify the subgroup of patients that might benefit from non-high-dose PPI treatment.
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Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy

Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy

Preclinical studies have suggested that low-dose radi- ation, although not tumoricidal on its own, may activate and stimulate immune cells and modulate the stromal microenvironment so as to facilitate the action of im- munotherapy [3]. Our own post-hoc analysis of a re- cently completed trial of ipilimumab with high-dose radiation revealed that tumors exposed to low-dose scat- ter radiation (owing to their proximity to the targeted tumor) were more likely to show a response than were distant tumors exposed to no radiation [4]. From these observations, we developed a model where high-dose and low-dose radiation may work synergistically to pro- mote systemic immunotherapy: In this model, high-dose radiation increases antigen release and presentation and primes immune cells [5], whereas low-dose radiation promotes immune-cell infiltration into the stroma and tumor bed.
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<p>High dose vs low dose irradiation of the subventricular zone in patients with glioblastoma&mdash;a systematic review and meta-analysis</p>

<p>High dose vs low dose irradiation of the subventricular zone in patients with glioblastoma&mdash;a systematic review and meta-analysis</p>

The search for papers yielded 2573 unique records. During screening we excluded papers for the following reasons: studies not on the topic, studies that didn ’ t compare high dose with low dose irradiation, studies that didn ’ t target the SVZ zone, studies that didn ’ t use irradiation, other gliomas, case reports, abstracts of congress presentations, reviews. After screening 17 were assessed for eligibility, and in the end 8 were included in the qualitative and 4 in the quantita- tive analysis (Figure 1). Four studies were excluded from the quantitative analysis for the following reasons: Gupta et al, 33 2012 – was excluded for having continuous dose, not in the binary form, high dose vs. low dose, while all the other studies had it in binary format. Kusumawidjaja et al, 20 2014 – was excluded for having irradiation doses that were not comparable with the other studies (70 dose escalated vs 60 conventional, and no dose below 60 – while all the others
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High-dose Epinephrine Is Not Superior to Standard-dose Epinephrine in Pediatric In-hospital Cardiopulmonary Arrest

High-dose Epinephrine Is Not Superior to Standard-dose Epinephrine in Pediatric In-hospital Cardiopulmonary Arrest

Before 1992, the standard dose of epinephrine used in pediatric resuscitative efforts was 0.01 to 0.02 mg/kg per dose, a dose empirically derived from adult and animal studies. A series of reports of both animal and human trials using 10- to 20-fold higher doses of epinephrine during resuscitation, including a single report from the pediatric age group, led in 1992 to the acceptance by the American Heart Asso- ciation of high-dose epinephrine (HDE) for second and subsequent doses of epinephrine as a class IIa (“probably helpful”) recommended therapy in pedi- atric cardiopulmonary resuscitation (CPR) and as a class IIb (“may be helpful and probably not harm- ful”) therapy in adult CPR. 11 This recommendation
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High-dose intravenous vitamin C as an Antican...

High-dose intravenous vitamin C as an Antican...

debated is whether vitamin C has any therapeutic effect in the treatment of cancer. In the 1950s, vitamin C was originally hypothesized to be protective against cancer, 6, and 7 but in the 1970s, Ewan Cameron and Linus Pauling suggested that it also had a therapeutic effect, reporting increased survival of patients with advanced cancer following high-dose IV vitamin C treatment (typically 10 g/day, by intravenous infusion for about 10 days and orally thereafter) 8 . Other researchers reported benefit consisting of increased survival, improved well-being and reduced pain 9, 10 . In contrast, several subsequent randomized controlled trials (RCTs) of high-dose oral vitamin C failed to demonstrate a similar benefit, 11–13 opening the issue of therapeutic effectiveness to controversy. Some research groups conducted rigorous research, particularly in the area of administering mega-doses of ascorbate intravenously 14 .
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Trends in high-dose opioid prescribing in Canada

Trends in high-dose opioid prescribing in Canada

Although guidelines suggest that high-dose opioid for- mulations might be appropriate in some instances, there is little evidence to support this practice. On the other hand, high-dose opioid prescribing is clearly associ- ated with increased risk of fracture, trauma, overdose, and death. Our findings suggest that use of high-dose opioids is widespread in Canada and highlight the pro- found regional variation in prescribing of high-dose formulations. This has important clinical and policy con- sequences. Clinical guidelines are increasingly establish- ing upper dose thresholds for opioids in patients with chronic noncancer pain, and a growing body of evi- dence has described the relationship between increas- ing opioid dose and risk of overdose and death. Indeed, daily doses exceeding 100 mg of morphine (or equiv- alent) have been associated with a 9-fold increased risk of overdose, 13 and a doubling of the risk of opioid-
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Is There A Role for Adjuvant High Dose Interferon in the Management of Melanoma

Is There A Role for Adjuvant High Dose Interferon in the Management of Melanoma

should be encouraged to participate in well-de- What about the question regarding which subset signed controlled trials, and clinical trials in inter- of high-risk melanoma patients should be offered mediate-risk patients should also continue, includ- adjuvant interferon-α-2b? One possible explanation ing trials of less intense interferon- α -2b regimens of the available data is that the efficacy of inter- and also phase II and III vaccine trials. However, feron-α-2b is consistent across all subsets of high- until that information is published, how does one risk patients, that is, patients with thick node-nega- make a decision based on the available data? tive and patients with one or more positive lymph The routine use of adjuvant high-dose interferon- nodes. It must be noted, however, that the subset of α-2b is certainly not without its controversy and high-risk patients with the least clinical trial data is opponents. Attempts to clarify the issue through the group of patients that is now most commonly reviews and meta-analyses of the available data treated with adjuvant interferon-α-2b – namely, have yielded conflicting recommendations and been those patients with a single, microscopically posi- hampered by methodological limitations. [7,17,18,24,25]
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Potential for Single High-Dose Influenza Immunization in Unprimed Children

Potential for Single High-Dose Influenza Immunization in Unprimed Children

After the first dose, the high-dose vac cine was a significantly better stimulator of serum HAl antibody in initially seronegative persons than the standard dose vaccine by three methods[r]

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Lung Function in Adolescents Receiving High-Dose Methotrexate

Lung Function in Adolescents Receiving High-Dose Methotrexate

Strieder Lung Function in Adolescents Receiving High-Dose Methotrexate. http://pediatrics.aappublications.org/content/63/5/741[r]

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Leptotrichia Bacteremia in Patients Receiving High Dose Chemotherapy

Leptotrichia Bacteremia in Patients Receiving High Dose Chemotherapy

In conclusion, Leptotrichia spp. are emerging pathogens in neutropenic patients receiving high-dose chemotherapy. At our institution, there was an apparent association between Leptotri- chia BSI and the chemotherapeutic agents used for multiple myeloma patients undergoing auto-HSCT. In particular, L. hon- gkongensis was shown to be the predominant species in this pop- ulation, further defining the clinical relevance of this recently de- scribed species. Molecular methods have greatly improved the clinical laboratories’ ability to identify these potential pathogens, which have fortunately remained susceptible to most antimicro- bial agents.
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The role of high-dose chemotherapy in the treatment of testicular cancer

The role of high-dose chemotherapy in the treatment of testicular cancer

factors, although the final model included only platinum- refractory disease, while the use of HDC later than the first relapse and initial IGCCCG high-risk stage, were the other two adverse prognostic features. The overall results were better than those reported by Beyer, with 63% of patients being disease-free after a median follow up of 4 years. Most of these patients (90%) had been followed up for a minimum of 2 years. The superior results of Einhorn and colleagues may be attributed to several factors; earlier use of HDC, administration of two rather than one cycles of HDC and the omission of cyclophosphamide from the high-dose regimen, thus allowing for higher doses of the two most active drugs
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High-dose atorvastatin versus moderate dose on early vascular protection after ST-elevation myocardial infarction

High-dose atorvastatin versus moderate dose on early vascular protection after ST-elevation myocardial infarction

Background and aim: Clinical benefits of early high-dose statin therapy after acute coronary syndromes are widely known; however, there is poor evidence on the specific setting of ST-elevation myocardial infarction (STEMI) and dose-dependent effects of this therapy on endothelial function and inflammatory biomarkers in the most vulnerable phase after acute coronary syndromes: the postdischarge period. In our study, we compared the short-term effects of high (80 mg) vs moderate doses of atorvastatin (20 mg) in patients with STEMI undergoing primary percutaneous coronary intervention on endothelial function and vascular inflammation. The aim of our study was the evaluation of dose-dependent short-term effects.
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High-energy, high-dose O implantation in Si

High-energy, high-dose O implantation in Si

This is one of the first reports of an implantation-induced vacancy excess as detected by DCXRD measurements. The tensile strain at depths shallower than the Rp is not generally observed since -0.01% of ion-atom and atom-atom contribute to the vacancy excess. Hence, implantation to high doses as well as implant conditions that inhibit dynamic annealing (low implant temperatures, for example) are necessary to observe this phenomenon. It should be noted that such phenomena was also evident in high-dose Si-implanted Si under implant conditions which resulted in the same vacancy production (as modeled by TRIM) within the Si overlayer as that of O-implanted Si. The relaxation of tensile strain was apparent for Si and O implantation at two different doses. However, the Si critical dose and the O critical dose produced the same athermal vacancy concentration within the Si overlayer, indicating chemical effects are minimal. It was further shown that in addition to atomic displacements, the presence of the high O concentration in the SIMOX process contributes to amorphous layer formation at Rp. However, within the Si overlayer the type and depth of defect formation were quite similar in O- and Si-implanted Si over the implant temperature range studied (150-450°C), again indicating that defect formation at depths <Rp is essentially independent of impurity concentration.
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High Dose Haloperidol for Delirium in HIVAssociated Dementia

High Dose Haloperidol for Delirium in HIVAssociated Dementia

An additional randomized, double blind trial compared haloperidol, chlorpromazine, and lorazepam in medically hospitalized AIDS patients with delirium [8]. Relevant exclusion criteria included schizophrenia, bipolar disorder, or schizoaffective disorder; presence of neuroleptic malignant syndrome; seizure disorder; withdrawal syndrome or anticholinergic delirium; or those who were experiencing delirium due to a terminal event (i.e., passing away in less than 24 hours). A total of 30 patients with an average age of 39 years, mostly men (77%), were included. Doses were titrated hourly until the patient was stabilized on a dose or scored a 12 or less on the Delirium Rating Scale (DRS). Subsequently, a maintenance dose was continued for up to 6 days. During the first 24 hours, the mean doses of chlorpromazine, haloperidol, and lorazepam were 50 mg, 2.8 mg, and 3 mg respectively, and the average maintenance doses were 36 mg, 1.4 mg, and 4.6 mg respectively. Delirium improved in both the haloperidol and chlorpromazine group on day 2, but not the lorazepam group. From day 2 to the end of treatment, there were no significant changes in any of the 3 groups on the DRS. Five patients died within 8 days of initiation. Patients in the chlorpromazine group did show significant improvement on the Mini-Mental State exam on day 2, but scores declined by the end of treatment. Patients only scored on the Parkinsonism subscale of the EPS Rating Scale, and these scores were not Hospital Day Scheduled Prn and 1× orders Lorazepam
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High-dose intravenous pamidronate for metastatic bone pain

High-dose intravenous pamidronate for metastatic bone pain

Thirty-four normocalcaemic patients with painful progressing bone metastases 22 from breast, five prostate and seven others received a single intravenous infusion of 120 mg of pamidronat[r]

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Methemoglobinemia in an Infant After Sclerotherapy With High-Dose Doxycycline

Methemoglobinemia in an Infant After Sclerotherapy With High-Dose Doxycycline

Methemoglobinemia occurs when the heme moiety of hemoglobin (Hb) is oxidized from the ferrous to ferric state, leading to impairments in oxygen transport and delivery. Methemoglobinemia is rare in pediatric patients but has been described in the setting of congenital abnormalities in the Hb structure, inherited enzyme deficiencies, oxidative Hb injury in response to illness, and oxidative Hb injury due to toxicants. We present a 1-week-old infant born with a cervical lymphangioma who developed persistent desaturations that were unresponsive to oxygen after sclerotherapy with doxycycline. Arterial blood gas revealed a high Pa O 2 despite low saturations
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HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis

HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis

Clinical research in PCNSL is currently focused on de- fining the optimal consolidation treatment after HDMTX- based induction. With studies exploiting conventional non-cross resistant systemic chemotherapy [10], high dose chemotherapy with autologous stem cell transplantation (HD-ASCT) [11] or dose-reduced WBRT [12], 2-years PFS of 37–77% and 2-years OS of 42–90% have been re- ported. Two randomized studies compared standard-dose WBRT and HD-ASCT for consolidation in younger pa- tients. No significant difference in 2-years PFS between WBRT and ASCT (80% vs 69%, p = 0,17) was found in the IELSG-32 trial [13], but a 24% better 2-years PFS: 86.8% vs. 63.2% was found with HD-ASCT in the French PRE- CIS trial [14] which, however, was not designed for a dir- ect comparison. In conclusion, an optimal consolidation after HDMTX-based induction therapy has not been established thus far.
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Are there candidates for high-dose chemotherapy in ovarian carcinoma?

Are there candidates for high-dose chemotherapy in ovarian carcinoma?

chemotherapy and better outcome [35,36]. Of note, recent data have shown that this phenotype could be extended to a larger group of tumors without germline BRCA mutations, the so-called “BRCAness” phenotype [37,38]. Thus, the benefit of alkylating agents-based HDC in younger patients observed in this study may reflect the enrichment in BRCA-related or BRCAness- associated forms in this subgroup and therefore a higher sensitivity of ovarian cancer cells to DNA damages that can be induced by alkylating agents. As suggested by the dose-effect concept, more chemotherapy –and thus more DNA lesions- may lead to an increase in tumor cells death.
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