Cancer by Sfakianakis Alexandros: 06/02/17

Παρασκευή 2 Ιουνίου 2017

The 21-gene recurrence score in special histologic subtypes of breast cancer with favorable prognosis

Abstract

Background/purpose

The 21-gene recurrence score (RS) assay predicts the likelihood of distant recurrence and chemotherapy benefit in early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. Data on the RS of special histologic subtypes of invasive breast carcinoma with favorable prognosis are limited.

Methods

We reviewed our institutional database to identify patients with special histologic subtypes of breast cancer associated with favorable prognosis and available RS results. Our cohort consists of fifty-seven women: thirty-three patients with pure mucinous carcinoma (MC), ten with tubular carcinoma (TC), nine with encapsulated papillary carcinoma (EPC), and five with solid papillary carcinoma (SPC).

Results

Most (44/57, 77.2%) carcinomas had low RS (≤17), and none had high RS (≥31). All EPCs had low RS, but other subtypes had RS 18–30. Higher RS was associated with lower progesterone receptor (PR) expression by immunohistochemistry and lower PR mRNA scores (P ≤ 0.007). No morphologic feature (tumor grade, biopsy site changes, cellular stroma, inflammatory cells) was associated with RS ≥ 18. At a median follow-up of 40 months, the distant recurrence-free survival was 100%. One patient with SPC developed locoregional recurrence at 22 months.

Conclusions

As the largest series to date, our study raises the question of whether the RS assay is necessary for breast cancers with favorable histology. Reflex testing of node-negative, ER+/HER2− breast cancers may be deferred for these special histologic subtypes, emphasizing the need for multidisciplinary discussions between breast pathologists and other members of the breast cancer team.

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Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells [Research Articles]

Some patients with otherwise treatment-resistant Hodgkin lymphoma (HL) could benefit from chimeric antigen receptor T cell (CART) therapy. However, HL lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in HL, CART should target both malignant cells and the TME. We demonstrated CD123 on both HL cells and TME, including tumor-associated macrophages (TAM). In vitro, HL cells convert macrophages towards immunosuppressive TAM that inhibit T cell proliferation. In contrast, anti-CD123 CART recognized and killed TAM thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicate HL, and establish long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu.

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BCAT1 Enhances BCAA Production to Drive Myeloid Leukemia [Research Watch]

BCAT1 is highly expressed in BC-CML and AML and promotes BCAA production to drive tumor progression.

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CPS1 Promotes Tumor Growth in KRAS/LKB1-Mutant NSCLC [Research Watch]

LKB1 loss upregulates CPS1 to increase tumor growth by maintaining pyrimidine levels.

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Ceritinib Has Clinical Activity in Patients with ROS1-Rearranged NSCLC [Research Watch]

Ceritinib has manageable toxicity and achieves whole-body and intracranial responses.

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IFN{gamma} Induces FOXP3+ Treg Dysfunction to Promote Antitumor Immunity [Research Watch]

NRP^– Treg–derived IFN is a critical mediator of FOXP3⁺ Treg functional fragility.

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The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression

Abstract

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4–6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.

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The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression

Abstract

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In sickness and in health: The many roles of the minichromosome maintenance proteins

Publication date: Available online 1 June 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Henrique Neves, Hang Fai Kwok
Cell division is a tightly-regulated process that involves the contribution of a large number of proteins. Before they are able to undergo mitosis, cells must first synthesize new DNA, effectively duplicating their genome. This occurs during what is called the S-phase and requires a fine control in order to avoid replication errors.The synthesis of new DNA takes place in origin sites, specific locations in the genome where the double strands of DNA are unwound and separated, allowing for the binding of proteins and complexes that will build new strands of the genomic material, using the existent ones as molds, in what is referred to as semi-conservative process.While the overall flow of the DNA synthesis process has been elucidated, its regulation and the exact role of its contributors are not yet entirely understood. It is believed that the Minichromosome Maintenance (MCM) proteins occupy a central role in DNA synthesis. While the functions of each protein in this family vary, they are believed to have helicase and proofreading activity.Given their contribution to a central aspect in the conservation of life, further studies have been launched to understand how the MCM proteins may affect or be affected by pathologies involving cell division, namely neoplasia.In this review, we aim to give an overview on the members of the MCM family, what their functions are in a healthy environment and how they are altered in a variety of pathologies.

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Präoperative Evaluation erwachsener Patienten vor elektiven, nicht herz-thoraxchirurgischen Eingriffen1*

Anästhesiol Intensivmed Notfallmed Schmerzther
DOI: 10.1055/s-0043-111784

Die präoperative Anamnese und körperliche Untersuchung sind anerkannter Standard bei der Risikoevaluation von Patienten vor elektiven chirurgischen Eingriffen. Ob und unter welchen Umständen technische Voruntersuchungen dazu beitragen können, das perioperative Risiko zu reduzieren, ist bislang nur unzureichend untersucht. Auch besteht unter Anästhesisten, Chirurgen und Internisten vielfach Unsicherheit im perioperativen Umgang mit der Dauermedikation. Die deutschen wissenschaftlichen Fachgesellschaften für Anästhesiologie und Intensivmedizin (DGAI), Chirurgie (DGCH) und Innere Medizin (DGIM) haben daher eine gemeinsame Empfehlung zur präoperativen Evaluation erwachsener Patienten vor elektiven, nicht herz-thoraxchirurgischen Eingriffen erarbeitet und erstmals im Jahr 2010 publiziert. Die vorliegende Fassung ist eine Überarbeitung der Stellungnahme von 2010 unter Einbeziehung der seither publizierten Literatur sowie von aktuellen Leitlinien internationaler Fachgesellschaften. Zunächst werden die allgemeinen Prinzipien der präoperativen Evaluation dargestellt (Teil A). Das Vorgehen bei Patienten mit bekannten oder vermuteten kardiovaskulären Vorerkrankungen wird gesondert betrachtet (Teil B: „Erweiterte kardiale Diagnostik"). Abschließend wird der perioperative Umgang mit der Dauermedikation diskutiert (Teil C). Die vorgestellten Konzepte stellen fachübergreifende Empfehlungen dar, die ein strukturiertes und gemeinsames Vorgehen ermöglichen sollen. Ihr Ziel ist es, durch transparente und verbindliche Absprachen eine hohe Patientenorientierung unter Vermeidung unnötiger Voruntersuchungen zu gewährleisten, präoperative Untersuchungsabläufe zu verkürzen sowie letztlich Kosten zu reduzieren. Die gemeinsamen Empfehlungen von DGAI, DGCH und DGIM spiegeln den gegenwärtigen Kenntnisstand, aber auch die Meinungen von Experten wider, da nicht für jede Fragestellung wissenschaftliche Evidenz besteht. Daher werden eine regelmäßige Überprüfung und Aktualisierung der Empfehlungen erfolgen, sobald gesicherte neue Erkenntnisse vorliegen.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents | Abstract | Full text

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Evaluation of haematological and serum biochemical changes associated with constant rate infusion tramadol hydrochloride as an adjunct to ketoprofen in laparotomized and ovariohysterectomized dogs

Abstract

Tramadol hydrochloride (an opioid-like analgesic) and ketoprofen (a non-steroidal anti-inflammatory drug) are routinely used in human and veterinary medicine for the management of post-surgical pain. However, data on the safety of constant rate infusion tramadol as an adjunct to ketoprofen for peri-operative analgesia is lacking. This study evaluated changes in haematology and serum biochemistry associated with constant rate infusion (CRI) tramadol hydrochloride as an adjunct to ketoprofen for analgesia in adult female dogs following laparotomy (LP) and ovariohysterectomy (OVH). Thirty (30) adult female dogs randomly assigned into six groups of five dogs each were used in studies 1 and 2. In both studies, group 3 served as the control which received normal saline while groups 1 and 2 were given 1.0 and 2.0 mg/kg/h of tramadol Hcl, respectively. Dogs in study 1 were laparotomized while OVH was performed on dogs in study 2. Ketoprofen (4 mg/kg) was given subcutaneously for 3 days post-surgery (PS) to all the groups. There was no significant difference in the haematological parameters of treated and control groups. There was a transient significant rise in some serum biochemical parameters of the treated groups but these decreased to baseline values by day 7 post-surgery. Based on the findings in this study, it was concluded that constant rate infusion of 1 and 2 mg/kg/h of tramadol hydrochloride as an adjunct to ketoprofen caused no clinically observable deleterious effect on haematology and serum biochemistry of dogs post-laparotomy and ovariohysterectomy.

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Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study)

Purpose. Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. Experimental design. This prospective study enrolled consecutive mCRC patients receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C₀), second (C₁) and/or third (C₂) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). Computed tomography scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity and treatment line. Results. Eighty-two mCRC patients treated in first (82.9%) or second (17.1%) line chemotherapy were included. Patients with a high (>10ng/mL) versus low (≤0.1ng/mL) ctDNA concentration at C₀ had a shorter overall survival (OS) (6.8 versus 33.4 months: adjusted HR=5.64; CI_95%[2.5-12.6], P<0.0001). By analyzing the evolution of the ctDNA concentration between C₀ and C₂ or C₁ (C_2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n=58) versus "bad ctDNA responder" (n=15) had a better objective response rate (P<0.001), and a longer median progression-free survival (8.5 vs 2.4 months: HR=0.19, CI_95%[0.09-0.40], P<0.0001) and OS (27.1 vs 11.2 months: HR=0.25, CI_95%[0.11-0.57], P<0.001). Conclusion. This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in mCRC patients.

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Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study)

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Elucidating the molecular basis of msh2-deficient tumors by combined germline and somatic analysis

Abstract

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level.

Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel.

Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 somatic alterations in other MMR genes and/or proof-reading polymerases.

In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors. This article is protected by copyright. All rights reserved.

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Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva: A systematic review and meta-analysis

Abstract

In this updated systematic review and meta-analysis we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase, and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I² statistic was used to describe the amount of heterogeneity. In meta-regression analyses potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5015 cases of vulvar cancer (64 papers) and 2764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1–44.4%). Overall, 76.3% (95% CI: 70.1–82.1%) of VIN lesions tested HPV-positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5–95.5%) and 2.0% (95% CI: 0–10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I² = 88.4%; VIN: I² = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions. This article is protected by copyright. All rights reserved.

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The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: a study in the Swedish AMORIS cohort

Abstract

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis.

A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 to December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis.

There were 766 PLC and 2,775 cirrhosis cases over 13-years. Raised TG, low TC, raised glucose, diabetes and low HDL were associated with an increased risk of developing PLC and cirrhosis. ApoB/ApoA-I ratio were also associated with PLC, whilst low LDL, raised TG/HDL, low ApoA-I and low ApoB were associated with cirrhosis. Obesity was significantly associated with PLC but not cirrhosis. Raised TG, low TC, raised glucose and diabetes showed stronger associations with PLC in participants with cirrhosis but many participants developed PLC without cirrhosis.

Individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity) were associated with an increased risk of developing PLC or cirrhosis. MetS components were more strongly associated with PLC with preceding cirrhosis history but many participants developed PLC without cirrhosis. This article is protected by copyright. All rights reserved.

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Cetuximab or Nimotuzumab plus Intensity-modulated Radiotherapy Versus Cisplatin plus Intensity-modulated Radiotherapy for Stage II-IVb Nasopharyngeal Carcinoma

Abstract

To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II - IV_b NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, P>0.05), LRRFS (96.2% vs. 96.3%, P>0.05), DMFS (91.1% vs. 92.3%, P>0.05), and OS (91.7% vs. 91.9%, P>0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, P=0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (P<0.05). 3.4-4.7% patients experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related-skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC. This article is protected by copyright. All rights reserved.

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uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

Abstract

In the present manuscript we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5β1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIFα pathway. HIF-1α trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e. uPAR/IL-TKRs axis) for the therapy of melanoma. This article is protected by copyright. All rights reserved.

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Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva: A systematic review and meta-analysis

Abstract

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Elucidating the molecular basis of msh2-deficient tumors by combined germline and somatic analysis

Abstract

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The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: a study in the Swedish AMORIS cohort

Abstract

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Cetuximab or Nimotuzumab plus Intensity-modulated Radiotherapy Versus Cisplatin plus Intensity-modulated Radiotherapy for Stage II-IVb Nasopharyngeal Carcinoma

Abstract

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uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

Abstract

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[Correspondence] Incidence and prognosis of carcinoid syndrome: hormones or tumour burden? – Authors' reply

We appreciate the thoughtful commentary from Wouter Zandee and colleagues, and agree with their conclusion that our population-based study1 provides unique information about the incidence of carcinoid syndrome, with certain limitations by design.

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[Correspondence] Genetics of gallbladder cancer

Sharayu Mhatre and colleagues1 published the first genome-wide association study (GWAS) on gallbladder cancer and found a strong, replicated association at chromosome 7q21.12, which harbours ATP binding cassette subfamily B genes ABCB1 and ABCB4. The authors additionally estimated the combined heritability of the GWAS data using the Genome-Wide Complex Trait Analysis tool, and reported that their data explain 23% of gallbladder cancer risk variation, corresponding to a familial relative risk (FRR) of 3·15.

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[Review] Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer

For patients with high-risk stage II or stage III colon cancer, adjuvant chemotherapy with fluoropyrimidine monotherapy reduces the risk of recurrence and death by approximately 20–30%. Additional improvements have been reported in three phase 3 colon cancer trials when oxaliplatin was added to the chemoradiation regimen, although the effect was mainly on disease-free survival. However, patients with rectal cancer were specifically excluded from these landmark studies because of potential toxicity and the confounding impact of radiotherapy and chemoradiation.

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[Correspondence] Do cytogenetics of acute lymphoblastic leukaemia blasts affect required duration and intensity of maintenance therapy?

In The Lancet Oncology, Stine Nielsen and colleagues1 describe the importance of achievement of optimal concentrations of DNA-incorporated thioguanine nucleotides (DNA-TGN; a main cytotoxic metabolite of 6-mercaptopurine) during acute lymphoblastic leukaemia maintenance therapy, by showing a linear association of DNA-TGN concentration and relapse risk. The authors conclude that measurement of DNA-TGN concentration might provide a new strategy to improve dose adjustment in maintenance therapy.

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[Correspondence] Do cytogenetics of acute lymphoblastic leukaemia blasts affect required duration and intensity of maintenance therapy? – Authors' reply

We thank Ravi Shah for his interest in our report1 describing a linear association between DNA-incorporated thioguanine nucleotides (DNA-TGN) level and risk of relapse among non-high-risk children with acute lymphoblastic leukaemia. We did not include karyotypes as covariates in the analyses, because the 5-year relapse rate for patients with ETV6/RUNX-translocation (seven relapses in 246 patients) was only 3·8% (95% CI 0·9–6·6), whereas it was 4·0% (1·5–6·4) for patients with a high-hyperdiploid clone (ten relapses in 326 patients), which precluded reliable conclusions.

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[Corrections] Correction to Lancet Oncol 2017; 18: 63–74

Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017; 18: 63–74—In the Summary and Results of this Article, the sentences regarding adverse events should have read "The most common grade 3–4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 178 participant cycles in the sodium thiosulfate group vs 145 [65%] of 224 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 149 vs 22 [12%] of 187)".

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[Clinical Picture] Malignancy in a child or something else?

A 2-year-old girl presented at the outpatient centre for rare skeletal diseases in children at the Children's Hospital, University of Cologne (Cologne, Germany) in 2015 with a massive swelling of the left femur, which her family reported had grown rapidly during the preceding 3 weeks. Radiography showed a large tumour on her left proximal femur with a homogenous hyperdense structure with visible cortical structures. A few small spikes were present at the edge of the mass but no signs of necrosis or periostal calcification were visible.

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[Cancer and Society] Chernobyl's tomb

It was a disaster on an unprecedented scale. When Reactor Number 4 at the Chernobyl nuclear power plant exploded in the early hours of April 26, 1986, it spewed out 400 times as much radiation as the bomb that devastated Hiroshima, Japan. The clean-up operation enlisted some 600 000 people. They hosed down surfaces and bulldozed and buried contaminated buildings. But the molten core of the nuclear reactor could not be buried, and more than 200 million tonnes of radioactive debris remained in the reactor building.

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[Review] Evolving adoptive cellular therapies in urological malignancies

Immunotherapies have long been used to treat urological cancers but rarely lead to cure. In the past 5 years, success of immune checkpoint inhibition has led to a resurgence of enthusiasm for immunotherapy in the treatment of solid tumours. Increased understanding of tumour immune biology, technological advancements of gene transfer and cell culture, and improved clinical infrastructures for routine delivery of cell products, has made cell-based immunotherapeutics a real prospect for cancer therapy.

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[Comment] Neoadjuvant chemotherapy in localised soft-tissue sarcomas: where do we go from here?

In The Lancet Oncology, Alessandro Gronchi and colleagues report a phase 3 trial1 randomly assigning 287 patients with localised, high-risk extremity and trunk wall soft-tissue sarcomas to receive three cycles of histotype-tailored chemotherapy versus a standard control of full-dose chemotherapy with epirubicin plus ifosfamide. With a median follow-up of 12·3 months (IQR 2·75–28·20), the trial was closed prematurely after the third interim analysis for futility because superiority for the histotype-tailored chemotherapy group was not to be expected for both the primary endpoint disease-free survival and the secondary endpoint overall survival.

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[Review] European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma

Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase.

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[Corrections] Correction to Lancet Oncol 2017; 18: 719–31

Steliarova-Foucher E, Colombet M, Ries LAG, et al, and the IICC-3 contributors. International incidence of childhood cancer, 2001–10: a population-based registry study. Lancet Oncol 2017; 18: 719–31—In this Article, the coverage of the population of east Asia in table 1 in the "Age 0–14 years" column should have been 4·4%, and in the "Age 15–19 years" column, 4·0%. Consequently, the fourth sentence in the first paragraph of the Results should have read "Approximately 11·4% of the world population aged 0–14 years (contributing 18 376 710 144 person-years) was covered by the registries included in our study, ranging from 1·7% in south Asia (India) to 99·4% in North America (table 1)." These corrections have been made to the online version as of June 2, 2017, and the printed Article is correct.

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[Correspondence] Short-course radiotherapy with delayed surgery for rectal cancer – Authors' reply

We thank Tomohiro Kurokawa and colleagues and Li Xie and colleagues for the interest in our trial, Stockholm III, and for their important comments.

http://ift.tt/2szorXM

[Comment] Improving childhood cancer care in Latin America and the Caribbean: a PAHO Childhood Cancer Working Group position statement

Most children with cancer live and die in low-income and middle-income countries (LMICs). Medical and health system advances have brought cure to more than 80% of children with cancer in high-income countries (HICs),1 but such advances have eluded children in most LMICs, where inequities can yield cure percentages anywhere from 5% to 60%.2 Multiple factors contribute to the inadequate care of childhood cancers in LMICs, including resource scarcity, health system fragility, limited provider awareness, and absence of political attention.

http://ift.tt/2rBkIMe

[Correspondence] Short-course radiotherapy with delayed surgery for rectal cancer

We read the article by Johan Erlandsson and colleagues 1 with great interest, and appreciate the authors' efforts to assess clinical outcomes for intermediate-risk patients with rectal cancers. Although the authors suggest that short-course radiotherapy with delayed surgery could be an alternative to conventional short-course radiotherapy with immediate surgery based on their non-inferiority trial, we would like to point out several concerns.

http://ift.tt/2sznDlA

[Comment] Under-representation of peritoneal metastases in published clinical trials of metastatic colorectal cancer

The present landscape of clinical trials for metastatic colorectal cancer is dominated by visceral metastases, as was highlighted at the recent American Society of Clinical Oncology Gastrointestinal Cancers conference held in San Francisco, CA, USA, in 2017. Peritoneal metastases are difficult to image by cross-sectional imaging and this leads to a disproportionate under-representation of this site of metastases in clinical trials.

http://ift.tt/2rBt9Hs

[Correspondence] Genetics of gallbladder cancer – Authors' reply

We would like to thank Kari Hemminki and colleagues for presenting empirical familial relative risk (FRR) estimates for gallbladder cancer based on the Swedish Family-Cancer Data (SFCD) providing a benchmark for comparison of heritability estimation for this rare malignancy. We do not find it surprising that the point estimate of GWAS FRR (FRR 3·15 [95% CI 1·80–5·49])1 from our study of Indian origin was higher than that from the empirical estimate in SFCD (2·47 [1·59–3·65]) in view of the difference in underlying populations and the large confidence intervals in both sets of estimates.

http://ift.tt/2szqLhz

[Correspondence] Short-course radiotherapy with delayed surgery for rectal cancer

We read with great interest the results from the recent Stockholm III trial, a multicentre, randomised, non-blinded, phase 3, non-inferiority trial done by Johan Erlandsson and colleagues,1 which compared short-course radiotherapy with immediate surgery, short-course radiotherapy with delayed surgery, and long-course radiotherapy with delayed surgery in locally advanced rectal cancer. However, some aspects of the study warrant closer attention.

http://ift.tt/2szpzuv

[Correspondence] “Finding NEMO” in NRAS-mutant melanoma: a step towards a sequential strategy?

We read with great interest the results of the NEMO trial by Reinhard Dummer and colleagues,1 a phase 3 study of binimetinib versus dacarbazine in advanced melanoma, which offers a long-awaited therapeutic alternative for patients with NRAS-mutant melanoma.

http://ift.tt/2szvyPU

[Cancer and Society] Art and emotion in health care

Cancer is about more than just a diagnosis; it's about the emotions, feelings, and families working through it together. The Summit Medical Group (Berkeley Heights, NJ, USA) is hosting the Visions of Hope/Voices of the Journey art exhibit that presents artwork from many perspectives and through the eyes of many current and former patients with cancer.

http://ift.tt/2szdFkb

Antagonistic Effect of Laver, Pyropia yezonensis and P. haitanensis , on Subchronic Lead Poisoning in Rats

Abstract

Lead, one of the most harmful heavy metals, can cause various hazardous effects on living organisms. This study was undertaken to evaluate the antagonistic and protective effects of two economically important laver species, Pyropia yezoensis and P. haitanensis, against subchronic lead poisoning in rats by a 30-day feeding test. Sixty-four healthy Wistar rats were randomly divided into eight groups with eight rats (4♂ + 4♀) per group, among which, one group was served as the control, the others were respectively treated with lead acetate (5 mg/kg b w), and a combination of lead acetate and P. yezoensis or P. haitanensis at different dosages. Weight gain of rats was observed and recorded. Changes in antioxidant indexes, and liver and renal function markers were determined to evaluate the antagonistic effect. Lead content in rats was determined to investigate lead excretion effect of laver. The results showed that exposure to lead caused lead accumulation in kidney and liver, thus leading to significant oxidative damage and impaired liver and renal function compared to the control group. The co-treatment of laver slightly increased body weight compared to the lead-treated group. The co-administration of laver restored liver and renal function of rats by preventing the increment in the activities of alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate transaminase (AST), and the levels of blood urea nitrogen (BUN) and creatinine (Cr). The increasing of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and lowering of the enhanced malondialdehyde (MDA) contents of rats were observed in the laver co-treated groups, which indicated that laver enhanced the antioxidative capacity of rats. The laver also enhanced lead content in feces and reduced it in liver and kidney. The results indicated that P. yezoensis and P. haitanensis could maintain or promote the normal physiological and biochemical function of lead-induced subchronic poisoning of rats, probably owing to their enhancements of antioxidant capacity and lead excretion.

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Dietary Iodine Affected the GSH-Px to Regulate the Thyroid Hormones in Thyroid Gland of Rex Rabbits

Abstract

Iodine (I) is an essential trace element that can influence animal health and productivity. In this study, we investigated the effects of dietary iodine on the antioxidant indices of organ (liver and thyroid gland) and messenger RNA (mRNA) expression of glutathione peroxidase (GSH-Px) in Rex rabbits. A total of 120 4-month-old Rex rabbits (2235.4 ± 13.04 g BW) were divided into four equal groups, and their diets were supplemented with iodine (0, 0.2, 2, or 4 mg/kg dry matter (DM)). The iodine concentration in basal diet (control group) was 0.36 mg/kg DM. In most of measured parameters, supplemental iodine exerted no significant effect. Growth and slaughter performance and organ weight were not influenced significantly by iodine supplementation. Serum T₃ was significantly lower in 2-mg I group than in 0.2 and 4-mg I groups (P < 0.05). Superoxide dismutase (SOD), GSH-Px, methane dicarboxylic aldehyde (MDA), and thyroperoxidase (TPO) in the serum and liver were not influenced (P > 0.05). Conversely, serum catalase (CAT) was significantly reduced (P < 0.05). In the thyroid, GSH-Px was higher in the 2-mg I group than in the 0.2- and 4-mg I groups (P < 0.05). RT-PCR results showed that the mRNA expression level of GSH-Px in the liver was not significantly influenced (P > 0.05). In the thyroid gland, the mRNA expression level of GSH-Px was higher in the 2-mg I group than in the 4-mg I group (P < 0.05), which agreed with the activity of GSH-Px. In conclusion, iodine supplementation exerted no effect on the performance and antioxidant capacity of the body, but dietary iodine influenced serum T₃ or GSH-Px in the thyroid gland. Thus, on the basis of serum T₃ and GSH-Px levels in the thyroid gland, we hypothesized that GSH-Px secretion was increased by adding dietary iodine in the thyroid, which may inhibit the H₂O₂ generation and further influence the thyroid hormone synthesis.

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Antagonistic Effect of Laver, Pyropia yezonensis and P. haitanensis , on Subchronic Lead Poisoning in Rats

Abstract

http://ift.tt/2sojAcT

Dietary Iodine Affected the GSH-Px to Regulate the Thyroid Hormones in Thyroid Gland of Rex Rabbits

Abstract

http://ift.tt/2rP11RP

Unusual neoplasm on the hard palate of a child: a case report

Myoepitheliomas account for less than 1% of salivary gland tumors. They mostly affect the parotid glands of adults during the third to fifth decades.

http://ift.tt/2rANcFN

Dissection of the internal carotid artery and stroke after mandibular fractures: a case report and review of the literature

We present a report of a patient with blunt trauma and mandibular fractures who developed a significant cerebral infarction due to an initially unrecognized injury of her left internal carotid artery. We belie...

http://ift.tt/2syTQcH

Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America

Abstract

Purpose

Acral lentiginous melanoma (ALM) is a poor prognosis subtype and is the most prevalent in non-Caucasian populations. The presence of tumor infiltrating lymphocytes (TILs) has been associated with poor prognosis in melanoma. A large cohort of ALM cases was studied to determine status of TIL and its association with outcome.

Methods

All patients with cutaneous melanoma presenting from 2005 to 2012 at Instituto Nacional de Enfermedades Neoplasicas in Peru were retrospectively identified. Clinicopathological information was obtained from the medical charts. A prospective evaluation of TIL was performed. Analysis of association between ALM and clinicopathological features including TIL as well as survival analysis compared the outcome of ALM to whole group and extremity NALM was performed.

Results

537 ALM from a total of 824 cutaneous melanoma cases were studied. Older age (p = 0.022), higher Breslow (p = 0.008) and ulceration (p < 0.001) were found to be more frequent in ALM. Acral had worse overall survival (OS) compared with the whole group (p = 0.04). Clinical stage (CS) I–II patients had a median OS of 5.3 (95% CI 4.3–6.2) for ALM and 9.2 (95% CI 5.0–7.0) for extremity NALM (p = 0.016). Grade 0 (absence of TIL), I, II and III were found in 7.5, 34.5, 32.1, and 25.9%, respectively. Lower TIL grade was associated with larger tumor size (p = 0.003), higher Breslow (p = 0.001), higher Clark level (p = 0.007), higher CS (p = 0.002), extremity location (p = 0.048), histological subtype ALM (p = 0.024) and better OS (p = 0.001).

Conclusions

ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

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Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

Abstract

Purpose

Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance.

Methods

To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters.

Results

Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data.

Conclusions

Simulations predicted lower steady-state peak/trough olaparib exposure through 24–36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

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Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America

Abstract

Purpose

Methods

Results

Conclusions

ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

http://ift.tt/2rtdAiM

Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

Abstract

Purpose

Methods

Results

Conclusions

Simulations predicted lower steady-state peak/trough olaparib exposure through 24–36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

http://ift.tt/2rtp0De

Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

Abstract

Purpose

Methods

Results

Conclusions

Simulations predicted lower steady-state peak/trough olaparib exposure through 24–36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

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Receptor activator of nuclear factor kappa B (RANK) expression in primary breast cancer correlates with recurrence-free survival and development of bone metastases in I-SPY1 (CALGB 150007/150012; ACRIN 6657)

Abstract

Purpose

The receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis may contribute to the development of bone metastases (BM). We studied gene expression in this pathway in primary breast cancer (BC) to determine correlations with clinical characteristics and outcomes in the neoadjuvant I-SPY1 study.

Methods

We evaluated RANK/RANKL/OPG expression using expression microarrays in I-SPY1 (n = 149). Associations with clinical features were determined using t test and ANOVA. Associations between biomarker high versus low groups (dichotomized at an optimal cutpoint) and recurrence-free survival (RFS) were evaluated using the log-rank test and in a multivariate Cox proportional hazard model. A pooled external neoadjuvant cohort with gene expression data (GSE25066) (Hatzis et al. in JAMA 305(18):1873–1881, 30) (n = 425) was used for validation. Associations with site-specific relapse were evaluated using the t-test and multivariate logistic regression adjusting for hormone receptor (HR) status.

Results

RANK was significantly higher in HR negative versus HR positive (p = 0.027), in basal versus non-basal disease (p = 0.004), and in those achieving pathologic complete response (p = 0.038); the associations with HR negative and basal BC were also significant in GSE25066. In both datasets, higher RANK associated with significantly worse RFS (I-SPY1: p = 0.045, GSE25066: p = 0.044). However, this association did not remain significant after adjusting for HR status. In I-SPY1 patients with recurrence, higher RANK correlated with BM versus non-BM (p = 0.045), even after adjusting for HR status (p = 0.035).

Conclusions

RANK is increased in HR negative and basal BC, and correlates with worse RFS and risk of BM. The RANK pathway is a potential therapeutic target in BC.

http://ift.tt/2qP6Rxu

Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America

Abstract

Purpose

Methods

Results

Conclusions

ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

http://ift.tt/2rtdAiM

Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America

Abstract

Purpose

Methods

Results

Conclusions

ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

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Assessment of treatment response during chemoradiation therapy for pancreatic cancer based on quantitative radiomic analysis of daily CTs: An exploratory study

by Xiaojian Chen, Kiyoko Oshima, Diane Schott, Hui Wu, William Hall, Yingqiu Song, Yalan Tao, Dingjie Li, Cheng Zheng, Paul Knechtges, Beth Erickson, X. Allen Li

Purpose

In an effort for early assessment of treatment response, we investigate radiation induced changes in quantitative CT features of tumor during the delivery of chemoradiation therapy (CRT) for pancreatic cancer.

Methods

Diagnostic-quality CT data acquired daily during routine CT-guided CRT using a CT-on-rails for 20 pancreatic head cancer patients were analyzed. On each daily CT, the pancreatic head, the spinal cord and the aorta were delineated and the histograms of CT number (CTN) in these contours were extracted. Eight histogram-based radiomic metrics including the mean CTN (MCTN), peak position, volume, standard deviation (SD), skewness, kurtosis, energy and entropy were calculated for each fraction. Paired t-test was used to check the significance of the change of specific metric at specific time. GEE model was used to test the association between changes of metrics over time for different pathology responses.

Results

In general, CTN histogram in the pancreatic head (but not in spinal cord) changed during the CRT delivery. Changes from the 1^st to the 26^th fraction in MCTN ranged from -15.8 to 3.9 HU with an average of -4.7 HU (p Conclusions

Significant changes in CT radiomic features, such as the MCTN, skewness, and kurtosis in tumor were observed during the course of CRT for pancreas cancer based on quantitative analysis of daily CTs. These changes may be potentially used for early assessment of treatment response and stratification for therapeutic intensification.

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Assessment of treatment response during chemoradiation therapy for pancreatic cancer based on quantitative radiomic analysis of daily CTs: An exploratory study

by Xiaojian Chen, Kiyoko Oshima, Diane Schott, Hui Wu, William Hall, Yingqiu Song, Yalan Tao, Dingjie Li, Cheng Zheng, Paul Knechtges, Beth Erickson, X. Allen Li

Purpose

Methods

Results

http://ift.tt/2s2DL2q

Unenhanced magnetic resonance screening using fused diffusion-weighted imaging and maximum-intensity projection in patients with a personal history of breast cancer: role of fused DWI for postoperative screening

Abstract

Purpose

To assess the diagnostic performance of unenhanced abbreviated protocol (AP) comprising fused diffusion-weighted imaging (DWI) using T1-weighted imaging (T1WI) with DWI maximum-intensity projections (DWI MIPs) for screening patients with a personal history of breast cancer (PHBC).

Methods

This institutional review board-approved retrospective observational study included 343 patients with PHBC who underwent 3T breast magnetic resonance imaging (MRI) between November 2013 and September 2015. Three breast radiologists reviewed the DWI MIPs of the AP to identify lesions, and the remaining axial AP images to characterize the detected lesions and establish the breast imaging reporting and data system final assessment. The conventional protocol (CP) images were also evaluated in the same way. The decision-making times were recorded.

Results

MRI acquisition time was approximately 5 min for AP. The mean times to read MIPs and remaining images were shorter in AP than in CP (5.5 and 22.1 s vs. 7.8 and 29.6 s). On DWI MIPs, the readers detected 9, 8, and 9 of 9 pathologically proven cancers, with negative predictive values (NPVs) of 100.0, 99.6, and 100.0%. Complete AP showed sensitivities of 88.9, 100.0, and 88.9% and specificities of 94.8, 93.4, and 95.1%. Complete CP showed sensitivities of 100.0, 100.0, and 88.9% and specificities of 93.4, 94.0, and 96.3%.

Conclusions

An unenhanced AP had a short acquisition time of 5 min, and DWI MIPs showed NPVs greater than 99% across readers. The diagnostic performance of complete AP was equivalent to that of CP for screening patients with PHBC.

http://ift.tt/2rkdawN

Deep neuromuscular block to optimize surgical space conditions during laparoscopic surgery: a systematic review and meta-analysis

Abstract

Neuromuscular block (NMB) is frequently used in abdominal surgery to improve surgical conditions by relaxation of the abdominal wall and prevention of sudden muscle contractions. The evidence supporting routine use of deep NMB is still under debate. We aimed to provide evidence for the superiority of routine use of deep NMB during laparoscopic surgery. We performed a systematic review and meta-analysis of studies comparing the influence of deep vs moderate NMB during laparoscopic procedures on surgical space conditions and clinical outcomes. Trials were identified from Medline, Embase, and Central databases from inception to December 2016. We included randomized trials, crossover studies, and cohort studies. Our search yielded 12 studies on the effect of deep NMB on the surgical space conditions. Deep NMB during laparoscopic surgeries improves the surgical space conditions when compared with moderate NMB, with a mean difference of 0.65 (95% confidence interval (CI): 0.47–0.83) on a scale of 1–5, and it facilitates the use of low-pressure pneumoperitoneum. Furthermore, deep NMB reduces postoperative pain scores in the postanaesthesia care unit, with a mean difference of − 0.52 (95% CI: −0.71 to − 0.32). Deep NMB improves surgical space conditions during laparoscopic surgery and reduces postoperative pain scores in the postanaesthesia care unit. Whether this leads to fewer intraoperative complications, an improved quality of recovery, or both after laparoscopic surgery should be pursued in future studies. The review methodology was specified in advance and registered at Prospero on July 27, 2016, registration number CRD42016042144.

http://ift.tt/2sn2rjM

Bank blood shortage, transfusion containment and viscoelastic point-of-care coagulation testing in cardiac surgery

In January 2017, many Italian hospitals (including my own institution) were forced to reduce the number of major surgical operations because of a severe shortage of packed red blood cells (RBCs). Blood banks warned that donors with blood group O (both O+ and O–) were scarce, and imposed that units of RBCs of this group were to be reserved for non-postponable major surgeries. Subsequently, other blood groups were affected by the shortage. On January 12, 2017 the National Blood Center warned that about 2600 RBC units were lacking in nine Italian regions. This emergency, resulting from the combination of Christmas holidays and an outbreak of influenza, came to an end by the end of January.

http://ift.tt/2rN7dtD

Hydrogen peroxide: more harm than good?

Editor—Hydrogen peroxide remains a frequently used agent in operating theatres despite its marginal benefits and potential for serious complications. We are writing to remind anaesthetists of the risks of hydrogen peroxide use and pose the question: does hydrogen peroxide cause more harm than good?

http://ift.tt/2smPVAr

More or less? The Goldilocks Principle as it applies to red cell transfusions

The quest for the optimal haemoglobin threshold (previously referred to as 'trigger') for red blood cell transfusion seems a never-ending journey. As if we are chasing a mirage, the closer we seem to think we get to the 'just right' haemoglobin level, the further it seems to move away. Applying the 'Goldilocks Principle' to transfusion of red cells, regardless of the population queried, appears to yield results that satisfy some investigators but leave many practitioners still wondering what is best for the patient.

http://ift.tt/2rNjjCY

Maintaining oxygenation with high-flow nasal cannula during emergent awake surgical tracheostomy

Editor—Patients presenting with acute upper airway obstruction are at significant risk of morbidity and continue to be managed poorly.¹ Although several approaches can be taken, surgical tracheostomy placement under local anaesthesia is recommended because it ensures patients are kept awake, maintaining airway patency.² This poses several challenges for the anaesthetist, including limited access to the surgical field and risk of complete airway obstruction in a patient with potentially limited reserve.

http://ift.tt/2smz4Oa

The great fluid debate: time for Flexit?

'Insanity is doing the same thing over and over again and expecting different results'—attributed to A. Einstein

http://ift.tt/2rNPzG2

Oesophageal Doppler guided goal-directed haemodynamic therapy in thoracic surgery - a single centre randomized parallel-arm trial

Abstract

Background: Postoperative pulmonary and renal complications are frequent in patients undergoing lung surgery. Hyper- and hypovolaemia may contribute to these complications. We hypothesized that goal-directed haemodynamic management based on oesophageal Doppler monitoring would reduce postoperative pulmonary complications in a randomized clinical parallel-arm trial.Methods: One hundred patients scheduled for thoracic surgery were randomly assigned to either standard haemodynamic management (control group) or goal-directed therapy (GDT group) guided by an oesophageal Doppler monitoring-based algorithm. The primary endpoint was postoperative pulmonary complications, including spirometry. Secondary endpoints included haemodynamic variables, renal, cardiac, and neurological complications, and length of hospital stay. The investigator assessing outcomes was blinded to group assignment.Results: Forty-eight subjects of each group were analysed. Compared to the control group, fewer subjects in the GDT group developed postoperative pulmonary complications (6 vs. 15 patients; P = 0.047), while spirometry did not differ between groups. Compared to the control group, patients of the GDT group showed higher cardiac index (2.9 vs. 2.1 [l min⁻¹ m ^− 2]; P < 0.001) and stroke volume index (43 vs. 34 [ml m²]; P < 0.001) during surgery. Renal, cardiac and neurological complications did not differ between groups. Length of hospital stay was shorter in the GDT compared to the control group (9 vs. 11 days; P = 0.005).Conclusions: Compared to standard haemodynamic management, oesophageal Doppler monitor-guided GDT was associated with fewer postoperative pulmonary complications and a shorter hospital stay.Clinical trial registration. The study was registered in the German Clinical Trials Register (DRKS 00006961). http://ift.tt/2lU1COS

http://ift.tt/2smEgSs

Perioperative use of beta-blockers in vascular and endovascular surgery

Editor—We were disappointed to read the content of the recent article by Hajibandeh and colleagues¹ in the British Journal of Anaesthesia. Since the early, implausible reports of long-term benefit attributable to short-term perioperative beta-blockade, there has been increasing scepticism of this treatment among both anaesthetists and cardiologists.^2–8 Following the early criticisms of publications by Mangano and colleagues and Poldermans' group, the specialty of anaesthesia has discovered that the conclusions of these workers were baseless.⁹ This is because of a flawed analysis on the basis of 'intention to treat' with respect to the study by Mangano and colleagues and a seriously discredited first author in the case of the Poldermans' study.² ⁸ ³

http://ift.tt/2smRPkU

Perioperative use of beta-blockers in vascular and endovascular surgery

Editor—I thank Drs Bolsin and Conroy¹ for raising their concerns regarding a recent publication by Hajibandeh and colleagues² in the British Journal of Anaesthesia. There is no doubt that the role of perioperative beta-blockade has come under close scrutiny since the 1990s,³ ⁴ but it is misleading to describe the conclusions of the trial by Mangano and colleagues⁵ as 'baseless' despite there being some legitimate criticisms of its design and interpretation. The Mangano data have been used by others in other systematic reviews.⁶ ⁷ We agree that data derived from the DECREASE trials are unreliable.

http://ift.tt/2rNyHQ3

Characterization of peripheral and central sensitization after dorsal root ganglion intervention in patients with unilateral lumbosacral radicular pain: a prospective pilot study

Abstract

Background. Quantitative sensory testing (QST) has been used to predict the outcome of epidural steroid injections in lumbosacral radicular pain and has the potential to be an important tool in the selection of appropriate treatment (such as epidural steroid injections vs surgery) for patients with chronic radicular pain. In addition, QST assists in identification of the pain pathways of peripheral and central sensitization in selected groups of patients.Methods. Twenty-three patients were given dorsal root ganglion (DRG) infiltration with local anaesthesia and steroid ('DRG block'), and those who demonstrated at least 50% pain relief were offered pulsed radiofrequency (PRF) to the DRG. Questionnaires and QST scores were measured before the DRG blocks and at 1 week and 3 months after their procedure. Those who received PRF also answered questionnaires and underwent QST measurements at 1 week and 3 months after their procedure.Results. There was a significant increase in pressure pain threshold scores after DRG blocks. A reduced conditioned pain modulation response was seen before DRG, which increased after the procedure. Ten out of 23 patients underwent PRF to the DRG, and an increase in pressure pain threshold scores after PRF was observed. The conditioned pain modulation response was maintained in this group and increased after PRF.Conclusions. The study demonstrates that patients with unilateral radicular low back pain who receive dorsal root ganglion interventions show changes in pressure pain thresholds and conditioned pain modulation that are consistent with a 'normalization' of peripheral and central sensitization.

http://ift.tt/2rNn8If

Raw EEG characteristics, bispectral index, and suppression ratio variations during generalized seizure in electroconvulsive therapy

Editor—We wish to report our findings of an observational prospective study of raw EEG characteristics, bispectral index (BIS) and suppression ratio (SR) variations during a generalized tonic–clonic seizure induced by electroconvulsive therapy (ECT). After obtaining the approval of the Ethics Committee for biomedical research, 20 patients were included for a total of 39 sessions. The BIS sensor (BIS Quatro, Medtronic-minneapolis USA) was connected to the BIS-VISTA^® (Medtronic-minneapolis USA) monitor (smoothing rate, 10 s). The BIS and SR values were retained for analysis if their corresponding signal quality index were ≥50 and EMG ≤50. To overcome electromagnetic interference, we excluded from analysis all BIS and SR values obtained from the end of the electrical impulse to 15 s later. Sedation was induced with a bolus of propofol [(median dose 0.86 (interquartile range 0.68–1) mg kg⁻¹] after 3 min of preoxygenation. Suxamethonium [median dose 1.1 (range 1–1.2) mg kg⁻¹] was injected 30 s after loss of the ciliary reflex. Electroconvulsive therapy began at least 30 s after the end of fasciculation and after the stabilization of BIS. The lungs were ventilated until ECT began, in order to avoid hypercapnia. Differences between BIS and SR values were analysed with the Friedman test, and when a significant difference was encountered the trend over time was analysed by a Mann–Kendall test. Statistical significance was assumed at P<0.05.

http://ift.tt/2rNnPSb

Perioperative use of beta-blockers in vascular and endovascular surgery

Editor—Thank you for the opportunity to respond to the letter from Bolsin and Conroy¹ in reference to our systematic review and meta-analysis of randomized clinical trials and observational studies investigating the effect of perioperative use of beta-blockers in vascular and endovascular surgery.² They express their concerns regarding the inclusion of two observational studies³ ⁴ and a randomized clinical trial,⁵ and suggest that these studies should be excluded from the meta-analysis because of allegations of scientific misconduct of the senior (or first) author, D. Poldermans, of these studies. Of note, the randomized trial⁵ (related to the DECREASE-1 study) has already been excluded from our analysis in light of the expression of concern published by the editors of the European Heart Journal.⁶

http://ift.tt/2rN9hle

Ventilation through an extraglottic tracheal tube: a technique for deep extubation and airway control

Editor—Tracheal extubation after general anesthesia is a critical event of an anaesthetic, probably more important than induction and intubation of the airway; minor complications can result in significant morbidity and even mortality.¹ ² Both the Fourth National Audit Project and the ASA closed claims analysis reported complications from extubation.³ ⁴ The Difficult Airway Society developed a systematic approach to anticipated easy extubations and to those deemed difficult. Asleep extubation (commonly referred to as deep extubation), as opposed to awake extubation, is in a different arm of the Difficult Airway Society algorithm from the easy airway extubation.⁵

http://ift.tt/2smo2IV

25-Hydroxyvitamin D deficiency among anaesthesiologists and anaesthesiology residents in Chile

Editor—Approximately one billion people worldwide have 25-hydroxyvitamin D (25OHD) deficiency.^1–3 The Endocrine Society considers plasma levels equal or lower than 20 ng mL⁻¹ as a deficiency and levels higher than 30 ng mL⁻¹ as optimal levels.⁴ Low sunlight exposure is the determining factor for 25OHD deficiency. Such factor relies on the season and the latitude of residence, among others.⁵ ⁶ Indoor work is associated with a low sunlight exposure. Therefore, anaesthesiologists may be at risk of developing deficient levels of 25OHD. The prevalence of 25OHD deficiency in this population remains unknown.

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Prediction of postoperative mortality in elderly patients with hip fracture: are specific and geriatric scores better than general scores?

Editor—Elderly patients with hip fracture are at high risk of mortality. An accurate prediction of postoperative mortality is important for communicating information, in guiding decision-making, and management. Among preoperative scores, the ASA physical status score does not consider the surgery, makes no adjustment for age, and is subjective.¹ The PreOperative Score to predict PostOperative Mortality (POSPOM) is more accurate but has not been validated specifically in elderly patients.² Many geriatric scores focusing on multimorbidity, such as the Cumulative Illness Rating Scale (CIRS)³ and Charlson comorbidity index,⁴ have been proposed but not validated for postoperative prediction, and specific scores, such as the Nottingham Hip Fracture Score (NHFS), have also been proposed.⁵ We tested the hypothesis that specific or geriatric scores predict postoperative mortality better than general scores in this frail population.

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Effects of arterial load variations on dynamic arterial elastance: an experimental study

Abstract

Background. Dynamic arterial elastance (Ea_dyn), the relationship between pulse pressure variation (PPV) and stroke volume variation (SVV), has been suggested as a functional assessment of arterial load. The aim of this study was to evaluate the impact of arterial load changes during acute pharmacological changes, fluid administration, and haemorrhage on Ea_dyn.Methods. Eighteen anaesthetized, mechanically ventilated New Zealand rabbits were studied. Arterial load changes were induced by phenylephrine (n=9) or nitroprusside (n=9). Thereafter, animals received a fluid bolus (10 ml kg⁻¹), followed by stepwise bleeding (blood loss: 15 ml kg⁻¹). The influence of arterial load and cardiac variables on PPV, SVV, and Ea_dyn was analysed using a linear mixed-effects model analysis.Results. After phenylephrine infusion, mean (sd) Ea_dyn decreased from 0.89 (0.14) to 0.49 (0.12), P<0.001; whereas after administration of nitroprusside, Ea_dyn increased from 0.80 (0.23) to 1.28 (0.21), P<0.0001. Overall, the fluid bolus decreased Ea_dyn [from 0.89 (0.44) to 0.73 (0.35); P<0.01], and haemorrhage increased it [from 0.78 (0.23) to 0.95 (0.26), P=0.03]. Both PPV and SVV were associated with similar arterial factors (effective arterial elastance, arterial compliance, and resistance) and heart rate. Furthermore, PPV was also related to the acceleration and peak velocity of aortic blood flow. Both arterial and cardiac factors contributed to the evolution of Ea_dyn throughout the experiment.Conclusions. Acute modifications of arterial load induced significant changes on Ea_dyn; vasodilatation increased Ea_dyn, whereas vasoconstriction decreased it. The Ea_dyn was associated with both arterial load and cardiac factors, suggesting that Ea_dyn should be more properly considered as a ventriculo-arterial coupling index.

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Pharmacokinetics and pharmacodynamics of propofol: changes in patients with frontal brain tumours

Abstract

Background: Models of propofol pharmacokinetics and pharmacodynamics developed in patients without brain pathology are widely used for target-controlled infusion (TCI) during brain tumour excision operations. The goal of this study was to determine if the presence of a frontal brain tumour influences propofol pharmacokinetics and pharmacodynamics and existing PK-PD model performance.Methods: Twenty patients with a frontal brain tumour and 20 control patients received a propofol infusion to achieve an induction–emergence–induction anaesthetic sequence. Propofol plasma concentration was measured every 4 min and at each transition of the conscious state. Bispectral index (BIS) values were continuously recorded. We used non-linear mixed-effects modelling to analyse the effects of the presence of a brain tumour on the pharmacokinetics and pharmacodynamics of propofol. Subsequently we calculated the predictive performance of Marsh, Schnider, and Eleveld models in terms of median prediction error (MdPE) and median absolute prediction error (MdAPE).Results: Patients with brain tumours showed 40% higher propofol clearance than control patients. Performance of the Schnider model (MdPEpk −20.0%, MdAPEpk 23.4%) and Eleveld volunteer model (MdPEpk −8.58%, MdAPEpk 21.6%) were good. The Marsh model performed less well (MdPEpk −14.3%, MdAPEpk 41.4%), as did the Eleveld patient model (MdPEpk −30.8%, MdAPEpk 32.1%).The first-order rate constant (k_e0; 0.108 min⁻¹), the concentration in the effects compartment associated with 50% of the maximum effect (Ce₅₀; 2.77 ml litre⁻¹) and γ (1.49) did not significantly differ between groups. Lower baseline BIS values were found in patients with brain tumours (90 vs 95).Conclusions: Brain tumours might alter the pharmacokinetics of propofol. Caution should be exerted when using propofol TCI in patients with frontal brain tumours due to higher clearance.Trial registry number: NCT01060631.

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Randomized equivalence trial of the King Vision aBlade videolaryngoscope with the Miller direct laryngoscope for routine tracheal intubation in children <2 yr of age

Abstract

Background. We conducted a randomized equivalence trial to compare direct laryngoscopy using a Miller blade (DL) with the King Vision videolaryngoscope (KVL) for routine tracheal intubation. We hypothesized that tracheal intubation times with DL would be equivalent to the KVL in children <2 yr of age.Methods. Two hundred children were randomly assigned to tracheal intubation using DL or KVL. The primary outcome was the median difference in the total time for successful tracheal intubation. Secondary outcomes assessed were tracheal intubation attempts, time to best glottic view, time for tracheal tube entry, percentage of glottic opening score, airway manoeuvres needed, and complications.Results. The median difference between the groups was 5.7 s, with an upper 95% confidence interval of 7.5 s, which was less than our defined equivalence time difference of 10 s. There were no differences in the number of tracheal intubation attempts and the time to best glottic view [DL median 5.3 (4.1–7.6) s vs KVL 5.0 (4.0–6.3) s; P=0.19]. The percentage of glottic opening score was better when using the KVL [median 100 (100–100) vs DL median 100 (90–100); P<0.0001]. Use of DL was associated with greater need for airway manoeuvres during tracheal intubation (33 vs 7%; P<0.001). Complications did not differ between devices.Conclusions. In children <2 yr of age, the KVL was associated with equivalent times for routine tracheal intubation when compared with the Miller blade.Clinical trial registration NCT02590237.

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Predictive performance of the modified Marsh and Schnider models for propofol in underweight patients undergoing general anaesthesia using target-controlled infusion

Abstract

Background: In our preliminary study, the modified Marsh (M-Marsh) model caused an inadvertent underdosing of propofol in underweight patients. However, the predictive performance of the M-Marsh and Schnider models incorporated in commercially available target-controlled infusion (TCI) pumps was not evaluated in underweight patients.Methods: Thirty underweight patients undergoing elective surgery were randomly allocated to receive propofol via TCI using the M-Marsh or Schnider models. The target effect-site concentrations (Ces) of propofol were, in order, 2.5, 3, 4, 5, 6 and 2 μg ml⁻¹. Arterial blood samples were obtained at least 7 min after achieving each pseudo-steady-state.Results: A total of 172 plasma samples were used to determine the predictive performance of both models. The pooled median (95% confidence interval) biases and inaccuracies at a target Ce ≤ 3 μg ml⁻¹ were −22.6 (−28.8 to −12.6) and 31.9 (24.8–36.8) for the M-Marsh model and 9.0 (1.7–16.4) and 28.5 (21.7–32.8) for the Schnider model, respectively. These values at Ce ≥ 4 μg ml⁻¹ were −9.6 (−16.0 to −6.0) and 24.7 (21.1–27.9) for the M-Marsh model and 19.8 (12.9–25.7) and 36.2 (31.4–39.7) for the Schnider model, respectively.Conclusions: The pooled biases and inaccuracies of both models were clinically acceptable. However, the M-Marsh and Schnider models consistently produced negatively and positively biased predictions, respectively, in underweight patients. In particular, the M-Marsh model showed greater inaccuracy at target Ce ≤ 3 μg ml⁻¹ and the Schnider model showed greater inaccuracy at target Ce ≥ 4 μg ml⁻¹. Therefore, it is necessary to develop a new pharmacokinetic model for propofol in underweight patients.Clinical trial registration: KCT0001502.

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