Ayurveda metallic-mineral 'Bhasma-associated severe liver injury

Ayurveda Bhasma is a metallic-mineral preparation homogenised with herbal juices or decoctions and modified with heat treatment to apparently detoxify the heavy metals. It is widely recommended for the treatment of many disease conditions by practitioners of complementary and alternative medicine in the absence of good quality clinical trial evidence on its safety and efficacy. Heavy metal-induced liver injury is widely reported in the literature, and heavy metal adulteration of non-Bhasma-related Ayurveda and herbal products has been well described. We report a patient who developed severe liver injury requiring listing for liver transplantation for improved survival, after consumption of Bhasma for dyspepsia. This case describes the first documented case and toxicology analysis of Ayurveda Bhasma associated with severe drug-induced liver injury. Physicians must be alert regarding patient's use of supposedly safe Ayurveda Bhasma that may promote acute severe liver injury in the absence of other known aetiologies.

https://ift.tt/2lGflHo

Phytobezoar and duodenal ulcer as complication of Duodopa therapy in a patient affected by Parkinsons disease

Continuous duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established treatment to control motor fluctuations in Parkinson's disease. Duodenal infusion allows a steady absorption of the drug in the small bowel, reducing plasmatic fluctuations of levodopa. Some complications may occur during the treatment, often related to intrajejunal percutaneous endoscopic gastrostomy (PEG-J). We report a case of duodenal ulcer associated with a phytobezoar involving the end of jejunal probe, in a patient who underwent PEG-J for LCIG infusion. In the last 2 weeks, the patient suffered from abdominal pain and dyspepsia. Oesophagogastroduodenoscopy showed an ulcerative lesion of the duodenum due to traction of the jejunal tube; the end of the jejunal tube was wrapped in a phytobezoar. This case is interesting because of the extension of the ulcerative lesion due to PEG-J dislocation and because of the subtle symptoms associated with it.

https://ift.tt/2yYgQdo

Just another case of bacterial meningitis... or... is it?

Non-traumatic cerebrospinal fluid (CSF) rhinorrhoea is a rare condition. We describe a case of a 62-year-old woman with pneumococcal bacterial meningitis who later was found to have CSF rhinorrhoea secondary to an eroding skull base tumour, which was proven to be pituitary macroadenoma on biopsy. She recovered well from meningitis without any neurological sequelae and underwent trans-sphenoidal surgery for tumour removal as well as dural repair.

https://ift.tt/2lHuCHK

Ectopic insulinomas in the pelvis secondary to rectum neuroendocrine tumour

We describe a middle-aged woman with recurrent hypoglycaemia, who confirmed with rectum G1 neuroendocrine tumour (NET) 6 years ago. Biochemical assay showed high concentration of serum insulin and C-peptide associated with hypoglycaemia. Because of recurrent hypoglycaemia in June 2015, she underwent a resection of the tail of the pancreas. However, hypoglycaemia attack happened more frequently and severely. ⁶⁸Ga-DOTA-NOC positron emission tomography/CT revealed five foci in the pelvis with intense uptake. Immediately after excision of the pelvic lesions, insulin and C-peptide decreased to normal levels promptly, and therefore, serum glucose increased significantly. Hypoglycaemia was disappeared, and insulin and C-peptide were normal at 2 years follow-up after surgery. Immunohistochemistry validated the primary rectum NET and pelvic tumours expressed with higher insulin, somatostatin receptor and glucagon-like peptide-1. This is the first reported ectopic pelvic insulinomas secondary to rectum NET, which may originate both from neuroendocrine cells in the rectum and pelvic tissues.

https://ift.tt/2z2JsCu

Pineal gland apoplexy mimicking as migraine-like headache

Description 

A 24-year-old female patient presented with acute-onset, vertex headache associated with photophobia, nausea and vomiting. Initially, the headache was mild (pain scale 4/10), but over the next 4–5 hours, the severity of the headache increased to pain scale of 8/10. She had a history of similar headaches of lesser intensity in the past. There was also a strong family history of migraine. Her mother and younger sister used to get similar headaches and got relieved with antimigraine medications. Exact details of her medication history were unavailable since the progression of severity of her headache was gradual. This was unlike thunderclap headache and, in high likelihood, another episode of migraine.

Her vitals were stable. Neurological examination, including funduscopy, was grossly normal

On radiological evaluation, the MRI brain showed T1-weighted hyperintense pineal gland, as seen on the axial view suggestive of intrapineal gland apoplexy (figure 1). The fluid–fluid interface is depicted by the horizontal...

https://ift.tt/2lIXmzR

Unusual cause of elbow pain in a baseball pitcher

An adolescent, right hand-dominant, baseball pitcher presented to sports medicine clinic with posterolateral right elbow pain over 4 months. He rated his pain as 8/10 with pitching, especially at the late cocking phase of throwing. Prior to consult, he had rested 3 months from pitching, progressing to strengthening exercises, with no pain relief. On physical examination, he had 120° of active external rotation, 80° of active internal rotation, mild tenderness to palpation over the capitellum and normal elbow radiography. Magnetic resonance arthrogram of the right elbow revealed subtle, posterolateral joint capsular tear and adjacent synovial hypertrophy. The patient was diagnosed with elbow synovial fold syndrome that was causing impingement at the radiocapitellar joint and was referred to an orthopaedic surgeon. Arthroscopy revealed redundant tissue; scar formation at the radiocapitellar joint was debrided. The patient participated in physical therapy for 2 months and was able to start throwing 3 months later.

https://ift.tt/2tN90xe

Double tongue signs in a case of submandibular space infection

Description

Double tongue signs are a unique physical finding which involve an elevation of floor of the oropharynx caused by a bilateral infection of the submandibular space (a well-known example is Ludwig's angina) (figure 1A).1 2 In this case, an 80-year-old woman with a 10-year history of diabetes mellitus was referred to our emergency department. She presented with swelling from the submandibular region to the neck surface, with a 3-day history of continuous fever, weakness and fatigue. Physical examination revealed neck oedema with erythema and tenderness (figure 1B), without lymphadenopathy. The floor of the oropharynx was clearly swollen and elevated, such that it appeared to be a double tongue; this was erythematous and tender. Enhanced CT of the neck was performed, which revealed bilateral fluid retention with swollen surrounding soft tissues in the submandibular space (figure 2). We...

https://ift.tt/2lKpjYn

Early-stage right temporal lobe variant of frontotemporal dementia: 3 years of follow-up observations

The right temporal lobe variant of frontotemporal dementia (FTD) is an uncommon progressive neurodegenerative disorder. We present the case of a 77-year-old right-handed man who presented with altered behaviour and problems with interpersonal relationships. He had no decline in cognitive function but brain perfusion single-photon emission CT demonstrated distinct hypoperfusion in the right temporal pole. At 2-year follow-up, he could not recognise his wife's relatives; and at 3-year follow-up, he had semantic aphasia. Decreased brain perfusion extended from the right temporal lobe into the contralateral temporal and both frontal lobes. These findings suggest that the right temporal lobe variant of FTD should be considered in elderly patients with altered behaviour and problems with interpersonal relationships, even if dementia is not suspected. The right anterior temporal lobe may play a key role in the onset of the early symptoms of this disease.

https://ift.tt/2yWrl0P

Pseudo-Wellens syndrome secondary to concurrent cannabis and phencyclidine intoxication

Wellens' syndrome is an electrocardiographic pattern of T-wave changes associated with critical stenosis of the proximal left anterior descending artery, signifying imminent risk of an anterior-wall myocardial infarction. The Wellens' electrocardiographic pattern can also be noted in several cardiac and non-cardiac diseases. We chronicle here a unique case of a patient who presented with atypical left chest pain and dizziness for 6 hours. His pain started after he smoked phencyclidine-laced cannabis. Cardiac panel demonstrated normal troponin T levels. Electrocardiogram showed sinus rhythm with new deep biphasic T-wave inversions in anterolateral leads. Coronary angiography showed no pathological processes. Subsequently, ECG changes resolved coincidentally with the resolution of chest pain. He was eventually diagnosed with pseudo-Wellens' syndrome. This paper illustrates that physicians should be vigilant for Wellens' syndrome mimicked by acute phencyclidine and cannabis intoxication. Additionally, we present a review of various aetiologies of pseudo-Wellens' syndrome, especially in patients with substance abuse.

https://ift.tt/2lK3GaB

Suction-induced retinopathy: optical coherence tomography correlations

We report a clinical case of a teenager whose eyes were exposed to highly negative suction pressures for brief seconds. The patient presented with a bilateral cystoid macular oedema associated with a thickening of outer nuclear layer evidenced by optical coherence tomography. The patient's constellation of findings is most easily explained by the abrupt expansion and traction of a cohesive vitreous base onto the retinal layers.

https://ift.tt/2tO4lLG

Inflammatory myofibroblastic tumour: a rare cause of central airway obstruction

Description

A 70-year-old woman with no comorbidities presented with cough, wheezing, exertional dyspnoea and a sensation of throat fullness. She never smoked and was recently diagnosed with asthma based on a normal chest radiograph and pulmonary function testing but failed to improve with bronchodilators and steroids. Her initial chest radiograph was unremarkable, and spirometry suggested a fixed intrathoracic obstruction. CT of the chest obtained after 2 months showed an irregular density in the trachea, 1.4x1.7 cm (figure 1). Flexible bronchoscopy showed a polypoid mass 2–3 cm above the carina adherent to the right wall of the trachea (figure 2). Rigid bronchoscopy with neodymium-doped yttrium aluminium garnet (Nd:YAG) laser photoresection was performed. Given the vascular nature of the tumour, removal was complicated by significant bleeding, which required endobronchial epinephrine and laser coagulation. The patient recovered without further complications. Immunohistochemical staining on the excised tumour was positive for vimentin...

https://ift.tt/2lO7ho9

Second look at Streptococcus sanguinis and the colon

Although the link between Streptococcus bovis bacteraemia and colon cancer is well established, bacteraemia from other viridans group streptococci that commonly colonise colonic mucosa may also herald occult malignancy. We present a case of Streptococcus sanguinis bacteraemia in an elderly man with new anaemia that led to the detection and removal of a high-grade colon neoplasm. This case contributes to a growing body of literature contending that unexplained streptococcal bacteraemia merits a thorough workup that may include relatively invasive procedures such as endoscopy. Diagnostic colonoscopy provides an opportunity to prevent invasive malignancy that may outweigh bleeding and perforation risks in elderly patients.

https://ift.tt/2tSs1P5

Atypical presentation of type B aortic dissection mimicking appendicitis managed medically

This is a case of a 53-year-old male patient with a history of hypertension who developed sudden onset of right lower quadrant pain. On arrival, chest X-ray showed prominent aortic arch without cardiomegaly. CT of the abdomen/pelvis showed aortic dissection in descending aorta without rupture. CT of the chest displayed sparing of ascending and aortic arch. Ultrasound Doppler of the kidney displayed mild renal artery stenosis. Differential diagnosis was acute appendicitis, acute ureteric and severe gastroenteritis. The patient was started on oral blood pressure (BP) medicine to titrate off intravenous nicardipine and esmolol drip. After 10 days, he was switched to oral BP medicine. His leg pain was resolved with normal palpable pulse. One week later, his kidney function worsened. Thus, Lasix and minoxidil were stopped. The patient had no chest/abdominal pain and was tolerating the medicine well during his 2-week follow-up. Acute aortic dissection can be a fatal clinical emergency. Timing is critical during diagnosis and management of patients.

https://ift.tt/2lKw8sG

EBV colitis with ulcerative colitis: a double whammy

We report this case of a 21-year-old immunocompetent man presenting with ulcerative colitis and superimposed Epstein-Barr virus (EBV) colitis. He presented for the first time with symptoms of blood-mixed diarrhoea and raised inflammatory markers. His endoscopic and histological appearances were found to be due to ulcerative colitis for which he was started on standard therapy with intravenous steroids. In spite of this, he continued to be symptomatic and his inflammatory markers continued to rise. A virology screen done showed evidence of previous EBV infection, and in view of poor response to immunosuppression, a superimposed infection was suspected. EBV DNA PCR done on colonic biopsies was found to be positive and the patient was started on intravenous ganciclovir to which he responded well. This case highlights the importance of considering a superimposed infection in patients with poor initial response to steroid therapy in inflammatory bowel disease.

https://ift.tt/2yWqWeP

Adult-onset epileptic aphasia

Aphasia is a language disorder characterised by loss of ability to produce or comprehend written or spoken language. In majority of the cases, it is due to stroke. Aphasia may also present as an ictal or postictal state of temporal or frontal lobe seizures. Nevertheless, its isolated occurrence in individuals without a clear-cut history of seizures raises diagnostic difficulties with important therapeutic implications.

A case of epileptic aphasia is reported in which the diagnosis was confirmed by electroencephalogram with a dramatic therapeutic response to an antiepileptic drug.

https://ift.tt/2lKw7VE

Reversible cardiac dysfunction in long-standing hypertension may be global variant of stress cardiomyopathy

An adult man with long-standing poorly controlled cardiac risk factors presented with acute decompensated heart failure (ADHF). Echocardiogram, cardiac MRI and catheterisation suggested idiopathic dilated cardiomyopathy, severe systolic dysfunction, ejection fraction 25% with global left ventricular (LV) dilation and apical thrombus. He responded well to diuretics and gradual uptitration of lisinopril and carvedilol. Follow-up echocardiogram in 2 months demonstrated complete recovery of systolic function, normalisation of LV size and shape with severe LV hypertrophy. This presentation is potentially a global variant of stress cardiomyopathy with recovery of LV function, highlighting the importance of appropriate imaging, catheterisation and clinical monitoring in patients with ADHF.

https://ift.tt/2yWrdhR

Anomalous aortic origin of a coronary artery with an intraseptal course: novel techniques in haemodynamic assessment

Description

A 7-year-old boy presented to the emergency room after an episode of syncope while at home. Although, it was non-exertional, it lasted 2 min and was preceded by angina-like chest pain. Vitals, physical examination, chest radiograph and ECG were normal. Subsequent cardiology evaluation led to an echocardiogram that showed anomalous origin of the left main coronary artery from the opposite sinus of Valsalva with adjacent ostia which was confirmed on CT angiography. In addition, it showed a long 2.5–3 cm deep intraseptal course of the left anterior descending (LAD) and short intraseptal course of the left circumflex (LCX) artery. Stress nuclear perfusion scan and Holter monitoring were negative, but stress cardiac MRI showed an inducible perfusion defect along the anterior interventricular septal wall most prominent at the mid-ventricular and basilar levels. Coronary angiography (figure 1 and video 1) and intravascular ultrasound demonstrated significant systolic compression of the intraseptal segment...

https://ift.tt/2lI0Xyb

Biots breathing associated with acute bacterial meningitis in a child

Description

A 19-month-old boy presented to the emergency room of our hospital with fever and drowsiness following asymmetric focal seizure. On examination the patient was somnolent, had signs of meningeal irritation and intermittent nystagmus. Laboratory examination revealed increased C-reactive protein (200 mg/L), procalcitonin (25.9 ng/mL) and hyponatraemia (132 mEq/L). The initial CT of the brain was normal. Given presumed meningoencephalitis, intravenous dexamethasone, vancomycin, ceftriaxone and acyclovir treatment was started, and the child was admitted to the paediatric intensive care unit. Several hours after the admission, irregular, jerky respirations appeared, consistent with Biot's breathing (figure 1). The patient developed hypertension (129/90 mm Hg) and relative bradycardia (90 bpm). Due to these signs, consistent with increased intracranial pressure, lumbar puncture was deferred and the child received mannitol with notable improvement in his condition. On hospital day 2, lumbar puncture revealed turbid fluid with an opening pressure of 5 cmH₂O, white blood cells...

https://ift.tt/2tT6N3D

Subfoveal congenital hypertrophy of retinal pigment epithelium

Description

A 25-year-old man presented with slight blurring of vision in the right eye (RE), noted 3 years ago. There was no positive systemic history. His best corrected visual acuity was 6/9 in RE and 6/6 in the left eye (LE) at presentation. Anterior segment evaluation was unremarkable in both eyes with normal pupil light reflexes. Fundus evaluation revealed a flat circular lesion beneath the fovea, and was measured to be one-third of the size of the optic nerve head. It was a densely pigmented lesion, black in colour, with a surrounding depigmented whitish halo (figure 1). The LE was within normal range on clinical examination. Spectral domain optical coherence tomography (SD-OCT) of RE revealed the lesion to be irregular but flat with hyper-reflectivity at the level of the retinal pigment epithelium (RPE). Discontinuity of the ellipsoid zone was noted to be overlying some parts of the lesion. These findings were also accompanied...

https://ift.tt/2lMbVmq

A case of massive haemoptysis

Description

A 77-year-old female never-smoker presented with massive haemoptysis. Admission plain chest radiograph was normal.

She was haemodynamically stable on presentation but the following morning she had a further large-volume haemoptysis (>500 mL), resulting in respiratory arrest. Following resuscitation, haemoglobin fell from 94 to 66 g/dL. CT angiogram was performed (figure 1).

Figure 1

Sagittal CT angiogram, performed once the patient was stabilised.

She had previously been investigated for small volume haemoptysis and left upper lobe mass-like consolidation, which had fully resolved following a course of antibiotics. Recent bronchoscopy was normal, with no pathological organisms. There was no evidence of malignancy or connective tissue disease, and there was no additional past medical history. CT imaging had been reviewed at a thoracic oncology multi-disciplinary meeting and the previous episode was attributed to non-specific infection.

Question

What is the diagnosis (see figure 1)?

(A) Pulmonary artery...

https://ift.tt/2yWr9yD

Impact of Regional Anesthesia on Gastroesophageal Cancer Surgery Outcomes: A Systematic Review of the Literature

Regional anesthesia may play a beneficial role in long-term oncological outcomes. Specifically, it has been suggested that it can prolong recurrence-free survival and overall survival after gastrointestinal cancer surgery, including gastric and esophageal cancer, by modulating the immune and inflammatory response. However, the results from human studies are conflicting. The goal of this systematic review was to summarize the evidence on the impact of regional anesthesia on immunomodulation and cancer recurrence after gastric and esophageal surgery. We conducted a literature search of 5 different databases. Two independent reviewers analyzed the quality of the selected manuscripts according to prespecified inclusion and exclusion criteria. Randomized controlled trials were assessed for potential sources of bias by using the Cochrane Risk of Bias tool. A total of 6 studies were included in the quality analysis and systematic review. A meta-analysis was not conducted for several reasons, including high heterogeneity among studies, low quality of the reports, and lack of standardized outcomes definitions. Although the literature suggests that regional anesthesia has some modulatory effects on the inflammatory and immunological response in the studied patient population, our systematic review indicates that there is no evidence to support or refute the use of epidural anesthesia or analgesia with the goal of reducing cancer recurrence after gastroesophageal cancer surgery. Accepted for publication May 23, 2018. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Juan P. Cata, MD, Department of Anaesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Centre, 1515 Holcombe Blvd, Unit 409, Houston, TX 77005. Address e-mail to jcata@mdanderson.org. © 2018 International Anesthesia Research Society

https://ift.tt/2tIaAkO

Metabolic Disorders and Critically Ill Patients

No abstract available

https://ift.tt/2KCKlD6

Epidural Analgesia and Subcutaneous Heparin 3 Times Daily in Cancer Patients With Acute Postoperative Pain

The use of epidural analgesia in conjunction with subcutaneous administration of unfractionated heparin 3 times per day could increase the risk of spinal epidural hematoma, but insufficient patient experience data exist to determine this. We retrospectively reviewed the incidence of spinal epidural hematoma in 3705 cases at our institution over a 7-year period of patients receiving acute postoperative epidural analgesia and heparin 3 times per day. No cases of spinal epidural hematoma were reported (95% CI, 0–0.0009952). Accepted for publication May 23, 2018. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Jackson Su, MD, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Unit 409, 1515 Holcombe Blvd, Houston, TX 77030. Address e-mail to jsu@mdanderson.org. © 2018 International Anesthesia Research Society

https://ift.tt/2NcpAji

Proceedings From the Society for Advancement of Blood Management Annual Meeting 2017: Management Dilemmas of the Surgical Patient—When Blood Is Not an Option

Vigilance is essential in the perioperative period. When blood is not an option for the patient, especially in a procedure/surgery that normally holds a risk for blood transfusion, complexity is added to the management. Current technology and knowledge has made avoidance of blood transfusion a realistic option but it does require a concerted patient-centered effort from the perioperative team. In this article, we provide suggestions for a successful, safe, and bloodless journey for patients. The approaches include preoperative optimization as well as intraoperative and postoperative techniques to reduce blood loss, and also introduces current innovative substitutes for transfusions. This article also assists in considering and maneuvering through the legal and ethical systems to respect patients' beliefs and ensuring their safety. Accepted for publication April 20, 2018. Funding:None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Gee Mei Tan, MMED, MBBS, Department of Anesthesiology, University of Colorado, School of Medicine, 13123 E 16th Ave, B090, Aurora, CO 80045. Address e-mail to Geemei.tan@childrenscolorado.org. © 2018 International Anesthesia Research Society

https://ift.tt/2KysexW

Prospective Observational Investigation of Capnography and Pulse Oximetry Monitoring After Cesarean Delivery With Intrathecal Morphine

BACKGROUND: Intrathecal morphine provides excellent analgesia after cesarean delivery; however, respiratory events such as apnea, bradypnea, and hypoxemia have been reported. The primary study aim was to estimate the number of apneas per subject, termed "apnea alert events" (AAEs) defined by no breath for 30–120 seconds, using continuous capnography in women who underwent cesarean delivery. METHODS: We performed a prospective, observational study with institutional review board approval of women who underwent cesarean delivery with spinal anesthesia containing 150-µg intrathecal morphine. A STOP-Bang obstructive sleep apnea assessment was administered to all women. Women were requested to use continuous capnography and pulse oximetry for 24 hours after cesarean delivery. Nasal sampling cannula measured end-tidal carbon dioxide (EtCO2) and respiratory rate (RR), and oxygen saturation (SpO2) as measured by pulse oximetry. Capnography data were defined as "valid" when EtCO2 >10 mm Hg, RR >5 breaths per minute (bpm), SpO2 >70%, or during apnea (AAE) defined as "no breath" (EtCO2, 30 kg/m2/weight >90 kg, and 11% with suspected obstructive sleep apnea (known or STOP-Bang score >3). The duration of normal capnography and pulse oximetry data was mean (SD) (range) 8:28 (7:51) (0:00–22:32) and 15:08 (6:42) (1:31–23:07) hours:minutes, respectively; 6 women did not use the capnography. There were 198 AAEs, mean (SD) duration 57 (27) seconds experienced by 39/74 (53%) women, median (95% confidence interval for median) (range) 1 (0–1) (0–29) per subject. Observation of RR by nurses was ≥14 bpm at all time-points for all women, r = 0.05 between capnography and nurse RR (95% confidence interval, −0.04 to 0.14). There were no clinically relevant adverse events for any woman. Sixty-five women (82%) had complaints with the capnography device, including itchy nose, nausea, interference with nursing baby, and overall inconvenience. CONCLUSIONS: We report 198 AAEs detected by capnography among women who underwent cesarean delivery after receiving intrathecal morphine. These apneas were not confirmed by the intermittent hourly nursing observations. Absence of observer verification precludes distinction between real, albeit nonclinically significant alerts with capnography versus false apneas. Discomfort with the nasal sampling cannula and frequent alerts may impact capnography application after cesarean delivery. No clinically relevant adverse events occurred. Accepted for publication April 26, 2018. Funding: This study was supported by an Investigator Research Grant (VT ID# ISR-2013–10323) from Medtronic, which provided financial support and the capnography equipment. The funding body had no role in the study design, raw data extraction and processing, data analysis or interpretation, writing of the manuscript, or manuscript submission for publication. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). This study was conducted at the Lucile Packard Children's Hospital, Stanford, California. Clinical trial number: clinicaltrials.gov (NCT02417038; April 10, 2015). Institutional review board: Shana Stolarczyk, Research Compliance Office, Stanford University, 3000 El Camino Real, Five Palo Alto Sq, 4th Floor, Palo Alto, CA 94306. E-mail: irbeducation@lists.stanford.edu; Shana.Stolarczyk@stanford.edu. Reprints will not be available from the authors. Address correspondence to Carolyn F. Weiniger, MBChB, Division of Anesthesia, Critical Care and Pain, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Address e-mail to carolynfweiniger@gmail.com. © 2018 International Anesthesia Research Society

https://ift.tt/2tIaCsW

Opioids for Acute Pain Management in Patients With Obstructive Sleep Apnea: A Systematic Review

The intrinsic nature of opioids to suppress respiratory function is of particular concern among patients with obstructive sleep apnea (OSA). The association of OSA with increased perioperative risk has raised the question of whether patients with OSA are at higher risk for opioid-induced respiratory depression (OIRD) compared to the general population. The aims of this systematic review were to summarize current evidence with respect to perioperative OIRD, changes in sleep-disordered breathing, and alterations in pain and opioid sensitivity in patients with OSA. A systematic literature search of studies published between 1946 and October 2017 was performed utilizing the following databases: Medline, ePub Ahead of Print/Medline In-process, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed—NOT-Medline and ClinicalTrials.Gov. Of 4321 initial studies, 40 met the inclusion criteria. The Oxford level of evidence was assessed. Overall, high-quality evidence on the comparative impact of acute opioid analgesia in OSA versus non-OSA patients is lacking. The current body of evidence is burdened by significant limitations including risk of bias and large heterogeneity among studies with regard to OSA severity, perioperative settings, outcome definitions, and the presence or absence of various perioperative drivers. These factors complicate an accurate interpretation and robust analysis of the true complication risk. Nevertheless, there is some consistency among studies with regard to a detrimental effect of opioids in the presence of OSA. Notably, the initial 24 hours after opioid administration appear to be most critical with regard to life-threatening OIRD. Further, OSA-related increased pain perception and enhanced opioid sensitivity could predispose patients with OSA to a higher risk for OIRD without overdosing. While high-quality evidence is needed, retrospective analyses indicate that critical, life-threatening OIRD may be preventable with a more cautious approach to opioid use, including adequate monitoring. Accepted for publication May 8, 2018. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Stavros G. Memtsoudis, MD, PhD, Departments of Anesthesiology, Critical Care, and Pain Management and Public Health, Hospital for Special Surgery, Weill Cornell Medical College, 535 E 70th St, New York, NY 10021. Address e-mail to memtsoudiss@hss.edu. © 2018 International Anesthesia Research Society

https://ift.tt/2IEpc9M

Practice of Ultrasound-Guided Palpation of Neck Landmarks Improves Accuracy of External Palpation of the Cricothyroid Membrane

BACKGROUND: Ultrasonography can accurately identify the cricothyroid membrane; however, its impact on the subsequent accuracy of external palpation is not known. In this study, we tested the ability of anesthesia participants to identify the midpoint of the cricothyroid membrane using external palpation with and without ultrasound (US)-guided practice. METHODS: Following institutional ethics approval and informed consent, anesthesia participants consisting of anesthesia residents, fellows, and practicing anesthesia assistants underwent didactic teaching on neck landmarks. The participants were then randomized to practice palpation of neck landmarks with US guidance (US group) or without ultrasonography (non-US [NUS] group). After the practice session, each participant identified the cricothyroid membrane using external palpation on the neck of 10 volunteers and marked the anticipated entry point for device insertion (palpation point [PT]). The midpoint of the cricothyroid membrane of each volunteer had been premarked with invisible ink using ultrasonography (US point) by a separate member of the research team. The primary outcome was the accuracy rate defined as the percentage of the attempts with the distance ≤5 mm measured from the PT to US point for the participant. The primary outcome was compared between NUS and US groups using Wilcoxon rank sum test. A mixed-effect logistic regression or mixed-effect linear model was also conducted for outcomes accounting for the clustering and adjusting for potential confounders. RESULTS: Fifteen anesthesia participants were randomized to US (n = 8) and NUS (n = 7) groups. A total of 80 and 61 attempts were performed by the US and NUS groups, respectively. The median accuracy rate in the US group was higher than the NUS group (65% vs 30%; P = .025), and the median PT-US distance in the US group was shorter than in the NUS group (4.0 vs 8.0 mm; P = .04). The adjusted mean PT-US distance in the US group was shorter compared to the NUS group (adjusted mean [95% CI], 3.6 [2.9–4.6] vs 6.8 [5.2–8.9] mm; P

https://ift.tt/2tHh5Es

Dexmedetomidine Versus Remifentanil for Monitored Anesthesia Care During Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: A Randomized Controlled Trial

BACKGROUND: We hypothesized that, compared to remifentanil, dexmedetomidine used for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) performed under monitored anesthesia care (MAC) in nonintubated patients would result in fewer episodes of major respiratory adverse events (number of episodes of bradypnea, apnea or desaturation) but no difference in satisfaction with perioperative conditions. METHODS: Sixty (American Society of Anesthesiologists physical status I–III) patients scheduled to undergo EBUS-TBNA under MAC were randomized to receive either remifentanil (0.5 µg/kg IV bolus) in 10 minutes, followed by 0.05–0.25 µg/kg/min, or dexmedetomidine (0.4 µg/kg IV bolus) in 10 minutes, followed by 0.5–1.0 µg/kg/h. The primary outcome was the number of major respiratory adverse events (bradypnea, apnea, or hypoxia). The secondary outcomes included hemodynamic variables, discharge time from the postanesthesia care unit, endotracheal lidocaine use, patient's sedation using the Observer Assessment of Alertness/Sedation Scale, operative conditions, operator and patient satisfaction, pain, coughing, vocal cord mobility, recall, and nausea/vomiting. RESULTS: Dexmedetomidine produced significantly fewer episodes of major respiratory events (bradypnea, apnea, or desaturation), with 0 [0–0.5] episodes versus 2 [0–5] (median [interquartile range]) (P = .001), than did remifentanil. Fewer episodes of bradypnea or apnea (dexmedetomidine: 0 [0–0] versus remifentanil: 0 [0–0.5]; P = .031), and fewer episodes of desaturation (dexmedetomidine: 0 [0–0.5] versus remifentanil: 1 [0–4]; P = .039) were recorded in the dexmedetomidine group. The time needed for patients to meet postanesthesia care unit discharge criteria (Aldrete score: 9) after EBUS-TBNA was longer in the dexmedetomidine group (10 [3–37.5] minutes) versus the remifentanil group (3 [3–5] minutes) (P

https://ift.tt/2IEIDiC

Potent Inactivation-Dependent Inhibition of Adult and Neonatal NaV1.5 Channels by Lidocaine and Levobupivacaine

BACKGROUND: Cardiotoxic effects of local anesthetics (LAs) involve inhibition of NaV1.5 voltage-gated Na+ channels. Metastatic breast and colon cancer cells also express NaV1.5, predominantly the neonatal splice variant (nNaV1.5) and their inhibition by LAs reduces invasion and migration. It may be advantageous to target cancer cells while sparing cardiac function through selective blockade of nNaV1.5 and/or by preferentially affecting inactivated NaV1.5, which predominate in cancer cells. We tested the hypotheses that lidocaine and levobupivacaine differentially affect (1) adult (aNaV1.5) and nNaV1.5 and (2) the resting and inactivated states of NaV1.5. METHODS: The whole-cell voltage-clamp technique was used to evaluate the actions of lidocaine and levobupivacaine on recombinant NaV1.5 channels expressed in HEK-293 cells. Cells were transiently transfected with cDNAs encoding either aNaV1.5 or nNaV1.5. Voltage protocols were applied to determine depolarizing potentials that either activated or inactivated 50% of maximum conductance (V½ activation and V½ inactivation, respectively). RESULTS: Lidocaine and levobupivacaine potently inhibited aNaV1.5 (IC50 mean [SD]: 20 [22] and 1 [0.6] µM, respectively) and nNaV1.5 (IC50 mean [SD]: 17 [10] and 3 [1.6] µM, respectively) at a holding potential of −80 mV. IC50s differed significantly between lidocaine and levobupivacaine with no influence of splice variant. Levobupivacaine induced a statistically significant depolarizing shift in the V½ activation for aNaV1.5 (mean [SD] from −32 [4.6] mV to −26 [8.1] mV) but had no effect on the voltage dependence of activation of nNaV1.5. Lidocaine had no effect on V½ activation of either variant but caused a significantly greater depression of maximum current mediated by nNaV1.5 compared to aNaV1.5. Similar statistically significant shifts in the V½ inactivation (approximately −10 mV) occurred for both LAs and NaV1.5 variants. Levobupivacaine (1 µM) caused a significantly greater slowing of recovery from inactivation of both variants than did lidocaine (10 µM). Both LAs caused approximately 50% tonic inhibition of aNaV1.5 or nNaV1.5 when holding at −80 mV. Neither LA caused tonic block at a holding potential of either −90 or −120 mV, voltages at which there was little steady-state inactivation. Higher concentrations of either lidocaine (300 µM) or levobupivacaine (100 µM) caused significantly more tonic block at −120 mV. CONCLUSIONS: These data demonstrate that low concentrations of the LAs exhibit inactivation-dependent block of NaV1.5, which may provide a rationale for their use to safely inhibit migration and invasion by metastatic cancer cells without cardiotoxicity. Accepted for publication May 21, 2018. Funding: This study was supported by a BJA/RCoA grant awarded to T.G.H. via the National Institute of Academic Anaesthesia, UK. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). T. Elajnaf and D. T. Baptista-Hon contributed equally and share first authorship. Reprints will not be available from the authors. Address correspondence to Tim G. Hales, PhD, The Institute of Academic Anaesthesia, Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, United Kingdom. Address e-mail to t.g.hales@dundee.ac.uk. © 2018 International Anesthesia Research Society

https://ift.tt/2tG4IZo

Monitoring Depth of Hypnosis: Mid-Latency Auditory Evoked Potentials Derived aepEX in Children Receiving Desflurane-Remifentanil Anesthesia

BACKGROUND: The aepEXplus monitoring system, which uses mid-latency auditory evoked potentials to measure depth of hypnosis, was evaluated in pediatric patients receiving desflurane-remifentanil anesthesia. METHODS: Seventy-five patients, 1–18 years of age (stratified for age; 1–3, 3–6, 6–18 years, for subgroup analyses), were included in this prospective observational study. The aepEX and the bispectral index (BIS) were recorded simultaneously, the latter serving as a reference. The ability of the aepEX to detect different levels of consciousness, defined according to the University of Michigan Sedation Scale, investigated using prediction probability (Pk), and receiver operating characteristic (ROC) analysis, served as the primary outcome parameter. As a secondary outcome parameter, the relationship between end-tidal desflurane and the aepEX and BIS values were calculated by fitting in a nonlinear regression model. RESULTS: The Pk values for the aepEX and the BIS were, respectively, .68 (95% CI, 0.53–0.82) and .85 (95% CI, 0.73–0.96; P = .02). The aepEX and the BIS had an area under the ROC curve of, respectively, 0.89 (95% CI, 0.80–0.95) and 0.76 (95% CI, 0.68–0.84; P = .04). The maximized sensitivity and specificity were, respectively, 81% (95% CI, 61%–93%) and 86% (95% CI, 74%–94%) for the aepEX at a cutoff value of >52, and 69% (95% CI, 56%–81%) and 70% (95% CI, 57%–81%) for the BIS at a cutoff value of >65. The age-corrected end-tidal desflurane concentration associated with an index value of 50 (EC50) was 0.59 minimum alveolar concentration (interquartile range: 0.38–0.85) and 0.58 minimum alveolar concentration (interquartile range: 0.41–0.70) for, respectively, the aepEX and BIS (P = .69). Age-group analysis showed no evidence of a difference regarding the area under the ROC curve or EC50. CONCLUSIONS: The aepEX can reliably differentiate between a conscious and an unconscious state in pediatric patients receiving desflurane-remifentanil anesthesia. Accepted for publication May 8, 2018. Funding: This study was funded by Fonds NutsOhra, Amsterdam, the Netherlands (grant reference number: 1103-060) with an unrestricted project grant and departmental funding. The authors declare no conflicts of interest. Trial registration: https://ift.tt/2tH82DK, NTR2983. Reprints will not be available from the authors. Address correspondence to Yuen M. Cheung, MD, Department of Anesthesiology, Erasmus University Medical Center, Room H-1273, PO Box 2040, 3000 CA Rotterdam, the Netherlands. Address e-mail to y.m.cheung@erasmusmc.nl. © 2018 International Anesthesia Research Society

https://ift.tt/2IDv3Mm

Can STOP-Bang and Pulse Oximetry Detect and Exclude Obstructive Sleep Apnea?

BACKGROUND: Obstructive sleep apnea (OSA) is related to postoperative complications and is a common disorder. Most patients with sleep apnea are, however, undiagnosed, and there is a need for simple screening tools. We aimed to investigate whether STOP-Bang and oxygen desaturation index can identify subjects with OSA. METHODS: In this prospective, observational multicenter trial, 449 adult patients referred to a sleep clinic for evaluation of OSA were investigated with ambulatory polygraphy, including pulse oximetry and the STOP-Bang questionnaire in 4 Swedish centers. The STOP-Bang score is the sum of 8 positive answers to Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index >35 kg/m2, Age >50 years, Neck circumference >40 cm, and male Gender. RESULTS: The optimal STOP-Bang cutoff score was 6 for moderate and severe sleep apnea, defined as apnea-hypopnea index (AHI) ≥15, and the sensitivity and specificity for this score were 63% (95% CI, 0.55–0.70) and 69% (95% CI, 0.64–0.75), respectively. A STOP-Bang score of 15 and a STOP-Bang score of ≥6 had a specificity of 91% (95% CI, 0.87–0.94) for an AHI >15. The items contributing most to the STOP-Bang were the Bang items. There was a positive correlation between AHI versus STOP-Bang and between AHI versus oxygen desaturation index, Spearman ρ 0.50 (95% CI, 0.43–0.58) and 0.96 (95% CI, 0.94–0.97), respectively. CONCLUSIONS: STOP-Bang and pulse oximetry can be used to screen for sleep apnea. A STOP-Bang score of

https://ift.tt/2ICWOEZ

Observation and Experiment: An Introduction to Causal Inference

No abstract available

https://ift.tt/2N8wSnY

Remifentanil Stability

No abstract available

https://ift.tt/2IFwEkL

Cervical Spine Motion During Tracheal Intubation Using an Optiscope Versus the McGrath Videolaryngoscope in Patients With Simulated Cervical Immobilization: A Prospective Randomized Crossover Study

BACKGROUND: In patients with an unstable cervical spine, maintenance of cervical immobilization during tracheal intubation is important. In McGrath videolaryngoscopic intubation, lifting of the blade to raise the epiglottis is needed to visualize the glottis, but in patients with an unstable cervical spine, this can cause cervical spine movement. By contrast, the Optiscope, a rigid video-stylet, does not require raising of the epiglottis during tracheal intubation. We therefore hypothesized that the Optiscope would produce less cervical spine movement than the McGrath videolaryngoscope during tracheal intubation. The aim of this study was to compare the Optiscope with the McGrath videolaryngoscope with respect to cervical spine motion during intubation in patients with simulated cervical immobilization. METHODS: The primary outcome of the study was the extent of cervical spine motion at the occiput–C1, C1–C2, and C2–C5 segments. In this randomized crossover study, the cervical spine angle was measured before and during tracheal intubation using either the Optiscope or the McGrath videolaryngoscope in 21 patients with simulated cervical immobilization. Cervical spine motion was defined as the change in angle at each cervical segment during tracheal intubation. RESULTS: There was significantly less cervical spine motion at the occiput–C1 segment using the Optiscope rather than the McGrath videolaryngoscope (mean [98.33% CI]: 4.7° [2.4–7.0] vs 10.4° [8.1–12.7]; mean difference [98.33% CI]: −5.7° [−7.5 to −3.9]). There were also fewer cervical spinal motions at the C1–C2 and C2–C5 segments using the Optiscope (mean difference versus the McGrath videolaryngoscope [98.33% CI]: −2.4° [−3.7 to −1.2]) and −3.7° [−5.9 to −1.4], respectively). CONCLUSIONS: The Optiscope produces less cervical spine motion than the McGrath videolaryngoscope during tracheal intubation of patients with simulated cervical immobilization. Accepted for publication May 31, 2018. Funding: None. The authors declare no conflicts of interest. Clinical trial number: ClinicalTrials.gov (NCT03120546). Reprints will not be available from the authors. Address correspondence to Tae Kyong Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno, Seoul 03080, Republic of Korea. Address e-mail to ktkktk@gmail.com. © 2018 International Anesthesia Research Society

https://ift.tt/2tHTCmH

Preoperative High-Dose Methylprednisolone and Glycemic Control Early After Total Hip and Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: To evaluate the effect of a single preoperative dose of 125 mg methylprednisolone (MP) on glycemic homeostasis early after fast-track total hip and knee arthroplasty. METHODS: One-hundred thirty-four patients undergoing elective unilateral total hip arthroplasty and total knee arthroplasty were randomized (1:1) to preoperative intravenous MP 125 mg (group MP) or isotonic saline intravenous (group C). All procedures were performed under spinal anesthesia, using a standardized multimodal analgesic regime. The primary outcome was the change in plasma glucose 2 hours postoperatively, and secondary outcomes included plasma C-peptide concentrations, homeostatic model assessment (HOMA), HOMA-IR (insulin resistance), and HOMA-B (β-cell function). Fasting blood samples were collected at baseline and 2, 6 (nonfasting), 24, and 48 hours after surgery with complete samples from 122 patients (group MP = 62, group C = 60) for analyses. RESULTS: MP patients had increased plasma glucose levels at 2 hours (adjusted mean [95% CI], 7.4 mmol·L−1 [7.2–7.5] vs 6.0 mmol·L−1 [5.9–6.2]; P = .023) and 6 hours (13.9 mmol·L−1 [13.3–14.5] vs 8.4 mmol·L−1 [7.8–9.0]; P

https://ift.tt/2IFwE4f

Neuro-oncology perspective of treatment options in metastatic breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2KjVBbp

Association of five genetic variations in DNMT1 and DNMT3A with gastric cancer in a Chinese population

Future Oncology, Ahead of Print.


https://ift.tt/2IErUw1

Clinical features and psychological aspects of the decision-making process in stage I testicular germ cell tumors

Future Oncology, Ahead of Print.


https://ift.tt/2KvORX3

Are we doing enough to tackle preventable causes of cancer: an interview with Professor Linda Bauld

Future Oncology, Ahead of Print.


https://ift.tt/2IErO7D

The importance of science communication in cancer research: an interview with Martin Christlieb

Future Oncology, Ahead of Print.


https://ift.tt/2KtTP6z

Novel Application of 32P Brachytherapy: Treatment of Angiolymphoid Hyperplasia with Eosinophilia in the Right Auricle with 8-Year Follow-Up

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2KvutSz

Dual targeting of ErbB2/ErbB3 for treatment of SLC3A2-NRG1-mediated lung cancer

We characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the epidermal growth factor (EGF)-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3 with ERBB2. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth through PI3K-AKT and MAP kinase. The specific siRNAs for ERBB2 and ERBB3, pertuzumab, lumretuzumab, and afatinib all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or afatinib decreased tumor volume and weight, whereas combination treatment with these drugs and taxol enhanced generation of cleaved-caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors.

https://ift.tt/2tSfHhw

A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy

The identification of new therapeutic strategies against osteosarcoma (OS), the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. OS originates from the transformation of mesenchymal stem cells (MSCs) and/or osteoblast progenitors, and the loss of differentiation is a common biological OS feature which strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel non-nucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking OS cells in G1 or G2/M phases and induced osteoblastic differentiation through the specific re-expression of genes regulating this physiological process. While MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin (DXR) and cisplatin (CDDP), two major chemotherapeutic agents used to treat OS. Specifically, MC3343 increased stable DXR bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this non-nucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for OS patients who respond poorly to pre-adjuvant chemotherapy.

https://ift.tt/2lK9f91

Targeting Notch1 and IKKa enhanced NF-{kappa}B activation in CD133+ Skin Cancer Stem Cells

Cancer stem-like cells are hypothesized to be the major tumor initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remain undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31-CD45-CD61-CD24- (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem-like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo. Gene expression profiling of CD133+/- cells was compared and validated, and differentially expressed gene signatures and top pathways were identified. CD133+ cells expressed a repertoire of stemness and cancer related genes, including NOTCH and NOTCH1-mediated NF-kB pathway signaling. Other cancer-related genes from WNT, growth factor receptors, PI3K/mTOR, STAT pathways, and chromatin modifiers were also identified. Pharmacologic and genetic targeting Notch1, IKKa, RELA and RELB modulated NF-kB transactivation, the CD133+ population, and cellular and stemness phenotypes. Immunofluorescent staining confirmed co-localization of CD133+ and IKKa expression in SCC tumor specimens. Our functional, genetic and pharmacologic studies uncovered a novel linkage between Notch1, IKKα and NF-B pathway activation in maintaining the CD133+ stem SCC phenotypes. Studies investigating markers of activation and modulators of NOTCH, IKK/NF-kB and other pathways regulating these cancer stem gene signatures could further accelerate the development of effective therapeutic strategies to treat cSCC recurrence and metastasis.

https://ift.tt/2tQ8nDb

Arsenic trioxide and sorafenib induce synthetic lethality of FLT3-ITD acute myeloid leukemia cells

Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3β (GSK-3β), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK-3β is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD targeted therapy of AML patients.

https://ift.tt/2lK99OH

Cyclophilin A Function in Mammary Epithelium Impacts Jak2/Stat5 Signaling, Morphogenesis, Differentiation, and Tumorigenesis in the Mammary Gland

The prolyl isomerase cyclophilin A (CypA) regulates the Jak2/Stat5 pathway, which is necessary for mammary differentiation and the pathogenesis of breast cancer. In this study, we assessed the role of this isomerase during mammary gland development and erbB2-driven tumorigenesis. Genetic deletion of CypA resulted in delayed mammary gland morphogenesis and differentiation with corresponding decrease in Jak2/Stat5 activation; mammary gland cross-transplantation confirmed this defect was epithelial in nature. Analysis of mammary stem and progenitor populations revealed significant disruption of epithelial maturation. Loss of CypA in the erbB2 transgenic mouse model revealed a marked increase in mammary tumor latency that correlated with decreased Stat5 activation, associated gene expression, and reduced epithelial cell proliferation. These results demonstrate an important role for CypA in the regulation of Jak2/Stat5–mediated biology in mammary epithelium, identifying this isomerase as a novel target for therapeutic intervention.Significance: These findings reveal cyclophilin A functions in normal mammary epithelial development and ErbB2-driven mammary tumorigenesis and suggest therapies targeting cyclophilin A may be efficacious for breast cancer treatment. Cancer Res; 78(14); 1–11. ©2018 AACR. F1

https://ift.tt/2lLo3US

Pathology, Chemoprevention, and Preclinical Models for Target Validation in Barrett Esophagus

Despite esophageal adenocarcinoma (EAC) being the most widespread among gastrointestinal cancers, with an 11-fold increase in the risk of cancer for patients with Barrett esophagus (BE), its prognosis is still poor. There is a critical need to better perceive the biology of cancer progression and identification of specific targets that are the hallmark of BE's progression. This review explores the established animal models of BE, including genetic, surgical and nonsurgical approaches, potential chemoprevention targets, and the reasoning behind their applications to prevent Barrett-related EAC. The key methodological features in the design feasibility of relevant studies are also discussed. Cancer Res; 78(14); 1–8. ©2018 AACR.

https://ift.tt/2yTMkBx

LIFEx: a freeware for radiomic feature calculation in multimodality imaging to accelerate advances in the characterization of tumor heterogeneity

Textural and shape analysis is gaining considerable interest in medical imaging, particularly to identify parameters characterizing tumor heterogeneity and to feed radiomic models. Here we present a free, multiplatform, and easy-to-use freeware called LIFEx, which enables the calculation of conventional, histogram-based textural and shape features from PET, SPECT, MR, CT, and US images, or from any combination of imaging modalities. The application does not require any programming skills and was developed for medical imaging professionals. The goal is that independent and multicenter evidence of the usefulness and limitations of radiomic features for characterization of tumor heterogeneity and subsequent patient management can be gathered. Many options are offered for interactive textural index calculation and for increasing the reproducibility among centers. The software already benefits from a large user community (more than 800 registered users), and interactions within that community are part of the development strategy.

https://ift.tt/2lHIRwj

Cancer-stimulated CAFs enhance monocyte differentiation and pro-tumoral TAM activation via IL-6 and GM-CSF secretion

Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs and monocytes as a major node in this network. Experimental Design: Monocyte co-cultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow monocytes. Orthotopic, syngeneic colon carcinoma models using co-transplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database. Results: Our co-culture studies identify IL-6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that co-operate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, co-transplanted CAFs elevated IL-6 and GM-CSF levels, TAM infiltration and metastasis. These pathological effects were dramatically reversed by joint IL-6 and GM-CSF blockade. A positive correlation between GM-CSF and IL-6 expression and disease course was observed by meta-analyses of the clinical data. Conclusions: Our studies indicate a significant reappraisal of the role of IL-6 and GM-CSF in metastasis and implicate CAFs as the 'henchmen' for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL-6 is a promising new approach for inhibiting metastasis.

https://ift.tt/2IEdZpL

An Anti-CLL-1 Antibody-Drug Conjugate for the Treatment of Acute Myeloid Leukemia

Purpose: The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine and anthracycline-based chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The re-approval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next generation ADC for AML to improve upon the initial success of Mylotarg. Experimental Design: The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys. Results: We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33 targeted ADCs. Our anti-CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys. Conclusions: Collectively, our data suggest that an anti-CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML.

https://ift.tt/2KtlzZ4

Functional parameters derived from magnetic resonance imaging reflect vascular morphology in preclinical tumors and in human liver metastases

Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo. Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and computed tomography (CT). Relationships between functional parameters from MR (iAUC, K^trans, and BAT_frac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether anti-angiogenic therapy altered these relationships. Finally, functional-structural relationships were measured in ten patients with liver metastases from colorectal cancer. Results: Functional parameters iAUC and K^trans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by anti-angiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and K^trans. For iAUC, structural parameters also modified each other's effect. Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels, and that anti-angiogenic therapy can affect this link. Our work also demonstrates the feasibility of 3D functional-structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility.

https://ift.tt/2IEdUlX

Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells

Purpose: Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases, Src and MAPK, are activated in high grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition. Experimental Design: MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene and proteomic analysis, cancer stem cells and xenografts. Results: Both Src and MAPK are co-activated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors, saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell cycle arrest in vitro and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout, decreased sphere formation and ALDH1+cells. In vivo, tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation and loss of tumor-initiating cells upon serial xenografting. Conclusions: Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating OVCA populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials.

https://ift.tt/2Kx9LVK

Skeletal Muscle Loss is an Imaging Biomarker of Outcome After Definitive Chemoradiotherapy for Locally Advanced Cervical Cancer

Purpose: This study investigates the association between body composition change during concurrent chemoradiotherapy (CCRT) and outcome in patients with locally advanced cervical cancer (LACC). Experimental Design: Pre- and post-treatment computed tomography (CT) images of 245 patients with LACC who were treated between 2004 and 2015 were analysed. Skeletal muscle index (SMI) and density (SMD), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) were measured from two sets of CT images at the level of the L3 vertebra. Sarcopenia and a low SMD were defined using published cut-points. Predictors of overall survival (OS) and cancer-specific survival (CSS) were analysed using Cox regression models. Results: The median follow-up was 62.7 (range, 7.3-152.3) months. Among the 245 patients, 127 (51.8%) had pre-treatment sarcopenia and 154 (62.9%) had a low SMD. SMI did not decrease significantly during CCRT, 0.6%/150 days (95% CI: -1.8 to 0.6; p = 0.35). However, a SMI loss during CCRT of >10.0%/150 days was independently associated with poorer OS (hazard ratio: 6.02, 95% confidence interval: 3.04-11.93; p < 0.001) and CSS (hazard ratio: 3.49, 95% confidence interval: 1.44-8.42; p = 0.006) when adjusted for FIGO stage, pathology, and treatment. Pre-treatment sarcopenia and change of SMD, SATI, and VATI during CCRT were not associated with survival. Conclusions: Skeletal muscle measurements could be imaging biomarkers to predict outcomes for patients with LACC in clinical practice. Further studies are needed to determine whether multimodal interventions can preserve skeletal muscle mass and thereby improve survival.

https://ift.tt/2IBHUyP

A Bibliometric Analysis of the Landscape of Cancer Rehabilitation Research (1992–2016)

Abstract

Cancer rehabilitation research has accelerated as great attention has focused on improving survivorship care. Recent expert consensus has attempted to prioritize research needs and suggests greater focus on studying physical functioning of survivors. However, no analysis of the publication landscape has substantiated these proposed needs. This manuscript provides an analysis of PubMed indexed articles related to cancer rehabilitation published between 1992 and 2017. A total of 22 171 publications were analyzed using machine learning and text analysis to assess publication metrics, topic areas of emphasis, and their interrelationships through topic similarity networks. Publications have increased at a rate of 136 articles per year. Approximately 10% of publications were funded by the National Institutes of Health institutes and centers, with the National Cancer Institute being the most prominent funder. The greatest volume and rate of publication increase were in the topics of Cognitive and Behavioral Therapies and Psychological Interventions, followed by Depression and Exercise Therapy. Four research topic similarity networks were identified and provide insight on areas of robust publication and notable deficits. Findings suggest that publication emphasis has strongly supported cognitive, behavioral, and psychological therapies; however, studies of functional morbidity and physical rehabilitation research are lacking. Three areas of publication deficits are noted: research on populations outside of breast, prostate, and lung cancers; methods for integrating physical rehabilitation services with cancer care, specifically regarding functional screening and assessment; and physical rehabilitation interventions. These deficits align with the needs identified by expert consensus and support the supposition that future research should emphasize a focus on physical rehabilitation.

https://ift.tt/2tGY19n

Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer

Bo Jan Noordman joins The Lancet Oncology to discuss the findings from his study of residual disease detection in oesophageal cancer.

https://ift.tt/2tFhlUr

[Addendum] Addendum to Lancet Oncol 2005; 6: 751–56

Höckel M, Horn L-C, Fritsch H. Association between the mesenchymal compartment of uterovaginal organogenesis and local tumour spread in stage IB–IIB cervical carcinoma: a prospective study Lancet Oncol 2005; 6: 751–56—The supplemental video accompanying this Article has been updated. This Addendum has been added to the online version as of June 29, 2018.

https://ift.tt/2KlOQ8X

[Clinical Picture] Oncogenic osteomalacia: diagnosis, localisation, and cure

A 37-year-old female patient was referred to the rheumatology department at Treliske Hospital (Truro, UK) in April, 2015, following 8 months of rib pain, initially thought to be costochondritis. She had isolated hypophosphataemia (serum phosphate level 0·50 mmol/L) and a pelvic MRI identified stress fractures (figure, A). 14 months after her presentation she had a persistently low serum phosphate concentration, with normal parathyroid hormone and serum calcium levels, and a 25(OH) vitamin D concentration of 32ng/mL.

https://ift.tt/2MCvf0X

[Correspondence] Adjuvant therapy in resectable gastric cancer—the CRITICS trial

We read the final report of the eagerly awaited CRITICS trial1 with interest, since its overall results showed a favourable outcome when compared with the previous landmark studies, INT01162 and MAGIC.3 Population-based data suggest that the approaches established by both studies have been successfully transferred into clinical practice. The authors provide comprehensive follow-up data, including long-term renal function tests, which will be useful to observe after longer follow-up. Reassuringly, toxicity with radiochemotherapy was not excessive versus chemotherapy alone, and the conclusion by Annemieke Cats and colleagues,1 to direct research toward intensification of preoperative strategies, is reasonable.

https://ift.tt/2KwQ3Jz

[Correspondence] Adjuvant therapy in resectable gastric cancer—the CRITICS trial

We read the results of the CRITICS study by Annemieke Cats and colleagues1 with great interest. This study was, to the best of our knowledge, the first trial to directly compare postoperative chemoradiotherapy with perioperative chemotherapy in patients with resectable gastric adenocarcinoma. Despite the negative results, some aspects of the study warrant closer attention.

https://ift.tt/2MyPSLb

[Correspondence] Adjuvant therapy in resectable gastric cancer—the CRITICS trial – Authors' reply

We appreciate the interest by Jingwen Wang and colleagues in our trial,1 about which they raise three important issues. First, we agree that the timing of randomisation does not allow for a direct comparison between postoperative chemotherapy and postoperative chemoradiotherapy because the subsets of patients who started postoperative treatment in each group could have different characteristics. However, we do not agree that the main purpose of the study was to compare only the postoperative treatment.

https://ift.tt/2KtbyuW

[Review] Cancer care in the Palestinian territories

The precise population of the Palestinian territories is disputed, but a 2017 estimate was 4 543 126 people, including 2 155 743 people in the West Bank and 1 795 183 in Gaza. The Palestinian territories rank 121st out of 233 countries and dependencies by population (its people comprise 0·07% of the world population). Palestinian health care has been a major concern since the 1994 Oslo agreement when the Palestinian Authority took over the administration of health care for the region. This effort has been supported by WHO and foreign donors, especially the US Government.

https://ift.tt/2MAnEzW

[Review] Cancer screening in the homeless population

Annually, 100 million people experience homelessness worldwide. Most adults that are struggling with homelessness are living to age 50 years or older and need age-appropriate screening for cancer. Cancer-related death in homeless adults is twice as high as the average in the adult population in the USA. However, few studies have examined the rates of and barriers to cancer screening in homeless people. This Review explores cancer-related health disparities between homeless people and the general population by providing a review of data and definitions relating to homelessness, an analysis of barriers to screening in this population, and a discussion of the current and potential interventions and strategies to improve cancer screening in homeless individuals.

https://ift.tt/2KnwkwL

[Corrections] Correction to Lancet Oncol 2017; 18: 1061–75

Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol 2017; 18: 1061–75—In this Article, the following sentence about the safety results in the findings section of the Summary should have read: "Commonly reported treatment-related adverse events were diarrhoea (41 [16%]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%])." The incidence of serious febrile neutropenia in the Summary findings and in the main Results (fourth paragraph, first sentence) should have been reported as 78 (31%).

https://ift.tt/2MxdnEC

[Perspectives] Can Google help us fight cancer?

Navigate to Google Trends and you can spend countless hours exploring the popularity of any Google search term. From Donald Trump to cystic fibrosis, worldwide to city-level, the past decade to the past hour, you can peruse relative volumes of Google searches. That is to say, you can look the number of searches for that term at a given time and location compared with the overall number of Google searches. This software has been used in hundreds of peer-reviewed medical publications. The most notable examples are efforts to track and predict infectious disease outbreaks, such as influenza, which have had mixed success.

https://ift.tt/2KwPCPr

[Perspectives] Building independence in health care and a partnership between nations

The Palestinian population of the West Bank and Gaza comprises 4·8 million people. Cancer is the second leading cause of death in Palestine, accounting for 12·4% of all deaths, of which the most common causes of death are lung cancer in men and breast cancer in women.

https://ift.tt/2MxewMw

[Perspectives] Miracle mineral or mesothelioma: cancer and asbestos in the USA

Asbestos is known to cause a number of illnesses, including asbestosis, lung cancer, and mesothelioma. In the USA, asbestos was designated a toxic substance by the Occupational Safety and Health Administration in 1926, but the scientific evidence linking asbestos to mesothelioma came in 1960 when Wagner and colleagues found that, in 32 (97%) of the 33 cases of this rare tumour, there was probable asbestos exposure.

https://ift.tt/2KgYE41

[Correspondence] Adjuvant therapy in resectable gastric cancer—the CRITICS trial

Stomach cancer is among the most common cancers in the world, and surgery remains the key curative therapy for localised gastric cancer. To reduce the risk of relapse and improve survival, two landmark trials, INT01161 and MAGIC,2 established the role of postoperative chemoradiation (INT0116) and perioperative chemotherapy (MAGIC) in treatment of resectable gastric cancer.3 These two approaches became standard practice for contemporary treatment: patients are treated with surgery and perioperative chemotherapy or postoperative chemoradiation in different centres.

https://ift.tt/2MC4GbV

[Editorial] Immunotherapy: hype and hope

As the dust settles after a busy week at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (June 1–5, 2018; Chicago, IL, USA), there is an opportunity to reflect on the impact of the largest cancer congress of the year. The goal of "Delivering discoveries: expanding the reach of precision medicine" was evident throughout the event. Among this year's highlights were a predictive 21-gene expression assay that suggests most women with early-stage breast cancer might not need chemotherapy, and findings that pre-operative chemoradiotherapy improves disease-free survival for patients with pancreatic cancer.

https://ift.tt/2KlOMWL

[Review] Lung transplantation for non-small cell lung cancer and multifocal bronchioalveolar cell carcinoma

Lung transplantation for primary bronchogenic cancer could lead to increased survival and improved quality of life for patients who have malignant disease, for which other therapies might be inappropriate. This Review examines the development of experience and outcomes for this indication and explores the limitations that are inherent in lung transplantation for malignant disease. Bronchogenic malignancy is a rare indication for lung transplantation constituting only 0·13% of all lung transplants in the USA from 1987 to 2010 and is only indicated for early-stage disease when conventional surgical techniques are contraindicated by poor lung function in which an unacceptably high risk of short-term mortality is expected.

https://ift.tt/2MA8QkK

[Corrections] Correction to Lancet Oncol 2018; 19: 51–64

Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018; 19: 51–64—In this Article, the legend of figure 2A should state that there were 27 confirmed responses (rather than 28). In figure 4A, the first subheading in the inset on the graph should have referred to median progression-free survival in weeks, not months, and the second subheading in the inset on the graph should have read "6-month PFS, rate (95% CI)".

https://ift.tt/2Ki3Yny

Tension band plating of an anterior tibial stress fracture nonunion in an elite athlete, initially treated with intramedullary nailing: a case report

Leg pain in athletes is a common condition and is often related to tibial stress fracture. When non-operative treatment fails, the optimal surgical treatment is controversial. The aim of this study was to repo...

https://ift.tt/2lHfFWd

[Correspondence] Gastrointestinal cancer risk in cystic fibrosis: more exploration is needed

In The Lancet Oncology, Akihiro Yamada and colleagues1 presented a meta-analysis that assessed the risk of gastrointestinal cancer in patients with cystic fibrosis by synthesis of results from six cohort studies. Patients with cystic fibrosis were shown to have a significantly increased risk of gastrointestinal cancer compared with the general population, including cancers of the small bowel, colon, biliary tract, and pancreas.

https://ift.tt/2MATEng

[Correspondence] Gastrointestinal cancer risk in cystic fibrosis: more exploration is needed – Authors' reply

We read with interest the letter by Li Yao and Wenquan Niu1 regarding our meta-analysis. We agree that, when a small number of studies is included in a meta-analysis, the robustness of the outcome should be interpreted with caution2 and the assessment of bias by funnel plots might not be useful.3

https://ift.tt/2KsYSV3

[Correspondence] How economic sanctions compromise cancer care in Iran

Last month, the US administration withdrew from the Iran nuclear deal with the P5+1 group of world powers. The Trump administration will now reinstitute the highest level of economic sanctions against Iran. These sanctions were waived as part of the deal in 2015. This withdrawal could compromise health of vulnerable populations, including patients with cancer, in several ways.

https://ift.tt/2MwPa14

[News] Concurrent chemotherapy improves outcomes in HNSCC

The addition of concurrent chemotherapy to cetuximab plus radiotherapy in the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) improves progression-free survival (PFS) compared with cetuximab and radiotherapy alone, according to a recent study.

https://ift.tt/2KjYYz0

[News] Variations in breast cancer treatment and outcomes

A study from the European Registry of Cancer Care has found that elderly English patients with breast cancer have worse survival rates than similar patients in Belgium, Ireland, the Netherlands, and Greater Poland.

https://ift.tt/2MylzUZ

NExT: Advancing Promising Cancer Therapies from the Lab to Clinical Trials

The NCI Experimental Therapeutics (NExT) program works with researchers and top scientific experts to advance promising or novel cancer therapies from the earliest stages of research to human clinical trials.

https://ift.tt/2tRfviz

Prognostic significance of high serum p53 antibody titers in patients with esophageal squamous cell carcinoma

Abstract

Background

The p53 protein overexpression that usually results from genetic alterations reportedly induces serum antibodies against p53. However, little information is available about the prognostic significance of perioperative serum p53 antibody (s-p53-Abs) titers in patients with esophageal squamous cell carcinoma.

Methods

In this study, we retrospectively evaluated the clinical significance of perioperative s-p53-Abs in 135 patients with esophageal squamous cell carcinoma. Of these, 58 patients received neoadjuvant chemotherapy comprising 5-FU and CDDP. While the cutoff level at 1.3 U/ml indicated seropositive patients, level of 13.4 U/ml was used to identify high-titer patients. We monitored serum titers seropositive patients after surgery and evaluated the prognostic significance by the univariate and multivariate analyses.

Results

In this study, 29 patients (21.5%) were positive for s-p53-Abs before treatment. The frequency of both seropositive patients and high-titer patients (> 13.4 U/ml) was not significantly associated with tumor progression. While seropositive patients did not demonstrate significant poor overall survival, high-titer patients demonstrated significant poor overall survival based on the multivariate analysis (P < 0.001). Moreover, the s-p53-Abs titer did not correlate with the response to neoadjuvant chemotherapy. Among seropositive patients, the negative conversion of s-p53-Abs more likely led to be long-term survival.

Conclusions

This study determined that the high-titer of s-p53-Abs was an independent risk factor to reduce the overall survival of patients with esophageal cancer patients. The negative conversion of s-p53-Abs could be a good indicator of favorable prognosis.

https://ift.tt/2KBG8Q4

Radiotherapy combined with zoledronate can reduce skeletal-related events in renal cell carcinoma patients with bone metastasis

Abstract

Background

Skeletal-related events (SRE) are common in patients with renal cell carcinoma (RCC) that includes bone metastasis. The purpose of this study was to clarify the effectiveness of zoledronate with and without sunitinib, combined with radiotherapy, for the treatment of bone metastasis from RCC.

Methods

We retrospectively analyzed 62 RCC patients with bone metastasis, who had been treated with radiotherapy at our institution. We divided the study cohort into two groups: patients treated with radiotherapy alone (RT; n = 27) and those treated with radiotherapy combined with zoledronate (RT + Z; n = 35). We investigated the overall survival and post-irradiation (PI)-SRE-free rate for each group, as well as the effect of sunitinib in the RT + Z treatment group. In addition, we determined treatment effectiveness by imaging assessments and relative response rates.

Results

There was no significant difference in the survival rates between the RT and RT + Z treatment groups (p = 0.11). However, the PI-SRE-free rate in the RT + Z group was significantly higher than that in the RT group (p = 0.02). The PI-SRE-free rate was significantly higher in patients who were treated with sunitinib after radiotherapy than in those who were treated without sunitinib (p = 0.03). However, there was no significant difference in the relative response rates, as assessed by imaging, in each group.

Conclusion

Radiotherapy combined with zoledronate is an effective treatment for RCC with bone metastasis to prevent PI-SRE. Sunitinib may reduce PI-SRE if used after radiotherapy and combined with zoledronate.

https://ift.tt/2Kw8ACM

Salubrinal Enhances Doxorubicin Sensitivity in Human Cholangiocarcinoma Cells Through Promoting DNA Damage

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2lGBipz

Optimal Sequence of Adjuvant Endocrine and Radiation Therapy in Early-Stage Breast Cancer – A Systematic Review

Publication date: Available online 28 June 2018
Source:Cancer Treatment Reviews
Author(s): S.F. McGee, S. Mazzarello, J.M. Caudrelier, M.A.G. Lima, B. Hutton, M. Sienkiewicz, C. Stober, R. Fernandes, M.F.K. Ibrahim, L. Vandermeer, J. Hilton, R. Shorr, D. Fergusson, M. Clemons
Importance:Clinical equipoise exists around the optimal time to start adjuvant endocrine therapy in patients who will receive post-operative radiotherapy for breast cancer. Concerns continue to exist regarding potential reduced efficacy, or increased toxicity, when radiation, and endocrine therapy are administered concurrently.Objective:To perform a systematic review of studies comparing outcomes between sequential and concurrent adjuvant radiation and endocrine therapy in early-stage breast cancer. All modalities of radiation therapy were considered, and endocrine therapy could be either tamoxifen or an aromatase inhibitor. Outcomes of interest included; local, regional or distant recurrence, overall survival and treatment-related toxicities.Evidence Reviewed:PubMed, Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1946 to December 2017. Two reviewers independently assessed each citation using the criteria outlined above. Study quality was assessed using the Cochrane Collaboration's tool for prospective studies, and the Newcastle-Ottawa scale for retrospective studies.Findings:Of 2137 unique citations identified, 13 met eligibility criteria. Eleven were unique studies (7569 patients), while 2 of the studies were updated analyses of previous studies. Studies evaluated the timing of adjuvant radiation, and tamoxifen (5 studies, 1550 patients), or aromatase inhibitors (6 studies, 6019 patients). We identified 1 complete randomized clinical trial (150 patients), and 5 retrospective studies (1580 patients), in addition to conference abstracts (5 studies, 5839 patients). Overall, none of the studies showed a significant difference in efficacy, or toxicity, with concurrent versus sequential treatment. However, given the significant heterogeneity of the study populations, it was not possible to conduct a meta-analysis.Conclusions and Relevance:In the absence of high quality data, adequately powered randomized trials are required to answer this important clinical question.



https://ift.tt/2lHOJWv

Overview of the LUX-Lung Clinical Trial Program of Afatinib for Non–Small Cell Lung Cancer

Publication date: Available online 28 June 2018
Source:Cancer Treatment Reviews
Author(s): Namita Sharma, Stephen Graziano
Tyrosine kinase inhibitors (TKIs) have emerged as first-line treatment for the management of epidermal growth factor receptor (EGFR)–mutated advanced non–small cell lung cancer (NSCLC). Erlotinib and gefitinib were the initial TKIs to be approved for lung cancer and showed improved response rates compared with chemotherapy. Afatinib is an irreversible ErbB family blocker that has also been shown to be active in EGFR-mutated NSCLC. Afatinib has been tested as first-line treatment of advanced NSCLC in the LUX-Lung trial program, as well as in the second- and third-line settings. In this article, we will review the data from the 8 reported LUX-Lung trials.



https://ift.tt/2yQT5Ec

Stress Granule Formation is One of the Early Antiviral Mechanisms for Host Cells Against Coxsackievirus B Infection

Abstract

Stress granules (SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B (CVB) infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3 (CVB3) could induce SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the elevated formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.

https://ift.tt/2yWHCmk

Cancers, Vol. 10, Pages 220: Establishing a Dedicated Lung Cancer Biobank at the University Center Hospital of Nice (France). Why and How?

Cancers, Vol. 10, Pages 220: Establishing a Dedicated Lung Cancer Biobank at the University Center Hospital of Nice (France). Why and How?

Cancers doi: 10.3390/cancers10070220

Authors: Kevin Washetine Simon Heeke Christelle Bonnetaud Mehdi Kara-Borni Marius Ilié Sandra Lassalle Catherine Butori Elodie Long-Mira Charles Hugo Marquette Charlotte Cohen Jérôme Mouroux Eric Selva Virginie Tanga Coraline Bence Jean-Marc Félix Loic Gazoppi Taycir Skhiri Emmanuelle Gormally Pascal Boucher Bruno Clément Georges Dagher Véronique Hofman Paul Hofman

Lung cancer is the major cause of death from cancer in the world and its incidence is increasing in women. Despite the progress made in developing immunotherapies and therapies targeting genomic alterations, improvement in the survival rate of advanced stages or metastatic patients remains low. Thus, urgent development of effective therapeutic molecules is needed. The discovery of novel therapeutic targets and their validation requires high quality biological material and associated clinical data. With this aim, we established a biobank dedicated to lung cancers. We describe here our strategy and the indicators used and, through an overall assessment, present the strengths, weaknesses, opportunities and associated risks of this biobank.

https://ift.tt/2IDiz7l

Cancers, Vol. 10, Pages 221: Dynamics of p14ARF and Focal Adhesion Kinase-Mediated Autophagy in Cancer

Cancers, Vol. 10, Pages 221: Dynamics of p14ARF and Focal Adhesion Kinase-Mediated Autophagy in Cancer

Cancers doi: 10.3390/cancers10070221

Authors: Rosa Fontana Maria Vivo

It has been widely shown that the focal adhesion kinase (FAK) is involved in nearly every aspect of cancer, from invasion to metastasis to epithelial&ndash;mesenchymal transition and maintenance of cancer stem cells. FAK has been shown to interact with p14ARF (alternative reading frame)&mdash;a well-established tumor suppressor&mdash;and functions in the negative regulation of cancer through both p53-dependent and -independent pathways. Interestingly, both FAK and ARF (human and mouse counterpart) proteins, as well as p53, are involved in autophagy&mdash;a process of &ldquo;self-digestion&rdquo;&mdash;whose main function is the recycling of cellular components and quality control of proteins and organelles. In the last years, an unexpected role of p14ARF in the survival of cancer cells has been underlined in different cellular contexts, suggesting a novel pro-oncogenic function of this protein. In this review, the mechanisms whereby ARF and FAK control autophagy are presented, as well as the role of autophagy in cell migration and spreading. Integrated investigation of these cell functions is extremely important to understand the mechanism of the basis of cell transformation and migration and thus cancer development.

https://ift.tt/2tG3bT7

Tuberculous arthritis: negative Xpert MTB/RIF assay does not rule out infection!

We present a case of a 31-year-old man of Indian origin with no previous medical history who presented with an inflamed knee. Treatment for bacterial infection was unsuccessful, and needle aspiration of the left knee effusion/collection was smear and culture positive for tuberculosis (TB), despite Xpert MTB/RIF being falsely negative. The patient was commenced on quadruple therapy for TB and within 2 months had improved significantly with no clinical evidence of ongoing inflammation.

https://ift.tt/2KyZsgy

Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-γ. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.

https://ift.tt/2tOeS9x

Remodeling of the Corneal Epithelial Scaffold for Treatment of Persistent Epithelial Defects in Diabetic Keratopathy

Background: To develop a strategy based on surgical removal of a degenerated corneal epithelial scaffold for treatment of persistent epithelial defects (PEDs) in diabetic keratopathy. Case Presentation: Three diabetic patients with PEDs were initially treated with eyedrops containing the fibronectin-based peptide PHSRN (Pro-His-Ser-Arg-Asn) or both the substance P-derived peptide FGLM-NH₂ and the insulin-like growth factor-1-derived peptide SSSR. A degenerated Bowman's layer or calcified lesion thought to be responsible for incomplete healing was surgically removed after confirmation of reactivity to the peptide eyedrops. All three patients achieved complete epithelial wound closure after surgery. Two cases treated by phototherapeutic keratectomy or lamellar keratoplasty did not show PED recurrence during 6 or 36 months of follow-up, respectively. One case treated by mechanical removal of a degenerated Bowman's layer manifested recurrence after 1 month, but resurfacing of the defect was again achieved after repeat surgery. Conclusion: We propose a new strategy for treatment of diabetic PEDs based on surgical remodeling of the corneal epithelial scaffold for patients who respond to peptide eyedrops but fail to achieve wound closure.
Case Rep Ophthalmol 2018;9:333–340

https://ift.tt/2z4ejyz

Leser-Trélat Sign Presenting in a Patient with Relapsing Mycosis Fungoides

The Leser-Trélat sign is a rare sign of some malignant tumors and is characterized by the sudden appearance of seborrheic keratosis in association with an underlying malignancy. We describe a 60-year-old Saudi man with mycosis fungoides (MF) who developed numerous, rapidly growing, seborrheic keratoses on his face and back. To the best of our knowledge, this is the first reported case of MF with the Leser-Trélat sign from Saudi Arabia.
Case Rep Oncol 2018;11:436–441

https://ift.tt/2IyI0Hn

A Case of Uterine Carcinosarcoma Detected Simultaneously with Breast and Colon Cancer (Triple Primary Malignant Tumor)

Uterine carcinosarcoma, also known as malignant mixed Mullerian tumor of the uterus, is rare and rarely diagnosed simultaneously with cancers in other organs. We report a case of a 63-year-old woman who was simultaneously diagnosed with uterine carcinosarcoma, breast cancer, and colon cancer.
Case Rep Oncol 2018;11:431–435

https://ift.tt/2KAIjpY

P53/PUMA are potential targets that mediate the protection of brain-derived neurotrophic factor (BDNF)/TrkB from etoposide-induced cell death in neuroblastoma (NB)

Abstract

The over-expressions of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to induce chemo-resistance in neuroblastoma (NB) cells. In this study, we investigated the roles of P53 and BCL2 family members in the protection of BDNF/TrkB from etoposide-induced NB cell death. TB3 and TB8, two tetracycline (TET)-regulated TrkB-expressing NB cell lines, were utilized. The expressions of P53 and BCL2 family members were detected by Western blot or RT-PCR. Transfection of siRNAs was used to knockdown P53 or PUMA. Activated lentiviral was used to over-express PUMA. Cell survival was performed by MTS assay, and the percentage of cell confluence was measured by IncuCyte ZOOM. Our results showed that etoposide treatment induced significant and time-dependent increase of P53, which could be blocked by pre-treatment with BDNF, and knockdown P53 by transfecting siRNA attenuated etoposide-induced TrkB-expressing NB cell death. PUMA was the most significantly changed BCL2 family member after treatment with etoposide, and pre-treatment with BDNF blocked the increased expression of PUMA. Transfection with siRNA inhibited etoposide-induced increased expression of PUMA, and attenuated etoposide-induced NB cell death. We also found that over-expression of PUMA by infection of activated lentiviral induced TrkB-expressing NB cell death in the absence of etoposide, and treatment of BDNF protected NB cells from PUMA-induced cell death. Our results suggested that P53 and PUMA may be potential targets that mediated the protection of BDNF/TrkB from etoposide-induced NB cell death.

https://ift.tt/2KzHbQb

Targeted therapy and immunotherapy for platinum-refractory advanced ovarian adenosquamous carcinoma: a case report

https://ift.tt/2Kpw1AN

Updates on the clinical diagnosis and management of ocular sebaceous carcinoma: a brief review of the literature

https://ift.tt/2Kuu4Dg

Chemotherapy with or without pemetrexed as second-line regimens for advanced non-small-cell lung cancer patients who have progressed after first-line EGFR TKIs: a systematic review and meta-analysis

https://ift.tt/2MyeELD

Frontal axial pattern flap combined with hard palate mucosa transplant in the reconstruction of midfacial defects after the excision of huge basal cell carcinoma

Abstract

Background

Our article describes our experience with using a frontal axial pattern flap combined with hard palate mucosa transplant to reconstruct midfacial defects after the excision of huge basal cell carcinoma.

Methods

We retrospectively reviewed four patients diagnosed with midface huge basal cell carcinoma through biopsy between 2014 and 2016. Both the eyelid and nose were involved in all the patients. All the patients underwent the studied surgical method and were followed up from 12 to 36 months.

Results

All the patients preserved good eyelid function and relatively good esthetic satisfaction. No basal cell carcinoma recurred.

Conclusions

This combined surgical procedure is a good method for reconstructing defects after the excision of huge basal cell carcinomas in the midface.

https://ift.tt/2yURnRX