CAR T cells targeting solid tumors: carcinoembryonic antigen (CEA) proves to be a safe target

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Coexistence of multiple genotypes of porcine epidemic diarrhea virus with novel mutant S genes in the Hubei Province of China in 2016

Abstract

The emergence of highly virulent porcine epidemic diarrhea virus (PEDV) variants in China caused huge economic losses in 2010. Since then, large-scale sporadic outbreaks of PED caused by PEDV variants have occasionally occurred in China. However, the molecular diversity and epidemiology of PEDV in different provinces has not been completely understood. To determine the molecular diversity of PEDV in the Hubei Province of China, we collected 172 PED samples from 34 farms across the province in 2016 and performed reverse transcription polymerase chain reaction (RTPCR) by targeting the nucleocapsid (N) gene. Seventy-four samples were found to be PEDVpositive. We further characterized the complete spike (S) glycoprotein genes from the positive samples and found 21 different S genes with amino acid mutations. The PEDV isolates here presented most of the genotypes which were found previously in field isolates in East and South-East Asia, North America, and Europe. Besides the typical Genotypes I and II, the INDEX groups were also found. Importantly, 58 new amino acids mutant sites in the S genes, including 44 sites in S1 and 14 sites in S2, were first described. Our results revealed that the S genes of PEDV showed variation and that diverse genotypes of PEDV coexisted and were responsible for the PED outbreaks in Hubei in 2016. This work highlighted the complexity of the epidemiology of PEDV and emphasized the need for reassessing the efficacy of classic PEDV vaccines against emerging variant strains and developing new vaccines to facilitate the prevention and control of PEDV in fields.

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Incidence and risk of cardiotoxicity in cancer patients treated with targeted therapies

Publication date: Available online 28 July 2017
Source:Cancer Treatment Reviews
Author(s): Matteo Santoni, Federico Guerra, Alessandro Conti, Alessandra Lucarelli, Silvia Rinaldi, Laura Belvederesi, Alessandro Capucci, Rossana Berardi
BackgroundCardiotoxicityis a serious side effect of molecularly targeted agents. The purpose of this study was to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade cardiotoxicity in patients with solid tumors receiving targeted agents through a revised meta-analysis of available clinical trials.MethodsThe scientific literature regarding cardiotoxicity was extensively analyzed using MEDLINE, PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.ResultsOur search yielded a total of 4998 clinical studies; of them, 31 trials were finally considered for this meta-analysis. A total of 28538 patients were included; 7995 of these patients had breast cancer (28%), 6151 (22%) prostate cancer and 14392 (50%) were treated for other malignancies. The highest RR of high-grade events was observed with Vandetanib (RR=7.71, 95% CI 1.04–56.99), followed by Ramucirumab (RR=5.0) and Aflibercept (RR=4.1). Grouping by drug category, the highest incidence of high-grade cardiotoxicity was shown by anti-VEGFR-TKIs (RR 5.62, 95% CI 1.49–21.24) and anti-VEGF mAbs/VEGF-trap (RR 1.82, 95% CI 1.24–2.69). Grouping by tumor type, the highest incidence of cardiotoxicity was observed in thyroid cancer (8%), followed by gastric cancer (4%).ConclusionsTreatment with targeted agents in cancer patients is correlated with a significant increase in the risk of cardiotoxicity. Frequent clinical monitoring should be emphasized when using these and newer biological agents.



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Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration

Publication date: Available online 27 July 2017
Source:Cell Stem Cell
Author(s): Yangfei Xiang, Yoshiaki Tanaka, Benjamin Patterson, Young-Jin Kang, Gubbi Govindaiah, Naomi Roselaar, Bilal Cakir, Kun-Yong Kim, Adam P. Lombroso, Sung-Min Hwang, Mei Zhong, Edouard G. Stanley, Andrew G. Elefanty, Janice R. Naegele, Sang-Hun Lee, Sherman M. Weissman, In-Hyun Park
Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development.

Graphical abstract

Teaser

Xiang and colleagues report a method for generating human medial ganglionic eminence (MGE)-like organoids (hMGEOs) and cortical-like organoids (hCOs), which resemble the developing human MGE and cortex, respectively. By fusing hMGEOs and hCOs, they establish a 3D model to investigate human interneuron migration.


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A Phase I study to determine safety, pharmacokinetics, and pharmacodynamics of ANF-RHO™, a novel PEGylated granulocyte colony-stimulating factor, in healthy volunteers

Summary

Patients receiving pegfilgrastim (Neulasta®) for the treatment of neutropenia can experience bone pain following the injections required to achieve effective neutrophil levels. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of ANF-RHO™, a novel pegylated granulocyte colony stimulating factor, were assessed in a randomized, controlled, double-blind Phase 1 clinical study in healthy volunteers. Subjects received a single subcutaneous dose of ANF-RHO over a range of 6 doses (5–50 μg/kg), placebo (saline), or the recommended clinical dose of pegfilgrastim administered at the labeled fixed 6 mg dosage (equivalent to 80–100 μg/kg). The primary outcome measure was safety and tolerability. Secondary outcomes included PK and PD effects on absolute neutrophil count (ANC) and number of CD34+ progenitor cells. Severity of bone pain was also assessed. In healthy volunteers, ANF-RHO was administered at ascending doses up to 50 μg/kg without significant adverse effects; appeared to be better (5 to 30 μg/kg) or equally well (50 μg/kg) tolerated, and had lower mean bone pain scores as compared to pegfilgrastim. ANF-RHO achieved CD34+ and ANC numbers at significantly lower doses, and had a significantly longer circulating half-life than pegfilgrastim. These results suggest that ANF-RHO can be provided less frequently, at a lower dose, and with fewer side effects. ANF-RHO had unique, prolonged PK/PD attributes as compared to marketed pegfilgrastim, suggesting that it may provide an improved clinical benefit in further clinical studies in patients with chemotherapy-induced or chronic idiopathic neutropenia.

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Acquired pachydermatoglyphia: the cutaneous manifestation of pulmonary tumours

Description

A 74-year-old man with active smoking habits presented to the emergency department with a 2-month history of weight loss (20% of previous body mass), dyspnoea and night sweats. Physical examination showed clinical signs of respiratory distress, significant cachexia and thickened velvety palms with pronounced folds (figure 1). The laboratory results revealed leucocytosis of 15 700 cells/µl, thrombocytosis of 547 000/µl and elevated C reactive protein of 6.65 mg/dL. A posteroanterior chest radiograph showed a right pleural effusion and consolidation suggestive of pneumonia.

Figure 1

Thickened velvety palms with pronounced folds consistent with acquired pachydermatoglyphia.

The patient was given antibiotics and submitted to pleural effusion drainage for symptomatic relief. A skin biopsy of the palms was obtained and the histopathological examination identified signs of hyperkeratosis, acanthosis and papillomatosis consistent with acquired pachydermatoglyphia (figure 2).

Figure 2

Skin biopsy consistent with acquired...

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Bacteraemia and liver abscess due to Fusobacterium necrophorum

Fusobacterium necrophorum is the oropharyngeal pathogen usually associated with Lemierre's syndrome, a pharyngeal infection which evolves to sepsis, septic emboli and thrombophlebitis of the adjacent neck vessels. It is an uncommon causative bacteria of a liver abscess, and an extensive workup should, therefore, be performed in order to rule out potential sources of the infection. This case report describes the workup that led to the diagnosis of a colorectal carcinoma, which was deemed to be the source of the Fusobacterium bacteraemia.

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Hypertrophic olivary degeneration

Description

A 30-year-old man underwent MRI of the internal auditory meatus as a routine follow-up after excision of a large left vestibular schwannoma, 2.5 years previously. MRI images showed an incidental finding of left hypertrophic olivary degeneration (figure 1 and figure 2). This phenomenon occurs as a result of Wallerian degeneration of the olivary nucleus secondary to a lesion in the triangle of Guillain and Mollaret, also known as the dento-rubro-olivary pathway (figure 3). The differential diagnoses of hypertrophic olivary degeneration include infarction, infection, neoplasms and demyelination. Differentials can be excluded by the absence contrast enhancement (figure 2).

Figure 1

Axial T2-weighted sequence showing intratumoral haemorrhage within a large left cerebello-pontine angle lesion in keeping with a vestibular schwannoma (panel A). Axial fluid attenuated inversion recovery (FLAIR) image through the posterior fossa after 6 months demonstrating atrophic changes and haemosiderin deposition in the left middle cerebellar peduncle...

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Hiatal hernia mimicking heart problems

Description

A 73-year-old man presented to the emergency department with symptoms of acute coronary syndrome. Findings on examination were dyspnoea, chest tightness and a burning sensation behind the sternum.

On admission, 3 hours after the onset of symptoms, his 12-lead ECG showed a left bundle branch block. Cardiac enzymes revealed only marginally elevated creatine kinase, aspartate transaminase and lactate dehydrogenase levels; however, troponin I (<0.04 ng/mL) was increased to 17 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) to 1472 pg/mL (73 year normal range: 10–220 pg/mL). Though the consulting cardiologist determined coronary angiography to be unnecessary at the time, the patient was promptly sent to the intensive care unit (ICU) for monitoring and for quick intervention, if needed.

At that time, further information was gathered from the patient and his family. Apparently, the symptoms had started during lunch. The patient had experienced these symptoms several times in the preceding months; this time, however, the...

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Postoperative gluteal compartment syndrome following microsurgical free-flap hand reconstruction: the importance of early recognition and treatment

Compartment syndrome, a surgical emergency, is caused by an increase in pressure within a closed osseofascial space, often due to trauma. This causes a decrease in tissue perfusion and ultimately tissue necrosis and multiorgan failure if not treated in a timely fashion. Gluteal compartment syndrome is a rare variant and often caused by a period of immobilisation secondary to intoxication with alcohol or drugs or during long operations, typically in the supine position. We report on a case of gluteal compartment syndrome developing in a patient postoperatively following a long microsurgical procedure to a hand, which has not been documented before. Although rare, we highlight the clinical course and diagnostic criteria, which are essential for early identification and treatment.

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Adjunctive extracorporeal carbon dioxide removal in refractory status asthmaticus

Status asthmaticus (SA) is a life-threatening disorder. Severe respiratory failure may require extracorporeal membrane oxygenation (ECMO). Previous reports have demonstrated utility of ECMO in SA in various patients with varying success. A 25-year-old man was admitted with status asthmatics and severe hypercapnic respiratory failure. Despite tailored ventilator therapies, such as pressure control ventilation and maximal pharmacological therapy, including general anaesthesia, the patientâ™s condition deteriorated rapidly. Veno-venous ECMO (VV-ECMO) was provided for respiratory support. The patientâ™s clinical condition improved over the following 72âhours and was discharged from the intensive care unit on day 3. This case report demonstrates the successful use of VV-ECMO in a patient with severe respiratory failure due to SA, who failed to respond to maximal therapy. This case adds support to a growing body of literature that shows that ECMO can be used with success for refractory status asthmaticus.

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Intraparotid ductal ectasia: rare cause of parotid swelling

A 41-year-old patient was hospitalised for a chronic right parotid mass. A cervical ultrasound revealed a cystic mass of the parotid. Cervical MRI found a ductal ectasia of the parotid and submandibular glands associated with a retention cyst of the right parotid. He had a right total parotidectomy. Histopathological examination of the lesion revealed a multilocular cystic mass with a diffuse glandular ectasia of salivary ducts. The patient had an uneventful postoperative course without any recurrence of symptoms.

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Gamna-Gandy nodules of the spleen and asplenism in SLE: a novel association?

Description

We present a case of a 53-year-old woman who presented to the emergency room with acute abdominal pain, fever and haemodynamic and respiratory instability and was admitted to the intensive care unit with fulminant septic shock with multiorgan failure. CT imaging of the abdomen showed no gross abnormalities, initial laboratory results are presented in table 1.

Table 1

Laboratory test results

ParameterValueReference valueUnitCRP96<10mg/LESR7<20mm/hourHb8.07.0–9.2mmol/LHt0.400.32–0.44L/LMCV9582–89fLWBC6.5

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Reversible Holmesa{euro}™ tremor due to spontaneous intracranial hypotension

Holmes' tremor is a low-frequency hand tremor and has varying amplitude at different phases of motion. It is usually unilateral and does not respond satisfactorily to drugs and thus considered irreversible. Structural lesions in the thalamus and brainstem or cerebellum are usually responsible for Holmes' tremor. We present a 23-year-old woman who presented with unilateral Holmes' tremor. She also had hypersomnolence and headache in the sitting posture. Her brain imaging showed brain sagging and deep brain swelling due to spontaneous intracranial hypotension (SIH). She was managed conservatively and had a total clinical and radiological recovery. The brain sagging with the consequent distortion of the midbrain and diencephalon was responsible for this clinical presentation. SIH may be considered as one of the reversible causes of Holmes' tremor.

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Androgenic alopecia: an entity to consider in adolescence

Description

A 15-year-old healthy adolescent girl went to her physician consultation because she was preoccupied with progressive thinning of her hair since 11 years old. In the last year, she noticed an aggravation, with an excessive hair loss. She does not have hirsutism, acne, asthenia, menstrual irregularities or weight variations. In her family history, she reported that her mother had 'excessive hair loss after pregnancy' and her maternal aunt has alopecia of unknown aetiology. At physical examination it was observed diffuse reduction of capillary thickness and density at the frontal scalp area (figure 1) and vertex (figure 2). Rare black dots were present and the pull test was negative. The analytical study including blood count, iron kinetics, thyroid function and hormonal study had no alterations. The pelvic and adrenal gland's ultrasound were normal. At dermatology consultation, scalp biopsy revealed findings compatible with androgenic alopecia. She started treatment...

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Extramacular dome-shaped elevation: a novel finding in a case of high myopia

Description

Dome-shaped macula (DSM) is an elevation at the macula seen in about 5%–10% cases of high myopia, usually within a posterior staphyloma, caused by localised inward scleral and choroidal convexity.1 It may lead to visual deterioration when associated with serous foveal detachment (44% cases).2 3 Herein, we describe a similar but 'Extramacular dome-shaped elevation (EDSE)' associated with a large retinal hole.

A 23-year-old myopic female patient was referred to our clinic for pre refractive surgery fundus screening. She had a history of diminution of vision in the left eye more than the right eye since childhood and was using myopic glasses for the same. Best-corrected visual acuity on Snellen chart was 20/20 in the right eye and 20/200 in the left eye. Lower acuity in the left eye was attributed to anisometropic amblyopia as her refractive error was –6.75 D sphere...

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Sclerosing lymphangitis of the penis associated with marked penile oedema and skin erosions

Sclerosing lymphangitis of the penis is a benign, under-reported condition consisting of a asymptomatic firm cord-like swelling around the coronal sulcus of the penis usually affecting men in the second or third decade of life. Penile oedema and erosions are rarely reported. Clinical signs may be remarkable contrasting with the self-limited character of the disease. We report a new case of sclerosing lymphangitis of the penis occurring in a 59-year-old patient marked by penile swelling and several overlying skin erosions, and discuss the clinical features and the pathogenesis aspects of the disease.

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Directly observed therapy for clozapine with concomitant methadone prescription: a method for improving adherence and outcome

A young male presented with many years of delusions and hallucinations, with concurrent heroin use and subsequent amphetamine uses. There were no depressive or manic symptoms and psychotic symptoms prior to the amphetamine use. After the trials of two atypical antipsychotics and later clozapine due to treatment resistance, adherence and functionality were poor and there was still persistent drug use. As a result, a long acting injectable adjunct was commenced, but only minimal effects were observed. However after initiation of directly observed treatment of clozapine with methadone, there has been functional and clinical response and drug use has ceased.

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Accidental hypothermic cardiac arrest and rapid mediastinal warming with pleural lavage: a survivor after 3.5 hours of manual CPR

A 30-year-old man suffered post-traumatic hypothermic cardiac arrest. On arrival in the emergency department, rectal core temperature was 23°C. Manual cardiopulmonary resuscitation (CPR) was continued as no mechanical chest compression device was available, and active and passive rewarming was undertaken. Bilateral thoracostomies confirmed good lung inflation. Defibrillation and intravenous epinephrine were discontinued until core temperature was elevated above 30°C. Extracorporeal rewarming was unavailable. When no increase in rectal temperature was achieved after 90 min, an alternative oesophageal probe confirmed mediastinal temperature as 23°C. Bilateral chest drain insertion, followed by microwave-heated saline pleural lavage, rapidly raised the oesophageal temperature above 30°C with subsequent successful defibrillation, initially to pulseless electrical activity and finally return of spontaneous circulation 3.5 hours after the commencement of CPR. The patient recovered fully and was discharged without neurological deficit. Rapid mediastinal warming with pleural lavage should be considered in units with no access to extracorporeal rewarming service.

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Disseminated tuberculosis in relatively asymptomatic young woman

Description

A previously healthy 20-year-old woman presented to the emergency department with a history of one episode of generalised tonic–clonic seizure. No history of fever or constitutional symptoms. At admission, she was haemodynamically stable and Glasgow Coma Scale was 8, with no focal neurological deficits. For the workup of seizures, MRI brain (figure 1) was done which revealed multiple ring-enhancing lesions in bilateral temporal, frontal and right parietal lobes. Cerebrospinal fluid examination showed normal cell count with high protein (84 mg/dL) and normal glucose levels (43 mg/dL), and high adenosine deaminase (9.3 U/L) level. Chest X-ray showed (figure 2A) miliary mottling which was confirmed by contrast-enhanced CT (CECT) chest (figure 2B and C). CECT abdomen (figure 3A and B) revealed thick-walled multiloculated collection (7.3x8.4x14.2 cm) with thick internal septations in the left lumbar and iliac fossa region. Pelvic collections were drained with an image-guided pig tail insertion and...

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A perforated caecal volvulus in the foramen of Winslow

The aim of this report is to discuss with high-quality images, a case of a caecal volvulus herniating through the foramen of Winslow with signs of perforation.

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Upper Abdominal Activity in Bone Scan

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TTK inhibitors as a targeted therapy for CTNNB1 ({beta}-catenin) mutant cancers

The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small molecule inhibitors. While the first TTK inhibitors have entered phase 1 dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of pre-clinical and clinical TTK inhibitors from different chemical series on a panel of sixty-six genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1. The association of CTNNB1 mutant status and TTK inhibitor sensitivity was confirmed with isogenic cell line pairs harboring either mutant or wild-type CTNNB1. Treatment of a xenograft model of CTNNB1 mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in CTNNB1 occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high TTK levels. We propose mutant CTNNB1 as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials.

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Mechanisms of resistance to NTRK inhibitors and therapeutic strategies in NTRK1-rearranged cancers

Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea (ENU) mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and IGF1R bypass pathway mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecular inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or LOXO101. Furthermore, cabozantinib with an insulin growth factor receptor type 1 (IGF1R) inhibitor such as OSI906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance.

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131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment

Purpose: <p>Camelid single-domain antibody-fragments (sdAbs) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here we describe the generation of a ¹³¹I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.</p> <br />Experimental Design: <p>Anti-HER2 sdAb 2Rs15d was labeled with ¹³¹I using [¹³¹I]SGMIB and evaluated in vitro. Biodistribution was evaluated in two HER2⁺ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [¹³¹I]SGMIB-2Rs15d  was investigated in two HER2⁺  tumor  mouse models. A single-dose toxicity study was performed in mice using unlabeled [¹²⁷I]SGMIB-sdAb at 1.4mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography.</p> <br />Results: <br /> <p>[¹³¹I]SGMIB-2Rs15d bound specifically to HER2⁺ cells (K_D=4.74±0.39nM). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3h. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo. [¹³¹I]SGMIB-2Rs15d alone, or in combination with trastuzumab extended median survival significantly. No toxicity was observed after injecting [¹²⁷I]SGMIB-2Rs15d.</p> <br />Conclusions: <br />These findings demonstrate the theranostic potential of [¹³¹I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [¹³¹I]SGMIB-2Rs15d, and could thereby impact therapy outcome on HER2⁺ BC patients.

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Head and Neck Carcinoma Immunotherapy: Facts and Hopes

Cancer of the head and neck (HNC) is a heterogeneous disease of the upper aerodigestive tract, encompassing distinct histological types, different anatomical sites and HPV+ as well as HPV^neg cancers. Advanced/recurrent HNCs have poor prognosis with low survival rates. Tumor-mediated inhibition of anti-tumor immune responses and a high mutational burden are common features of HNCs. Both are responsible for the successful escape of these tumors from the host immune system. HNCs evolve numerous mechanisms of evasion from immune destruction. These mechanisms are linked to genetic aberrations, so that HNCs with a high mutational load are also highly immunosuppressive. The tumor microenvironment of these cancers is populated by immune cells that are dysfunctional, inhibitory cytokines and exosomes carrying suppressive ligands. Dysfunctional immune cells in patients with recurrent/metastatic HNC can be made effective by the delivery of immunotherapies in combination with conventional treatments. With many promising immune-based strategies available, the future of immune therapies in HNC is encouraging, especially since methods for genetic profiling and mapping the immune landscape of the tumor are being integrated into a personalized approach. Efficiency of immune therapies is expected to rapidly improve with the possibility for patients' selection based on personal immunogenomic profiles. Non-invasive biomarkers of response to therapy will be emerging as a better understanding of the various molecular signals coopted by the tumors is gained. The emerging role of immunotherapy as a potentially beneficial addition to standard treatments for recurrent/metastatic HNC offers hope to the patients for whom no other therapeutic options exist.

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Association of FGFR1 with ER{alpha} maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer

Purpose: FGFR1 amplification occurs in ~15% of ER+ human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.<br /><br />Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 immunohistochemistry, FGFR1 FISH, and RNA-sequencing. ER+/FGFR1 amplified breast cancer cells and patient-derived xenografts (PDXs) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by co-immunoprecipitation and proximity ligation, ER genomic activity by ChIP-sequencing, and gene expression by RT-PCR.<br /><br />Results: ER+/FGFR1 amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER+/FGFR1 amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from FGFR1-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.<br /><br />Conclusions: These data suggest the ERα pathway remains active in estrogen-deprived ER+/FGFR1-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists.

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Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient survival

Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.<br /><br />Experimental Design: Patient-resected GBM, the cancer genome atlas, human T cell:GBM co-cultures, as well as nu/nu, NOD-scid and humanized (NSG-SGM3-BLT) mice engrafted human GBM, form the basis of our investigation.<br /><br />Results: In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P=0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially-engrafted human GBM revealed an IFNg-associated T cell-mediated increase of intratumoral IDO1. <br /><br />Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T cell-mediated effects against GBM, should consider combinatorial approaches that co-inhibit potential T cell-mediated IDO1 enhancement during therapy.

http://ift.tt/2uDHB2F

T2-FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower Grade Gliomas: A TCGA/TCIA Project

Purpose: Lower grade gliomas (WHO grade II/III) have been classified into clinically-relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower grade glioma molecular subtypes.<br /><br />Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n=125) were evaluated by 2 independent neuroradiologists to assess: 1) presence/absence of homogenous signal on T2WI; 2) presence/absence of "T2-FLAIR mismatch" sign; 3) sharp or indistinct lesion margins; 4) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review, and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort (n=82) was analyzed to validate the T2-FLAIR mismatch sign. <br /><br />Results: Among TCGA/TCIA cases, inter-reader agreement was calculated for lesion homogeneity (ĸ=0.234 [0.111-0.358]), T2-FLAIR mismatch sign (ĸ=0.728 [0.538-0.918]), lesion margins (ĸ=0.292 [0.135-0.449]), and peritumoral edema (ĸ=0.173 [0.096-0.250]). All 15 cases that were positive for the T2-FLAIR mismatch sign were IDH-mutant, 1p/19q-non-codeleted tumors (p<0.0001; PPV=100%, NPV=54%). Analysis of the validation cohort demonstrated substantial inter-reader agreement for the T2-FLAIR mismatch sign (ĸ=0.747 [0.536 - 0.958]); all 10 cases positive for the T2-FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (p<0.00001; PPV=100%, NPV=76%). <br /><br />Conclusion: Among lower grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q-non-codeleted molecular subtype.

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Gene Copy Number Estimation From Targeted Next Generation Sequencing Of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification.

Abstract <p>Purpose</p> <p>Precise detection of copy number aberrations (CNAs) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next generation sequencing (NGS) is inexpensive, high throughput and easily feasible, allowing single nucleotide variant calls, but CNA estimation from this remains challenging..</p> <p>Experimental Design</p> <p>We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration resistant prostate cancer biopsies, and used capture based whole exome sequencing (WES), array comparative genomic hybridization (aCGH), and fluorescent in situ hybridization (FISH) to explore the viability of this approach.</p> <p>Results</p> <p>We showed that this method produced highly reproducible CNA results (r=0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted next generation sequencing were comparable with WES (r=0.86) and aCGH (r=0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN and RB1) CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results.</p> <p>The frequency of CNAs in our population was comparable to that previously described (ie. deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intra-tumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.</p> <p>Conclusion</p> <p>Targeted NGS and CNVkit based analyses provide a robust, precise, high throughput and cost effective method for CNA estimation for the delivery of more precise patient care.  

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Exposure-Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies

Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure-response analysis to inform the phase II trial design. <p>Experimental Design: Pharmacokinetic, efficacy and safety data from 95 patients, who were administered 10 to 100 mg BID doses of veliparib for either 8, 14 or 21 days with T+C, were utilized for exposure-efficacy (objective response and overall survival) and exposure-safety (≥Grade 3  mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment and number of prior therapies.</p> <p>Results: The odds of having objective response were 1.08-fold with 1000 ng.hr/mL increase in AUC, 1.8-fold with >8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN) and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1000 ng.hr/mL increase in AUC, 39% with >8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥Grade 3 mucositis increased by 29% with 1000 ng.hr/mL increase in AUC.</p> Conclusions: Despite shallow exposure-efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC₅₀. Shallow exposure-mucositis relationship also supports the 80 mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg BID for at least 14 days in combination with T+C is recommended to be studied in MPN patients.

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Numb-/low enriches a castration resistant prostate cancer cell subpopulation associated with enhanced Notch and Hedgehog signaling

Purpose: To elucidate the role and molecular mechanism of Numb in prostate cancer (PCa) and the functional contribution of Numb^-/low PCa cells in castration resistance.<br /><br />Experimental Design: The expression of Numb was assessed using multiple Oncomine datasets and PCa tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human PCa cell lines were investigated in vitro and in vivo. In addition, we developed a reliable approach to distinguish between PCa cell populations with a high or low endogenous expression of Numb protein using a Numb promoter based lentiviral reporter system. The difference between Numb^-/low and Numb^high PCa cells in the response to androgen deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting and quantitative real-time PCR.<br /><br />Results: We show here that Numb was down-regulated and negatively correlated with PCa advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and CRPC development by suppressing Notch and Hedgehog signaling. Using a Numb promoter based lentiviral reporter system, we were able to distinguish Numb^-/low PCa cells from Numb^high cells. Numb^-/low PCa cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell-associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb^-/low cells in response to ADT.<br /><br />Conclusions:Numb^-/low enriches a castration resistant PCa cell subpopulation that is associated with unregulated Notch and Hedgehog signaling.

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miRomics and proteomics reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc feedback loop modulated by HDGF/DDX5/{beta}-catenin complex in lung adenocarcinoma

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.<br /><br />Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EDU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance, western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The  miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and Co-immunoprecipitation combined with mass spectrometry and  GST pull-down were respectively designed to analyze the DNA-protein complex and HDGF/DDX5/β-catenin complex.<br /><br />Results:We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to Cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK-Ras-c-Myc signaling thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF-β-catenin-c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA-FAK-Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin-c-Myc, which suppresses miR-296-3p and further activates PRKCA-FAK-Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with  HDGF/DDX5, but not PRKCA. <br /><br />Conclusions:Our study provides a novel mechanism that the miR-296-3p-PRKCA-FAK-Ras-c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC.

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Towards precision radiotherapy for use with immune checkpoint blockers

The first evidence that radiation therapy (RT) enhances the efficacy of immune checkpoint blockers (ICBs) was obtained a dozen years ago in a mouse model of metastatic carcinoma refractory to anti-CTLA-4 treatment. At the time, ICBs had just entered clinical testing, an endeavor that culminated in 2011 with the approval of the first anti-CTLA-4 antibody for use in metastatic melanoma patients (ipilimumab). Thereafter, some patients progressing on ipilimumab showed systemic responses only upon receiving radiation to one lesion, confirming clinically the pro-immunogenic effects of radiation. Preclinical data demonstrate that multiple immunomodulators synergize with RT to cause the regression of irradiated tumors and, less often, non-irradiated metastases. However, the impact of dose and fractionation on the immunostimulatory potential of RT has not been thoroughly investigated. This issue is extremely relevant given the growing number of clinical trials testing the ability of RT to increase the efficacy of ICBs. Recent data demonstrate that the recruitment of dendritic cells to neoplastic lesions (and hence the priming of tumor-specific CD8⁺ T cells) is highly dependent on RT dose and fractionation through a mechanism that involves the accumulation of double stranded DNA in the cytoplasm of cancer cells and consequent type I interferon release. The molecular links between the cellular response to RT and type I interferon secretion are just being uncovered. Here, we discuss the rationale for an optimized use of RT, as well as candidate biomarkers that may predict clinical responses to RT combined with ICBs.

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Pediatric phase 1 trial and pharmacokinetic study of trebananib in relapsed solid tumors ADVL1115: A Children's Oncology Group phase 1 consortium report

Purpose: Trebananib is a first-in-class anti-angiogenic peptibody (peptide-Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose limiting toxicities (DLT), recommended phase 2 dose (RP2D) and pharmacokinetics (PK).<br /><br />Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI.<br /><br />Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n=4), anemia, thrombocytopenia, neutropenia, vomiting and hypertension (n=1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI.<br /><br />Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg.

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FDA Approval Summary: Rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer

On December 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to rucaparib (RUBRACA, Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. FDA also approved the FoundationFocus™ CDx_BRCA test (Foundation Medicine Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 ovarian cancer patients, treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% (57/106; 95% CI: 44-64%), and median duration of response was 9.2 months (95% CI: 6.6, 11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval.

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Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)

Abstract

Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR_4vs1) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR_4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR_4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR_4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR_4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.

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Management of perioperative laryngospasm by French paediatric anaesthetists

Editor—Perioperative laryngospasm is a life-threating emergency in paediatric patients. A recent multicentre study of children undergoing surgery¹ found a high rate of severe critical events during the perioperative period (5.2%), with an incidence of respiratory critical events of 3.1%. Laryngospasm was one of most frequent respiratory complications (0.2–6.7%). Its effective management requires appropriate diagnosis, followed by prompt and aggressive management. The use of a structured algorithm would lead to earlier recognition and better management.² We undertook a survey in order to explore the practical management of laryngospasm by French paediatric anaesthetists.

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Electroencephalography and delirium in the postoperative period

Abstract

Delirium commonly manifests in the postoperative period as a clinical syndrome resulting from acute brain dysfunction or encephalopathy. Delirium is characterized by acute and often fluctuating changes in attention and cognition. Emergence delirium typically presents and resolves within minutes to hours after termination of general anaesthesia. Postoperative delirium hours to days after an invasive procedure can herald poor outcomes. Easily recognized when patients are hyperactive or agitated, delirium often evades diagnosis as it most frequently presents with hypoactivity and somnolence. EEG offers objective measurements to complement clinical assessment of this complex fluctuating disorder. Although EEG features of delirium in the postoperative period remain incompletely characterized, a shift of EEG power into low frequencies is a typical finding shared among encephalopathies that manifest with delirium. In aggregate, existing data suggest that serial or continuous EEG in the postoperative period facilitates monitoring of delirium development and severity and assists in detecting epileptic aetiologies. Future studies are needed to clarify the precise EEG features that can reliably predict or diagnose delirium in the postoperative period, and to provide mechanistic insights into this pathologically diverse neurological disorder.

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Abstracts for Spring BJA Research Forum meeting, Royal College of Anaesthetists, London, 5th and 6th April 2017

(The authors of all the following abstracts have confirmed that their research received ethics committee approval or was conducted under the Animal (Scientific Procedures) Act (1986) or equivalent.)

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Frequency of surgical treatment and related hospital procedures in the UK: a national ecological study using hospital episode statistics

Abstract

Background: Despite evidence of high activity, the number of surgical procedures performed in UK hospitals, their cost and subsequent mortality remain unclear.Methods: Time-trend ecological study using hospital episode data from England, Scotland, Wales and Northern Ireland. The primary outcome was the number of in-hospital procedures, grouped using three increasingly specific categories of surgery. Secondary outcomes were all-cause mortality, length of hospital stay and healthcare costs according to standard National Health Service tariffs.Results: Between April 1, 2009 and March 31, 2014, 39 631 801 surgical patient episodes were recorded. There was an annual average of 7 926 360 procedures (inclusive category), 5 104 165 procedures (intermediate category) and 1 526 421 procedures (restrictive category). This equates to 12 537, 8073 and 2414 procedures per 100 000 population per year, respectively. On average there were 85 181 deaths (1.1%) within 30 days of a procedure each year, rising to 178 040 deaths (2.3%) after 90 days. Approximately 62.8% of all procedures were day cases. Median length of stay for in-patient procedures was 1.7 (1.3–2.0) days. The total cost of surgery over the 5 yr period was £54.6 billion ($104.4 billion), representing an average annual cost of £10.9 billion (inclusive), £9.5 billion (intermediate) and £5.6 billion (restrictive). For each category, the number of procedures increased each year, while mortality decreased. One-third of all mortalities in national death registers occurred within 90 days of a procedure (inclusive category).Conclusions: The number of surgical procedures in the UK varies widely according to definition. The number of procedures is slowly increasing whilst the number of deaths is decreasing.

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How powerful is failure to rescue as a global metric? Not as powerful as a commitment to measurement

In a much-discussed study published in 2009, Dr Ghaferi and colleagues¹ revived the concept, originally described in the early 1990s by Jeffrey Silber and colleagues,² of 'failure to rescue'. Ghaferi and colleagues¹ used a prospective, multicentre clinical registry organized by the American College of Surgeons (ACS-NSQIP) to rank hospitals by mortality quintiles. They then evaluated adverse events and noted that across the different mortality quintiles the risk of an adverse event was remarkably consistent. What differed with respect to mortality was not so much the likelihood of a complication, but the ability of a hospital to 'save' a patient who experienced a complication. Hospitals in the lowest mortality quintile had very similar rates of both minor and major complications to those in the highest mortality quintile, yet had half the rates of death. They concluded that 'failure to rescue' patients with complications in the higher mortality quintiles represented an opportunity for improvement; it was not the complications per se that killed patients, but the inability to quickly recognize and respond to their deterioration.

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Simulated emergency cricothyroid incision length

Editor—The revised 2015 Difficult Airway Society (DAS) guidelines for the 'unanticipated difficult airway' include a standardized approach to performance of emergency front-of-neck access in the 'can't intubate, can't oxygenate' (CICO) scenario.¹ We have subsequently changed how we educate colleagues in the management of a CICO scenario using the surgical technique as part of our airway update days and on the Aintree Difficult Airway Management course.

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Delirium, what’s in a name?

Delirium has been known since ancient times. Hippocrates [460–370 Before Common Era (BCE)] may have been the first to describe the syndrome that he called 'phrenitis', marked by confusion and restlessness that fluctuated unpredictably and that was associated with physical illness.¹ Many other names have been used, including acute mental status change, confusional state, confusion, acute brain dysfunction, brain failure, encephalopathy, postoperative psychosis and acute organic syndrome.¹ Of these, the term delirium (derived from the Latin word delirare, deviate from a straight track) has gained acceptance. Besides a more uniform terminology, an important recent achievement includes publication of criteria to define delirium. Although criticized,²³ the criteria of the Diagnostic and Statistical Manual of Mental Disorders (5th edition, DSM-5) have become standard.⁴ According to these criteria, a patient can be considered delirious when all items listed in Table 1 are present at the same time.⁴ In essence, this means that a patient has acutely developed disturbed attention with other cognitive deficits, which is not solely due to underlying dementia and is caused by a physical condition. Table 1Criteria for delirium according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)⁴

• A. A disturbance in attention (i.e. reduced ability to direct, focus, sustain and shift attention) and awareness (reduced orientation to the environment).
• B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.
• C. An additional disturbance in cognition (e.g. memory deficit, disorientation, language, visuospatial ability or perception).
• D. The disturbances in Criteria A and C are not better explained by another pre-existing, established or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma.
• E. There is evidence from the history, physical examination or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (i.e. due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple aetiologies.

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Topics for the national audit projects of the Royal College of Anaesthetists

Editor—Moppett and colleagues¹ provide a very fair assessment of the value of the national audit projects (NAPs) performed in the UK during the last decade. However, I would question their statement that the choice of topics for the third and fourth projects performed by the Royal College of Anesthetists (NAP3 and NAP4) was 'in part serendipitous, as a result of the coincidence of the desires of the specialist societies (Pain and Difficult Airway) and the Royal College of Anaesthetists'. The subjects for both audits were discussed at meetings of College Council and, as a member of that group at the time, I remember no input from any society.

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Postoperative delirium portends descent to dementia

Many elderly patients worry that their thinking will be impaired after surgery. Concerns include acute confusion in the days to weeks following surgery, as well as persistent cognitive deficits lasting months to years.¹ Both postoperative delirium (POD) and delayed neurocognitive recovery lasting months after surgery are common in older adults, but reports of non-resolving cognitive decline or neurocognitive disorders (NCDs) are inconsistent.²³ The acute onset inattention and disorganized thinking characteristic of POD often manifest between one and four days after surgery.⁴ Delayed neurocognitive recovery is a subtle NCD that typically lasts weeks to months following surgery. Although transient, both disorders can significantly impact recovery. Patients with POD have increased morbidity and mortality, longer Intensive Care Unit (ICU) stays, decreases in quality of life and are likely to be vulnerable to delayed neurocognitive recovery.⁵⁶ While the pathophysiology of delirium remains unclear, it has been linked with NCDs and dementia in non-surgical patients,⁷ and several studies have suggested that POD may be a risk factor for non-resolving minor and even major NCD (or incident dementia).⁸⁹ In this issue of the British Journal of Anaesthesia, the retrospective cohort studies by Sauër and colleagues¹⁰ and Sprung and colleagues¹¹ investigate the association between POD and persistent NCDs; the conflicting results highlight the difficulties in studying postoperative cognition.

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In This Issue

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Post-anaesthesia care unit delirium: incidence, risk factors and associated adverse outcomes

Delirium is a sudden disturbance in attention and orientation to the environment that develops over a short period of time and tends to fluctuate in severity during the course of the day.¹ The acute confusional state of delirium occurs in 50–80% of critically ill patients and postoperatively (from the day after surgery onwards) in up to 54% of elective major non-cardiac surgical patients.¹ It incurs a huge societal burden, because of, in part, a result of its association with increased morbidity and mortality; each additional day of delirium has been independently associated with a 10% increased risk of death.² Increased morbidity contributes to prolonged hospital length of stay and significant financial implications: delirium is estimated to total $4–16 billion annually.³ Its association with long-term neuropsychological and cognitive deficits^4–7 mandates a better understanding of the pathogenesis of delirium⁸ and the mechanisms underlying the prolonged disruption of cognitive processing.⁹ Despite these apparent strong associations, it remains unclear whether delirium identified in the post-anaesthetic care unit (PACU) or recovery unit is associated with similar outcomes. For anaesthetists, this is a critical question that remains unanswered. Indeed at least some of these events are of limited duration and hence it could be assumed they would be associated with less severe consequences. In this context, PACU delirium is differentiated from postoperative delirium as the latter occurs from the day after surgery onwards whereas the former occurs in the PACU on the day of surgery.

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Approach affects injectate spread in ultrasound-guided thoracic paravertebral block: a cadaveric trial

Editor—Ultrasound-guided thoracic paravertebral block has made much progress, and various approaches have been developed in the past decade.¹ However, the differences in local anaesthetic distribution patterns are unknown. We adopted two patterns of injections, namely the intercostal approach (IC approach)² and the paralaminar in-plane approach (PL approach),³⁴ and compared their injectate spreading patterns in three Thiel-embalmed human cadavers using a dye injection method.⁵⁶ For the IC approach, a 6–13 MHz linear array transducer was placed at the T4, T5 and T9 intercostal levels to visualize the transverse process. An 18-gauge Tuohy needle was inserted from lateral to medial beside the probe to penetrate the internal intercostal membrane next to the tip of the transverse process. For the PL approach, the needle was inserted from medial to lateral using a 5–8 MHz microconvex array transducer to visualize the lateral edge of the vertebral lamina at the T6, T7 and T10 levels. We investigated five injections by the IC approach and four injections by the PL approach using 10 ml of dye of various colours. One injection in each group included real-time, direct observation of the distribution pattern after dissection via a pre-inserted catheter 2.5 cm beyond the needle tip. Paravertebral spread was confirmed in all procedures. In the IC approach group, dye covered the respective intercostal space and the adjacent paravertebral space (PVS) (Fig. 1A), consistent with previous reports.⁷ The injected dye in the PL approach group covered the more longitudinal and medial PVS rather than the lateral intercostal space (Fig. 1B).⁸ Real-time dye injections from the catheter showed that in the IC approach dye first spread to the respective intercostal level following PVS whereas in the PL approach dye first covered the area around the sympathetic trunk followed by the intercostal area.

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Predicting postoperative brain function from the blood: is there a role for biomarkers?

Loss of consciousness upon exposure to general anaesthetics reflects the powerful influence of these drugs on brain physiology. While this phenomenon is usually transient and rapidly resolves upon discontinuation of drug administration, an overwhelming number of both clinical and experimental observations suggest that even relatively short periods of anaesthesia can trigger a myriad of biochemical pathways which, in turn, can give rise to temporary or even lasting changes in neurobehavioural and cognitive function after emergence from anaesthesia.¹ Most of these functional alterations have been described as postoperative delirium or impaired cognitive performance and, therefore, have negative connotations. It is nevertheless important to note that exposure to anaesthetics can also improve both cognition and mood in some specific clinical states, such as in major depressive disorders. This context-dependent impact of anaesthetics on neuronal function probably reflects the major context-dependent modulatory influence of these drugs on neuronal plasticity.¹

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Mind the gap when performing emergency front-of-neck access

Editor—Plan D of the Difficult Airway Society guidelines¹ on managing the can't intubate can't oxygenate (CICO) scenario states that a 6.0 mm cuffed tracheal tube should be railroaded over the bougie when performing scalpel cricothyroidotomy. During our departmental CICO training sessions, conducted on sheep larynxes, we have noticed that candidates have difficulties railroading the tube over the bougie (Frova Intubating Introducer, Cook Medical Ltd. Limerick, Ireland) when using a 6 mm cuffed tracheal tube. This appears to be caused by the tip of the tube catching on the airway as it is being advanced, because of the large gap between the bougie and the tube (Fig. 1A). We noted that when using a smaller 5 mm tube, railroading appeared to be easier, perhaps because the gap between the bougie and the tube is smaller (Fig. 1B). The resistance to advancing the tube over the bougie was almost negligible when using a size 5 mm Melker cuffed emergency cricothyrotomy catheter (Cook Medical Ltd, Limerick, Ireland), as this tube has a tapered tip that fits snugly over the bougie (Fig. 1C).

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Using a worldwide in-app survey to explore sugammadex usage patterns: a prospective observational study

Editor—Via encapsulation, sugammadex can rapidly and completely reverse even profound neuromuscular block induced by rocuronium or vecuronium, which is not possible to achieve with cholinesterase inhibitors.^1–4 Although approved for use in Europe in 2008⁵ and available for several years elsewhere,⁶ the United States Food and Drug Administration (US FDA) delayed approval due to concerns regarding potential hypersensitivity reactions and effects on coagulation tests,⁷ which were ultimately satisfied.^8–10 We are interested in better understanding global experience with sugammadex and the impact, if any, of pharmacoeconomics on post-marketing policies. The present data were analysed from an ongoing, Institutional Review Board (IRB)-approved (Emory University, Atlanta, GA, USA, IRB# 00082571) study of a globally utilized anaesthesia calculator app for the Android platform ('Anesthesiologist')¹¹¹² fitted with a module capable of collecting survey data and app analytics.¹³ We used this tool to deploy a survey assessing global patterns of clinical practice and experience with sugammadex.

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The Princes of Serendip

Editor—We thank Professor Wildsmith¹ for his interest in our editorial² and for clarifying aspects of the process around NAP3.³

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Availability of critical care services in Taiwan under National Health Insurance

Editor—Since the implementation of Taiwan's National Health Insurance (NHI) programme in 1995, use of health-care services has significantly increased.¹ This is also true for the use of mechanical ventilation and extracorporeal membrane oxygenation.²³ In contrast, information is limited about use of intensive care unit (ICU) beds.⁴ We conducted this study to investigate the availability of the critical care service in Taiwan under the NHI programme.

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Abstracts from the BJA Research Forum Glasgow, November 10–11, 2016

(The authors of all the following abstracts have confirmed that their research received ethics committee approval or was conducted under the Animal (Scientific Procedures) Act (1986) or equivalent.)

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Ultrasound-guided central venous catheterization in the prone position

Editor—Central venous catheterization for patients positioned prone poses challenges to the anaesthesiologist, such as anatomical restrictions in head and neck position, lack of anatomical landmark points to approach, and difficult right internal jugular vein (RIJV) needle advancement with the left hand. Here we present an approach for RIJV catheterization in a patient positioned prone using in-plane needle ultrasound guidance.

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Association between delirium and cognitive change after cardiac surgery

Abstract

Background. Previous studies provide inconsistent data on whether postoperative delirium (POD) is a risk factor for postoperative cognitive decline (POCD). We thus investigated the relationship between POD and cognitive change after cardiac surgery and assessed the relationship between preoperative cognitive domain scores and POD.Methods. Postoperative delirium was assessed with the Confusion Assessment Method (CAM) adapted for the intensive care unit and the conventional CAM accompanied by chart review. Cognitive function was assessed with a neuropsychological test battery before elective cardiac surgery and 1 month and 1 yr afterwards. Cognitive change was calculated using the Reliable Change Index (RCI). Multiple linear regression was used to adjust for confounding.Results. Of the 184 patients who completed baseline assessment, 23 (12.5%) developed POD. At 1 month, the decline in cognitive performance was worse in patients with POD [median composite RCI −1.00, interquartile range (IQR) −1.67 to 0.28] than in patients without POD (RCI −0.04, IQR −0.70 to 0.63, P=0.02). At 1 yr, both groups showed cognitive improvement on average compared with baseline (POD patients median composite RCI 0.25, IQR −0.42 to 1.31, vs non-POD patients RCI 0.92, IQR 0.18–1.53; P=0.08). Correction for differences in age and level of education did not change the results. Patients with POD performed less well than patients without POD on the preoperative Trailmaking test part A (P=0.03).Conclusions. Postoperative delirium is independently associated with cognitive decline 1 month after surgery, but cognitive performance generally recovers in 1 yr. Patients with a predisposition to POD can be identified before surgery by worse performance in an attention task.Clinical trial registration. NCT00293592.

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Hepatotoxicity After Immune Checkpoint Inhibitor Therapy in Melanoma: Natural Progression and Management.

Objective: To report the clinical features, treatment, and outcomes of patients with immune checkpoint inhibitor-induced hepatotoxicity. Patients and Methods: In this retrospective observational study, we identified patients with metastatic malignant melanoma seen in consultation and/or treated between March 2011 and March 2016. Hepatotoxicity was assessed using the Common Terminology Criteria for Adverse Events, v4.0. Results: Seventeen patients were identified as having any degree of hepatotoxicity by history (grade 1 to 4). Twelve of 17 were diagnosed after ipilimumab, 3 of 17 were diagnosed after pembrolizumab, and 2 of 17 after ipilimumab combined with nivolumab. Median time from first dose of immune therapy to hepatotoxicity was 52 days. Clinical symptoms were variable: asymptomatic, fatigue, myalgias, headache, abdominal pain, nausea, vomiting, confusion, and/or jaundice. Eight patients had concurrent adverse events including colitis, hypophysitis, pneumonitis, and/or rash. Immune therapy was discontinued in all patients except 3. The patients were most commonly treated with systemic corticosteroids such as prednisone. Immunosuppression was discontinued by taper over a median of 42 days; in 3 patients steroids had to be reinitiated based on clinical or laboratory worsening of liver tests. Normalization of liver tests was seen within a median of 31 days of immunosuppression initiation. One patient with grade 4 hepatotoxicity had normalization with the addition of cyclosporine. Conclusions: Melanoma patients treated with immune checkpoint inhibitors should be monitored regularly for hepatotoxicity. Treatment with discontinuation of therapy and initiation of corticosteroids is indicated with grade 3 or 4 hepatotoxicity. Cyclosporine may be beneficial in steroid-refractory hepatotoxicity. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Changes in margin re-excision rates: Experience incorporating the “no ink on tumor” guideline into practice

Introduction

Prior to the "no ink on tumor" SSO/ASTRO consensus guideline, approximately 20% of women with stage I/II breast cancers undergoing breast conservation surgery at our institution underwent margin re-excision. On May 20, 2013, our institution changed the definition of negative margins from 2 mm to "no ink on tumor."

Methods

A retrospective review was conducted of patients who had surgery at our institution with clinical stage I/II breast cancers between June 1, 2011 and May 1, 2015. In the pre-guideline cohort (pre) and post-guideline cohort (post), negative margins were 2 mm and "no ink on tumor," respectively.

Results

Implementation of the guideline resulted in a significant decrease in the positive/close margin rate (29.6% pre vs 10.1% post; P < 0.001) and numerical decrease in re-excision rate (20.4% pre vs 16.3% post; P = 0.104). No significant difference was found in local recurrence between the cohorts with limited follow-up (1.2% pre vs 1.5% post; P = 0.787).

Conclusion

The implementation of the "no ink on tumor" guideline at our institution has resulted in a significant decrease in positive margin rates and a numerical decrease in margin re-excisions. In addition to margin status, surgeons continue to use individual patient and histologic factors to decide for or against margin re-excision.

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Strategies for Differentiating Gallbladder Carcinoma from Xanthogranulomatous Cholecystitis—a Tertiary Care Centre Experience

Abstract

Xanthogranulomatous cholecystitis (XGC) is an uncommon variant of chronic cholecystitis, characterized by focal or diffuse destructive inflammatory process. The importance of XGC is that it mimics gallbladder carcinoma (GBC) both preoperatively and intra-operatively, since it can present with pericholecystic infiltration, hepatic involvement and lymphadenopathy. As a result of this misdiagnosis which is not infrequent, the patient may need to undergo an unnecessary radical cholecystectomy rather than only a cholecystectomy which is associated with greater morbidity and mortality. Patients who underwent gallbladder and gallbladder-related operations during period of 5 years between 2010 and 2014 were reviewed (n = 462). A comparison of clinical, biochemical, radiological and operative features were made between patients with carcinoma gallbladder (n = 101) and xanthogranulomatous cholecystitis (n = 22). Patient with a long history of recurrent abdominal pain with leucocytosis and who on imaging are found to have a diffusely thickened gallbladder wall (p < 0.01), with cholelithiasis, choledocholithiasis and sub-mucosal hypoattenuated nodules (p < 0.05) are likely to have XGC while those with anorexia, weight loss, focal thickening of the gallbladder wall on imaging (p < 0.01) and dense local organ infiltration are more likely to have GBC. The presence of lymph nodes on imaging and the loss of fat plane interface between the liver and gallbladder are not differentiating factors. Differentiating XGC from GBC in preoperative setting is necessary to avoid radical procedures being done for a benign process. Certain clinical, radiological and intra-operative features aid in differentiating these benign and malignant process. However, the definitive diagnosis still remains a histopathological examination to avoid radical resection in patients who have a benign condition.

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Role of pulmonary metastasectomy in colorectal cancer in the era of modern multidisciplinary therapy

Abstract

Purpose

To clarify the role of pulmonary metastasectomy in colorectal cancer in the era of modern multidisciplinary therapy.

Methods

The characteristics and outcomes of the patients who underwent pulmonary metastasectomy for colorectal cancer through 2002 (n = 26) and from 2003 (n = 68) were compared.

Results

The patients treated from 2003 had a smaller tumor size and more frequently had a history of extra-pulmonary relapses than did those treated through 2002. There was a significant improvement in the 5-year overall survival (42.0% vs. 73.1%, p = 0.03) but not the 5-year relapse-free survival (41.4% vs. 37.5%, p = 0.85) after pulmonary metastasectomy from 2003. The rate of patients who received local therapy with curative intent after the first pulmonary metastasectomy was significantly higher in patients treated from 2003 than in those treated through 2002 [4/13, (31%) vs. 25/39 (64%), p = 0.04]. The survival after relapse after the first pulmonary metastasectomy was significantly longer in patients treated from 2003 than in those treated through 2002 (median survival time: 14 vs. 47 months).

Conclusions

Pulmonary metastasectomy for colorectal cancer remains an important treatment option in the sense that it can achieve a good relapse-free survival.

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Presurgical axitinib therapy increases fibrotic reactions within tumor thrombus in renal cell carcinoma with thrombus extending to the inferior vena cava

Abstract

Background

Clinical benefits of presurgical axitinib therapy for renal cell carcinoma (RCC) extending into the inferior vena cava (IVC) remain unclear. We aimed to investigate surgical benefits and pathological antitumor effects of presurgical axitinib therapy for RCC with IVC thrombus.

Methods

Of 56 consecutive RCC patients with IVC thrombus between January 1994 and December 2016, 41 patients who underwent radical nephrectomy (RN) were categorized as upfront RN (Upfront group) or presurgical axitinib followed by RN (Presurgical group). We retrospectively evaluated safety, radiologic tumor responses, and Ki-67 proliferation index before and after axitinib administration in the Presurgical group. Surgical outcomes, postoperative complications, and fibrosis within the IVC thrombus were compared between the Upfront and Presurgical groups.

Results

The number of patients in the Upfront and Presurgical groups was 31 and 10, respectively. Major presurgical axitinib-related adverse events were grade 2 or 3 hypertension (50%). The median radiological tumor response in the renal tumor, IVC thrombus length, and IVC thrombus volume were −19%, −21 mm, and −54%, respectively. The fibrosis within the IVC thrombus was significantly higher in the Presurgical group (10%) than in the Upfront group (3.4%). The Ki-67 proliferation index was significantly decreased in RN specimens (7.3%) versus needle biopsy specimens (23%) in the Presurgical group. Blood loss and operative duration were significantly lower and shorter, respectively, in the Presurgical group than in the Upfront group.

Conclusions

Presurgical axitinib therapy enhanced tumor reduction accompanied by fibrosis and may contribute to surgical risk reduction for selected patients.

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Changes in margin re-excision rates: Experience incorporating the “no ink on tumor” guideline into practice

Introduction

Prior to the "no ink on tumor" SSO/ASTRO consensus guideline, approximately 20% of women with stage I/II breast cancers undergoing breast conservation surgery at our institution underwent margin re-excision. On May 20, 2013, our institution changed the definition of negative margins from 2 mm to "no ink on tumor."

Methods

A retrospective review was conducted of patients who had surgery at our institution with clinical stage I/II breast cancers between June 1, 2011 and May 1, 2015. In the pre-guideline cohort (pre) and post-guideline cohort (post), negative margins were 2 mm and "no ink on tumor," respectively.

Results

Implementation of the guideline resulted in a significant decrease in the positive/close margin rate (29.6% pre vs 10.1% post; P < 0.001) and numerical decrease in re-excision rate (20.4% pre vs 16.3% post; P = 0.104). No significant difference was found in local recurrence between the cohorts with limited follow-up (1.2% pre vs 1.5% post; P = 0.787).

Conclusion

The implementation of the "no ink on tumor" guideline at our institution has resulted in a significant decrease in positive margin rates and a numerical decrease in margin re-excisions. In addition to margin status, surgeons continue to use individual patient and histologic factors to decide for or against margin re-excision.

http://ift.tt/2w3PlbR

Prognostic value of ion channel genes in Chinese patients with gliomas based on mRNA expression profiling

Abstract

Increasing evidence suggests that ion channels not only regulate electric signaling in excitable cells but also play important roles in the development of human cancer. However, the roles of ion channels in glioma remain controversial. We systematically analyzed the expression patterns of ion channel genes in a cohort of Chinese patients with glioma using whole-genome mRNA expression profiling. First, a molecular signature comprising 47 ion channel genes (IC47) was identified using Spearman's rank correlation test conducted between tumor grade and gene expression. We assigned a risk score based on IC47 to each glioma patient. We demonstrated that the risk score effectively predicted overall survival in glioma patients. Next, we screened IC47 in different molecular glioma subtypes. IC47 showed a Mesenchymal subtype and wild-type IDH1 preference. Gene ontology (GO) analysis and gene set variation analysis (GSVA) for the functional annotation of IC47 showed that patients with high-risk scores tended to exhibit the decreased expression of proteins associated with the apoptosis and cell adhesion, and higher expression of proteins associated with the cell cycle and cell proliferation. These results suggest that ion channel gene expression could improve the subtype classification in gliomas at the molecular level. The findings in the present study have been validated in two independent cohorts.

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Negative impact of leukoaraiosis on the incidence of brain metastases in patients with lung cancer

Abstract

The embolization of cancer cells to cerebral vessels occurs early in the multi-step metastatic process. We aimed to determine whether the presence of leukoaraiosis (LA) before treatment would predict the development of brain metastases (BM) in patients with lung cancer. Between January 2014 and June 2015, 1007 patients underwent initial (i.e., prior to any chemotherapy) or routine magnetic resonance (MR) imaging of the brain and exhibited no evidence of BM. Of these, 189 underwent repeat MR imaging; 34 of 189 patients (18%) developed new BM, whereas 155 patients did not. LA was retrospectively evaluated according to Fazekas scale on the initial screening MR images of these 189 patients. The frequency of grade 0 periventricular hyperintensity (PVH) was greater among patients with BM, compared to those without BM (p = 0.001). In a multivariate analysis, patients with adenocarcinoma (95% confidence interval [CI] 1.8–171.8) and small cell carcinoma (95% CI 1.4–172.4) respectively developed BM at 9.3- and 8.8-fold higher rates than those with squamous cell carcinoma. Patients with grade 0 PVH developed BM at a rate 3.5-, 8.6-, and 3.6-fold higher rates than those with grade 1 (95% CI 1.4–9.0), 2 (95% CI 2.4–41.9), and 3 (95% CI 1.02–15.0), respectively. Lung cancer patients with grade 0 PVH on initial MR images have a high subsequent incidence of BM. PVH is a useful method for evaluating risk of BM.

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Prevalence and Initial Prescription of Psychotropics in Patients with Common Cancers in Japan, based on a Nationwide Health Insurance Claims Database

Abstract

Objective

To investigate the prevalence of psychotropic medication use and identify factors affecting the prescription of psychotropics among patients newly diagnosed with any of eight common types of cancer.

Methods

This retrospective descriptive study examined data for patients newly diagnosed with breast, colorectal, liver, lung, ovarian, pancreatic, prostate, or stomach cancer between July 2009 and May 2014. The data were derived from a nationwide health claims database. The proportion of initial prescriptions for all oral psychotropics within 13 months of cancer diagnosis was analyzed by cancer type; the odds ratio (OR) for prescribing psychotropics was calculated using multivariable logistic regression models.

Results

A total of 14,661 patients were newly diagnosed with cancer. Psychotropics were prescribed for 6,593 (45%) patients. The highest and lowest proportions of psychotropic prescriptions were recorded for patients with lung cancer (62.6%) and prostate cancer (35.1%), respectively. The strongest predictors for psychotropic prescriptions were chemotherapy (OR, 2.59; 95% confidence interval [CI], 2.31–2.91; P < .001), lung cancer (OR, 2.47; 95% CI, 2.16–2.83; P < .001), and surgery (OR, 2.12; 95% CI, 1.97–2.28; P < .001).

Conclusions

The prevalence of and predictors for an initial prescription of psychotropics identified a potential target population of cancer patients requiring psychiatric treatment, particularly soon after a diagnosis of cancer.

http://ift.tt/2v17F8F

Protection Motivation Theory in Predicting Intention to Receive Cervical Cancer Screening in Rural Chinese Women

Abstract

Objective

Despite the significance of cervical cancer screening, motivating more women to participate remains a challenge in resource-limited settings. In this study, we tested the protection motivation theory (PMT) in predicting screening intentions.

Methods

Participants were women from Wufeng, a typical rural county in China. Participants (n=3000) with no cervical cancer history were recruited from 10 randomly selected villages. As mediating variables, six PMT constructs (Perceived Risk, Fear Arousal, Perceived Severity, Response Efficacy, Response Cost and Self-Efficacy) were measured using the standardized questionnaire. Structural equation modeling (SEM) method was employed to test PMT-based prediction models.

Results

Of the total sample, 57.77% believed that regular screening may reduce cervical cancer risk and 45.26% agreed that women should be screened regularly. Our data fit the PMT model well (GFI=0.95, AGFI=0.93, CFI=0.90, RMSEA= 0.06, SRMR=0.04, Chi-square/df =2.47). Knowledge of screening was directly and positively associated with screening intention. Age, annual income and awareness of and prior experience with screening were significantly associated with screening intention by enhancing cervical cancer risk perception and by reducing response cost (p<0.05 for both).

Conclusion

PMT can be used as guidance to investigate cervical cancer screening intentions among rural women in China with focus on cancer knowledge, some demographic factors and awareness of and previous experience with screening. These findings, if verified with longitudinal data, can be used for intervention program development.

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Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets

Publication date: October 2017
Source:Cancer Genetics, Volumes 216–217
Author(s): Rahul Agarwal, Jitendra Narayan, Amitava Bhattacharyya, Mayank Saraswat, Anil Kumar Tomar
A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis. The differential gene expression analysis using non-parametric Wilcoxon test revealed a total of 479 up-regulated and 91 down-regulated genes in HCC compared to controls. The list of top differentially expressed genes mainly consists of tumor/cancer associated genes, such as AFP, THBS4, LCN2, GPC3, NUF2, etc. The genes over-expressed in HCC were mainly associated with cell cycle pathways. In total, 59 kinases associated genes were found over-expressed in HCC, including TTK, MELK, BUB1, NEK2, BUB1B, AURKB, PLK1, CDK1, PKMYT1, PBK, etc. Overall four distinct HCC subtypes were predicted using consensus clustering method. Each subtype was unique in terms of gene expression, pathway enrichment and median survival. Conclusively, this study has exposed a number of interesting genes which can be exploited in future as potential markers of HCC, diagnostic as well as prognostic and subtype classification may guide for improved and specific therapy.



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PDGFRβ-P2A-CreER T2 mice: a genetic tool to target pericytes in angiogenesis

Abstract

Pericytes are essential mural cells distinguished by their association with small caliber blood vessels and the presence of a basement membrane shared with endothelial cells. Pericyte interaction with the endothelium plays an important role in angiogenesis; however, very few tools are currently available that allow for the targeting of pericytes in mouse models, limiting our ability to understand their biology. We have generated a novel mouse line expressing tamoxifen-inducible Cre-recombinase under the control of the platelet-derived growth factor receptor β promoter: PDGFRβ-P2A-CreER ^T2 . We evaluated the expression of the PDGFRβ-P2A-CreER ^T2 line by crossing it with fluorescent reporter lines and analyzed reporter signal in the angiogenic retina and brain at different time points after tamoxifen administration. Reporter lines showed labeling of NG2⁺, desmin⁺, PDGFRβ⁺ perivascular cells in the retina and the brain, indicating successful targeting of pericytes; however, signal from reporter lines was also observed in a small subset of glial cells both in the retina and the brain. We also evaluated recombination in tumors and found efficient recombination in perivascular cells associated with tumor vasculature. As a proof of principle, we used our newly generated driver to delete Notch signaling in perivascular cells and observed a loss of smooth muscle cells in retinal arteries, consistent with previously published studies evaluating Notch3 null mice. We conclude that the PDGFRβ-P2A-CreER ^T2 line is a powerful new tool to target pericytes and will aid the field in gaining a deeper understanding of the role of these cells in physiological and pathological settings.

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Six years genotype distribution of Human Papillomavirus in Calabria Region, Southern Italy: a retrospective study

Abstract

Background

Although analysis of the Human papillomavirus (HPV) genotype spread in a particular area has a crucial impact on public health and prevention programmes, there is a lack of epidemiological data regarding HPV in the Calabria region of Italy. We therefore update information on HPV age/genotype distribution by retrospectively analysing a cohort of women, with and without cervical lesions, living in Calabria, who underwent HPV DNA testing; moreover, we also evaluated HPV age/genotype distribution in a subset of patients with cervical lesions.

Methods

Cervical scrape specimens obtained from 9590 women (age range 20–75 years) from January 2010 to December 2015 were tested for HPV DNA. Viral types were genotyped by Linear Array HPV Genotyping® test (Roche, USA) at the Clinical Microbiology Operative Unit of six hospitals located in four provinces of the Calabria region.

Cervical scrape specimens were also used to perform Pap smears for cytological analysis in a subset of 405 women; cytological classification of the samples was performed according to the Bethesda classification system.

Results

A total of 2974 women (31%) (C.I. 95% 30.09–31.94) were found to be HPV DNA positive for at least one (57.3%) or several (42.7%) HPV genotypes. Of single genotype HPV infections, 46.5% and 36.4 % were classed as high-risk (HR, Group 1) and low-risk (LR, Group 3) respectively, while 16.9% were classed as probably/possibly carcinogenic and 0.2% undetermined risk. Stratified by age, total HPV distribution, showed the highest prevalence within the range 30–39 years (37.2%), while single genotype infection distribution displayed a peak in women from the age range 20–29 years (37.5%). The most common high-risk HPV type was HPV 16 (19.1%), followed by HPV 31 (9.1%).

Conclusions

We provide epidemiological data on HPV age/genotype distribution in women living in the Calabria region with or without cytological abnormalities, further to the enhancement of HPV screening/prevention programmes for the local population.

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miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma

Abstract

Background

miR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.

Methods

miR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.

Results

miR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.

Conclusion

our results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.

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