Double whammy: a tale of two malignancies

Description

A 61-year-old woman was referred to the dermatology clinic with multiple skin lesions on her scalp and central back. They were relatively asymptomatic but had increased in size over the previous few months. Her medical history was significant as she had a cerebellar medulloblastoma when she was 19 years old that was treated with a 6-month course of radiotherapy on her scalp and along the spinal cord.

On examination, she had multiple erythematous scaly plaques on the right occipital scalp and lower back, consistent with superficial basal cell carcinomas (BCC) and a nodular BCC in the left occipital scalp. They were present within the areas previously treated with radiotherapy, arising from the skin that showed poikilodermatous (atrophic) changes (figures 1 and 2). Scarring alopecia from the previous radiotherapy was also prominent in the occipital scalp. A diagnosis of postradiotherapy BCCs was made. In...

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Acquired capillary haemangioma of the eyelid in a 10-year-old boy

A 10-year-old boy presented with painless, gradually increasing mass in right upper lid without preceding trauma for the past 2 months. On examination, the mass was bluish red, soft to firm in consistency which bleeds on touch. Contrast-enhanced CT showed a well-defined heterogeneously enhancing mass lesion without any continuity with the underlying bone or the orbital cavity. Complete excision of the mass was performed under general anaesthesia, subsequent histopathological examination showed findings consistent with an acquired variant of capillary haemangioma. At the end of 1 year, patient is cosmetically fine without any recurrence/morbidity.

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Large chordoma of the sacrum

Description

A 53-year-old man presented to our service with a 1-month history of subacute bowel obstruction. Clinical examination was unremarkable with normal power and sensation in the lower limbs. This patient had no medical or surgical history. MRI of the pelvis identified a well-defined presacral midline lesion of 9.9 cm diameter, which appeared to arise from the S2 nerve root and below (figure 1A,B). These nerve roots control anal sphincter tone and prohibit faecal incontinence. Whole spine MRI and CT-thorax abdomen pelvis CT-TAP) out ruled metastasis. A biopsy confirmed diagnosis of chordoma. This patient was discussed by a multidisciplinary team consisting of orthopaedics, colorectal, vascular and plastic surgeons. Anterior mobilisation of the lesion, with ileostomy due to expected loss of anal tone and supporting vessel ligation, was undertaken. A wide sacral en-masse resection at the level of S1 disc and inferior nerve roots, incorporating partial gluteus...

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Carotid dissection presenting as a prolonged cluster-like headache in a patient with episodic cluster headache

We present a patient with known episodic cluster headache, who presented with cluster-like headache in the course of internal carotid artery dissection (ICAD) and discuss possible pathophysiological links between the two diseases. It is well known that cluster-like headache could be the presenting symptom of ICAD. However, ICAD occurring in a patient with a known episodic cluster headache was only once previously described. In the end of the manuscript, we propose red flags to help clinicians differentiate between primary cluster headache and cluster-like attacks masking underlying ICAD. Finally, we raise the question whether at least some proportion of those patients with cluster headache and Horner syndrome previously classified as a primary headache disorder might have been secondary cases to ICAD.

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The non-resolving lung cavity: a case of pulmonary cystic echinococcosis

The authors report a case of a 20-year-old woman who was diagnosed with pulmonary cystic echinococcosis. She was admitted to hospital with a 1-week history of unresolving cough, coloured sputum with occasional haemoptysis and fever despite oral antibiotics. Radiology revealed a cavitating right lower lobe lung abscess. After 4 weeks of treatment, follow-up radiology showed incomplete resolution. Bronchoscopy revealed a white, avascular cystic lesion in the right lower lobe and serology testing for Echinococcus granulosus was positive. Repeat imaging eventually confirmed the cystic lesion with the 'air bubble'sign. A thorough travel history, a high index of clinical suspicion and close follow-up are essential in making a diagnosis of pulmonary cystic echinococcosis.

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Early intracardiac thrombus and pulmonary embolus after trauma

Here, we present the case of a patient with the findings of an early intracardiac thrombus and a pulmonary embolus after major trauma. A large clot was identified extending from the inferior vena cava into the right atrium and ventricle in the setting of preserved right ventricular function. Post-traumatic intracardiac thrombus is extremely rare and no comparable cases have previously been described in the absence of a congenital heart defect and obvious myocardial injury. Best practice afterpost-traumatic intracardiac thrombus is not well established but we found that early inferior vena cava filter placement and treatment with therapeutic coagulation resulted in clinical improvement, resolution of the thrombus and no further emboli. The successful use of rivaroxaban, a direct-acting oral anticoagulant, to treat a right heart thrombus has, to our knowledge, not previously been reported. Early acute traumatic coagulopathy has received much attention but the hypercoagulable state that often follows is less well appreciated.

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Incidental finding of persistent left superior vena cava after 'bubble study verification of central venous catheter

We report a case of a patient with septic shock who underwent central venous catheter placement in the left internal jugular vein, and a bedside ultrasound 'bubble study' revealed venous cannulation. A chest X-ray postprocedure revealed concern for arterial system catheterisation. However, the possibility of a persistent left superior vena cava was discussed and confirmed with a formal transthoracic echocardiogram and CT. This case demonstrates the importance of ultrasound-guided visualisation of anatomical structures in real time during central venous catheterisation. Other similar cases from the literature are briefly described.

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Turbulent tackle: a novel surgical approach to a rugby-related jejunal perforation

Viscus perforation in the context of blunt-force abdominal trauma is a rarity. Within a sporting context, it is especially rare. However, the increasing physicality observed in rugby union, both in the amateur and professional setting, has resulted in a higher rate of serious injury. We report a novel laparoscopic surgical approach to the management of a traumatic jejunal perforation sustained on the playing field in a previously fit and healthy 28-year-old.

http://ift.tt/2tTRgPC

Valacyclovir-associated neurotoxicity treated with intensification of peritoneal dialysis

We report a 57-year-old woman with end-stage renal disease (ESRD) on maintenance peritoneal dialysis (PD), who presented to the emergency room (ER) by ambulance with complaints of confusion and altered sensorium for 48 hours. She had been reviewed in a walk-in clinic 72 hours earlier and had been prescribed the standard 1000 mg three times per day of valacyclovir for an acute attack of shingles instead of 500 mg once a day on ESRD. In the ER, she received further 500 mg of intravenous acyclovir as herpes encephalitis was clinically suspected. CT of the brain and lumbar puncture were non-contributory to the diagnosis. Valacyclovir and acyclovir were discontinued when the diagnosis of valacyclovir-associated neurotoxicity became clinically evident. As the patient's Glasgow Coma Scale declined, we intensified her PD regimen from one to six exchanges per day and 24 hours later there was a significant neurological improvement.

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Huge cardiac myxoma in pregnancy

A 28-year-old pregnant woman presented at 28 weeks of gestation. She was diagnosed to have a left atrial myxoma 2 years earlier, but was lost to follow-up. During this pregnancy, the transthoracic echocardiography showed a 9 cm mass in the left atrium obstructing mitral valve inflow, interfering with mitral valve closure, causing severe mitral regurgitation and severe pulmonary hypertension. However, there were no clinical signs of pulmonary and systemic congestion or obstruction. Based on the clinical symptoms of the patient, the echocardiographic findings and the term of her pregnancy, the patient decided to schedule for a vaginal delivery with surgical correction after delivery. She gave birth at 32 weeks of gestation. During labour, pulmonary oedema developed but was detected early and it responded to therapy. Two weeks after delivery, a right anterior thoracotomy was performed to facilitate the removal of the left atrial myxoma and repair of the mitral valve.

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Peripheral hepatojejunostomy: a last resort palliative solution in Greece during the economic crisis

The geographical distribution of Greece and the growing proportion of uninsured patients make imperative the need for effective and efficient palliative solutions regarding obstructive jaundice due to hepatic malignancy, while repeated endoscopic interventions and all associated materials are either not accessible to the whole population or not even available on a daily basis due to the economic crisis and the difficulties on the hospital supply. On this basis, palliative hepatojejunostomy, introduced more than 50 years ago, could be revisited in the Greek reality in very selected cases and under these special circumstances. We report on two patients with locally advanced hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma, respectively, who were treated with a combination of double hepaticojejunostomy with peripheral hepatojejunostomy or peripheral hepatoejunostomy alone, respectively. Both patients experienced an adequate decompression of the biliary tract over more than a year. Palliative hepatojejunostomy could be an ultimate solution for selected patients and circumstances in Greece during the economic crisis.

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Embryonal carcinoma presenting as a calcified solitary testicular mass on ultrasound

A 24-year-old man presented with a 2-week history of a painless right testicular mass; ultrasound demonstrated a dense, solitary calcified mass. The patient elected observation after further workup showed no evidence of metastasis.

A repeat ultrasound 3 months later showed interval growth and the patient underwent right radical orchiectomy. Pathology was consistent with pure embryonal carcinoma of the testis. Calcified testicular masses are typically benign but do carry a differential of spermatic granuloma, large-cell calcifying Sertoli cell tumour, trauma, tuberculosis, filariasis, calcified Leydig cell tumour and burned-out testicular tumour.

To our knowledge, this is the first case report of pure embryonal carcinoma presenting as a solitary calcified testicular mass.

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Wernickea{euro}™s encephalopathy associated with liver abscess

Wernicke's encephalopathy is a rare neurological disorder caused by thiamine deficiency, characterised by ocular motor dysfunction, ataxia and impairment in consciousness. It predominantly affects brain regions with a high metabolic rate such as mammillary bodies, medial thalamic nuclei, the tectal region and the cerebellum. Although chronic alcoholism is the most common cause of Wernicke's encephalopathy, various other conditions not related to alcohol consumption such as bariatric surgery, acute pancreatitis, hyperemesis gravidarum, prolonged fasting and gastrointestinal surgery have been implicated in its aetiology. We report the case of a patient who underwent surgery for liver abscess and subsequently developed Wernicke's encephalopathy; he showed a positive response to thiamine supplementation. This is the first report describing liver abscess as the cause of Wernicke's encephalopathy.

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Pseudo retinitis pigmentosa in a case of missed intraocular foreign body

A 35-year-old man presented with history of painless, progressive loss of vision in the left eye for the past 7 years. There was history of trauma to the same eye with an iron object 7 years prior. Fundus examination revealed pigmentary retinopathy (unilateral advanced retinitis pigmentosa (RP)-like picture). X-ray orbits were suspicious of retained intraocular foreign body (IOFB). CT orbits confirmed the presence of IOFB. Electroretinogram revealed depressed responses. Right eye examination was within normal limits. A diagnosis of siderosis bulbi with unilateral pseudo RP-like fundus was made. No surgical intervention was planned for IOFB in view of poor visual prognosis.

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Triggering of the abductor pollicis longus in association with deQuervain's tenosynovitis

DeQuervain's tenosynovitis is a common cause of radial-sided wrist pain. Symptoms result from a narrow first dorsal compartment and associated tendinosis of the enclosed extensor pollicis brevis and/or abductor pollicis longus (APL). Surgical intervention, offered when conservative measures fail to adequately relieve symptoms, requires a detailed understanding of potentially aberrant anatomy in order to avoid persistence or recurrence of symptoms. We describe a case whereby the patient presented with complaints of thumb triggering in extension and associated disabling first dorsal compartment tendinosis. Intraoperatively, after supernumerary tendons were identified and addressed, the APL was at risk for subluxation over a prominent fibroosseous ridge. Routine first dorsal compartment release alone may have failed to address all of this patient's pathology.

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Tuberculosis presenting as broncho-oesophageal fistula in a young healthy man

A 21-year-old Saudi man presented with a history of dysphagia and choking. CT scan of the chest showed clear evidence of chronic recurrent aspiration pneumonia in the left lung. It also showed a fistula connecting the left main bronchus to the oesophagus. Endoscopy showed clear opening on the oesophageal side. Bronchoscopy also confirmed the presence of a broncho-oesophageal fistula on the left bronchial side with the presence of secretions on swallowing. Bronchoalveolar lavage (BAL) was done and sent for mycobacterial tuberculosis culture. The fistula was closed with clips under endoscopic guidance, which alleviated his symptoms of dysphagia and choking. The BAL culture grew mycobacterial tubercle bacilli. The patient showed marked improvement after starting antitubercular therapy and was discharged to be followed up in the clinic.

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Patterns-of-failure guided biological target volume definition for head and neck cancer patients: FDG-PET and dosimetric analysis of dose escalation candidate subregions

To identify the radio-resistant subvolumes in pretreatment FDG-PET by mapping the spatial location of the origin of tumor recurrence after IMRT for head-and-neck squamous cell cancer to the pretreatment FDG-PET/CT.

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Nintedanib reduces radiation-induced microscopic lung fibrosis but this cannot be monitored by CT imaging: A preclinical study with a high precision image-guided irradiator

Nintedanib has anti-fibrotic and anti-inflammatory activity and is approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to noninvasively assess the efficacy of nintedanib in a mouse model of partial lung irradiation to prevent radiation-induced lung damage (RILD).

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Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A Systematic Review and Pooled Analysis

Publication date: Available online 31 July 2017
Source:Cancer Treatment Reviews
Author(s): Elisa Roca, Cristina Gurizzan, Vito Amoroso, William Vermi, Vittorio Ferrari, Alfredo Berruti
BackgroundLung adenocarcinoma can transform to small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. This phenomenon has repeatedly been described in several case reports and small patient series. The characteristics and treatment outcomes of this population, however, have not been comprehensively reported.MethodsWe performed a systematic review of the published literature to obtain explorative information on the clinical and pathological features and prognosis of the reported cases.ResultsTwenty-five eligible publications were identified, contributing to 39 patients. The median time from initial diagnosis of lung adenocarcinoma to the transformation to SCLC (ttSCLC) was 19 months (range 1-61 months). The median survival after SCLC diagnosis was 6 months. Female gender was significantly associated with longer ttSCLC at the multivariable analysis. Smoking status seemed to be associated with worse prognosis after the diagnosis of SCLC.ConclusionIn this series of published cases, the transformation to a SCLC phenotype after an initial diagnosis of lung adenocarcinoma following TKI therapy appeared to be a late phenomenon. The prognosis after SCLC diagnosis is poor and current treatment strategies derived from primary SCLC seem to be largely inefficacious. New therapies are needed in the management of transformed SCLC.



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Immunotherapy in ovarian, endometrial and cervical cancer: state of the art and future perspectives

Publication date: Available online 31 July 2017
Source:Cancer Treatment Reviews
Author(s): Jole Ventriglia, Immacolata Paciolla, Carmela Pisano, Sabrina Chiara Cecere, Marilena Di Napoli, Rosa Tambaro, Daniela Califano, Simona Losito, Giosuè Scognamiglio, Sergio Venanzio Setola, Laura Arenare, Sandro Pignata, Chiara Della Pepa
The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents.



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PRODIGE: PRediction models in prOstate cancer for personalized meDIcine challenGE

Future Oncology, Ahead of Print.


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Ribociclib for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer

Future Oncology, Ahead of Print.


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Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers

Summary

Background The prognosis of patients with metastatic carcinoma of the biliary tract (mBTC) is poor and a systemic therapy with gemcitabine and platinum-based is the gold standard. The addition of bevacizumab to the chemotherapy might increase patients' survival. Our aim was to assess and compare the efficacy of GEMOX (gemcitabine and oxaliplatin regimen) plus bevacizumab to GEMOX alone in mBTC. Methods Patients with mBTC who received the GEMOX-bevacizumab (n = 32; Group A) or GEMOX (n = 25; Group B) regimen as first-line treatment were compared. Treatment was repeated every two weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was the progression-free survival (PFS). Results A quarter of patients (8/32) from Group A and a fifth of patients (13/25) from Group B had an objective response. The median PFS was 6.48 months and 3.72 months in Group A and B, respectively (p = 0.049). The median OS was 11.31 months and 10.34 months in Group A and B, respectively. Grade 3/4 sepsis was identified in 9.4% and 12% in Group A and B, respectively, (p = 0.64). Conclusion In mBTC, the addition of bevacizumab to GEMOX increased the progression-free survival and was associated with manageable toxicity. These data pave the way for further evaluation of antiangiogenic agents in mBTC.

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Circulating tumor DNA reveals clinically-actionable somatic genome of metastatic bladder cancer

Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally-invasive tool to profile the tumor genome in real-time, but is critically under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease.</p> <p>Results: The majority of metastatic patients, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9 - 72.6%). 12% of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic BCa with 95% of patients harboring deleterious alterations to TP53, RB1 or MDM2, and 70% harbouring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A. Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1. A novel FGFR3 gene fusion was identified in consecutive samples from one patient.</p> <p>Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic BCa. The identification of a wide spectrum of clinically-informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in metastatic BCa.

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Normal and malignant cells exhibit differential responses to calcium electroporation

Calcium electroporation may offer a simple general tool for anticancer therapy. Transient permeabilization of cancer cell membranes created by applying short, high-voltage pulses in tumors enables high calcium influxes that trigger cell death. In this study, we compared the relative sensitivity of different human tumor models and normal tissues to calcium electroporation. Plasma membrane Ca2+-ATPase (PMCA) protein expression was confirmed in vitro in all cancer cell lines and normal primary dermal fibroblasts studied. In all tumor types tested in vivo, calcium electroporation effectively induced necrosis, with a range of sensitivities observed (36-88%) 2 days after treatment. Necrosis was induced using calcium concentrations of 100-500 mM and injection volumes 20-80% of tumor volume. Notably, only limited effects were seen in normal tissue. Calcium content increased >7-fold in tumor and skin tissue after calcium electroporation but decreased in skin tissue 4 hr after treatment to levels comparable to untreated controls, whereas calcium content endured at high levels in tumor tissue. Mechanistic experiments in vitro indicated that calcium influx was similar in fibroblasts and cancer cells. However, we observed decreased PMCA expression in cancer cells compared to fibroblasts offering a potential explanation for the different calcium content in tumor cells versus normal tissues. Overall, our results suggest that calcium electroporation can elicit a rapid and selective necrosis of solid tumors, with limited deleterious effects on surrounding normal tissues.

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FBW7 loss promotes chromosomal instability and tumorigenesis via Cyclin E1/CDK2-mediated phosphorylation of CENP-A

The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.

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Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors

Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GIST eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state. Using phospho-RTK and immunoblot assays, we demonstrate activation of KIT and insulin receptor (IR) in imatinib-resistant GIST cell lines (GIST430 and GIST48) and biopsies with acquisition of KIT secondary mutations, but not in imatinib-sensitive GIST cells (GIST882 and GIST-T1). Treatment with linsitinib, a specific IR inhibitor, inhibited IR and downstream intermediates AKT, MAPK, and S6 in GIST430 and GIST48, but not in GIST882, exerting minimal effect on KIT phosphorylation in these cell lines. Additive effects showing increased apoptosis, anti-proliferative effects, cell cycle arrest, and decreased pAKT and pS6 expression, tumor growth, migration, and invasiveness were observed in imatinib-resistant GIST cells with IR activation after coordinated inhibition of IR and KIT by linsitinib (or IR shRNA) and imatinib, respectively, compared to either intervention alone. IGF2 overexpression was responsible for IR activation in imatinib-resistant GIST cells, whereas IR activation did not result from IR amplification, IR mutation, or KIT phosphorylation. Our findings suggest that combinatorial inhibition of IR and KIT warrants clinical evaluation as a novel therapeutic strategy in imatinib-resistant GISTs.

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Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression

Gastric adenocarcinoma (GA) is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases which are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of GA tumorigenesis based on KrasG12D expression plus inactivation of E-cadherin (Cdh1) and p53 in the gastric parietal cell lineage. Intestinal and diffuse gastric tumors arise rapidly in this model, which displays a median survival of 76 days. Tumors occur throughout the stomach with metastases documented in lymph nodes, lung and liver. Mice otherwise identical but retaining one wild-type Cdh1 allele exhibited longer survival with only 20% penetrance of invasive tumors and no apparent lung or liver metastases. Notably, increased RAS activity and downstream MAPK signaling was observed in stomachs only when E-cadherin was absent. This model offers a valuable tool to investigate GA subtypes where RAS/MAPK pathway activation and E-cadherin attenuation are common.

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Survival of head and neck cancer cells relies upon LZK kinase-mediated stabilization of mutant p53

Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral and nasal cavity, larynx, and pharynx and accounts for ~350,000 deaths/year worldwide. Smoking-related HNSCC is associated with few targetable mutations but is defined by frequent copy number alteration, the most common of which is gain at 3q. Critical 3q target genes have not been conclusively determined for HNSCC. Here we present data indicating that MAP3K13 (encoding LZK) is an amplified driver gene in HNSCC. Copy number gain at 3q resulted in increased MAP3K13 mRNA in HNSCC tumor samples and cell lines. Silencing LZK reduced cell viability and proliferation of HNSCC cells with 3q gain but not control cell lines. Inducible silencing of LZK caused near complete loss of colony-forming ability in cells harboring 3q gain. These results were validated in vivo by evidence that LZK silencing was sufficient to reduce tumor growth in a xenograft model of HNSCC. Our results establish LZK as critical for maintaining expression of mutant stabilized p53.

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Evaluation of Mineral Concentrations in Maternal Serum Before and After Birth and in Newborn Cord Blood Postpartum—Preliminary Study

Abstract

The mineral levels in maternal serum change during pregnancy and may be correlated with those of newborn cord blood. The aim of this study was to evaluate the concentrations of calcium (Ca), magnesium (Mg), zinc (Zn), iron (Fe), and copper (Cu) in maternal blood before and after delivery and in umbilical cord vein and artery serum. The study was carried out in 64 Caucasian pregnant women who delivered in a district hospital in Greater Poland region, aged 28.1 ± 5.4 years, with a mean gestational age of 39.2 ± 1.3 weeks. Blood samples were taken from women 2–8 h before delivery and immediately after childbirth. The umbilical cord artery and vein blood of newborns was obtained immediately after childbirth. The levels of minerals in serum were determined by flame atomic absorption spectrometry. A significant drop in the concentrations of Mg (17.71 ± 1.51 vs 17.07 ± 1.61 μg/ml; p < 0.007), Fe (1.08 ± 0.46 vs 0.82 ± 0.35 μg/ml; p < 0.0004), and Zn (0.63 ± 0.17 vs 0.46 ± 0.16; p < 0.0001) in maternal serum was found after delivery. Moreover, higher levels of Ca, Fe, and Zn and lower levels of Cu were observed in the umbilical vein (Ca: 102.80 ± 7.80 μg/ml; p < 0.0001, Fe: 1.96 ± 0.43 μg/ml; p < 0.0001, Zn: 0.65 ± 0.16 μg/ml; p < 0.0001, Cu: 0.36 ± 0.09 μg/ml; p < 0.0001) and in the umbilical artery cord blood (Ca: 98.07 ± 8.18 μg/ml; p < 0.0001, Fe: 1.63 ± 0.30 μg/ml; p < 0.0001, Zn: 0.65 ± 0.15 μg/ml; p < 0.0001, and Cu: 0.36 ± 0.10 μg/ml; p < 0.0001) compared to the maternal serum (Ca: 85.05 ± 10.76 μg/ml, Fe: 0.82 ± 0.35 μg/ml, Zn: 0.46 ± 0.16 μg/ml, and Cu: 1.90 ± 0.35 μg/ml). Fe levels in the cord artery serum negatively correlated with blood loss during delivery (R = −0.48; p = 0.01), while the Ca concentration in the maternal serum after birth decreased with the age of the women (R = −0.25; p = 0.03). In conclusion, it seems that the process of birth alters the mineral levels in pregnant women's blood. Moreover, it was found that blood loss and the age of the mother are associated with mineral concentrations in the maternal serum and cord artery blood.

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Giant mucinous adenocarcinoma of the appendix: a case report

Appendiceal mucinous adenocarcinoma is an extremely rare disease in clinical practice. Here, we report a case of unprecedented size that occupied the entire abdomen of a man.

http://ift.tt/2weU7U0

Sevoflurane attenuates systemic inflammation compared with propofol, but does not modulate neuro-inflammation: A laboratory rat study.

BACKGROUND: Septic encephalopathy is believed to be a result of neuro-inflammation possibly triggered by endotoxins, such as lipopolysaccharides (LPS). Modulation of the immune system is a property of volatile anaesthetics. OBJECTIVE: We aimed to investigate the systemic and cerebral inflammatory response in a LPS-induced sepsis model in rats. We compared two different sedation strategies, intravenous propofol and the volatile anaesthetic sevoflurane, with the hypothesis that the latter may attenuate neuro-inflammatory processes. DESIGN: Laboratory rat study. SETTING: Basic research laboratories at the University Hospital Zurich and University Zurich Irchel between August 2014 and June 2016. PATIENTS: A total of 32 adult male Wistar rats. INTERVENTIONS: After tracheotomy and mechanical ventilation, the anaesthetised rats were monitored before sepsis was induced by using intravenous LPS or phosphate-buffered saline as control. Rats were sedated with propofol (10 mg kg-1 h-1) or sevoflurane (2 vol%) continuously for 12 h. MAIN OUTCOME MEASURES: Systemic inflammatory markers such as cytokine-induced neutrophil chemo-attractant protein 1, monocyte chemo-tactic protein-1 and IL-6 were determined. The same cytokines were measured in brain tissue. Cellular response in the brain was assessed by defining neutrophil accumulation with myeloperoxidase and also activation of microglia with ionised calcium-binding adaptor molecule-1 and astrocytes with glial fibrillary acidic protein. Finally, brain injury was determined. RESULTS: Animals were haemodynamically stable in both sedation groups treated with LPS. Blood cytokine peak values were lower in the sevoflurane-LPS compared with propofol-LPS animals. In brain tissue of LPS animals, chemoattractant protein-1 was the only significantly increased cytokine (P = 0.003), however with no significance between propofol and sevoflurane. After LPS challenge, cerebral accumulation of neutrophils was observed. Microglia activation was pronounced in the hippocampus of animals treated with LPS (P = 0.006). LPS induced prominent astrogliosis (P

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MALT1 promotes melanoma progression through JNK/c-Jun signaling

MALT1 promotes melanoma progression through JNK/c-Jun signaling

Oncogenesis 6, e365 (July 2017). doi:10.1038/oncsis.2017.68

Authors: Y Wang, G Zhang, J Jin, S Degan, Y Tameze & J Y Zhang

http://ift.tt/2weSqG8

ASCT2 regulates glutamine uptake and cell growth in endometrial carcinoma

ASCT2 regulates glutamine uptake and cell growth in endometrial carcinoma

Oncogenesis 6, e367 (July 2017). doi:10.1038/oncsis.2017.70

Authors: A D Marshall, M van Geldermalsen, N J Otte, T Lum, M Vellozzi, A Thoeng, A Pang, R Nagarajah, B Zhang, Q Wang, L Anderson, J E J Rasko & J Holst

http://ift.tt/2wfdlsJ

MeCP2, a target of miR-638, facilitates gastric cancer cell proliferation through activation of the MEK1/2–ERK1/2 signaling pathway by upregulating GIT1

MeCP2, a target of miR-638, facilitates gastric cancer cell proliferation through activation of the MEK1/2–ERK1/2 signaling pathway by upregulating GIT1

Oncogenesis 6, e368 (July 2017). doi:10.1038/oncsis.2017.60

Authors: L Y Zhao, D D Tong, M Xue, H L Ma, S Y Liu, J Yang, Y X Liu, B Guo, L Ni, L Y Liu, Y N Qin, L M Wang, X G Zhao & C Huang

http://ift.tt/2wf0Tt7

miR-151a induces partial EMT by regulating E-cadherin in NSCLC cells

miR-151a induces partial EMT by regulating E-cadherin in NSCLC cells

Oncogenesis 6, e366 (July 2017). doi:10.1038/oncsis.2017.66

Authors: I Daugaard, K J Sanders, A Idica, K Vittayarukskul, M Hamdorf, J D Krog, R Chow, D Jury, L L Hansen, H Hager, P Lamy, C L Choi, D Agalliu, D G Zisoulis & I M Pedersen

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Quadratus Lumborum Block Versus Transversus Abdominis Plane Block in Children Undergoing Low Abdominal Surgery: A Randomized Controlled Trial.

Background and Objectives: Truncal blocks have a place within multimodal analgesia techniques in abdominal surgery. The quadratus lumborum block is a new abdominal truncal block used for somatic analgesia of both the upper and lower abdomen. In this prospective, double-blind, randomized study, we aimed to compare quadratus lumborum block and transversus abdominis plane block in pediatric patients undergoing lower abdominal surgery. Methods: Fifty-three children undergoing unilateral inguinal hernia repair or orchiopexy surgery were randomized into 2 groups: transversus abdominis plane block and quadratus lumborum block. All blocks were performed under general anesthesia before surgery. Pain levels were assessed using an FLACC (Face, Legs, Activity, Cry, Consolability) scale. Results: The study included 50 patients, after excluding 3 patients who were not eligible. The number of patients who required analgesia in the first 24 hours postoperatively was significantly lower in the quadratus lumborum block group (P

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Ultrasound-Guided Regional Anesthesia Simulation Training: A Systematic Review.

Background and Objectives: Ultrasound-guided regional anesthesia (UGRA) has become the criterion standard of regional anesthesia practice. Ultrasound-guided regional anesthesia teaching programs often use simulation, and guidelines have been published to help guide URGA education. This systematic review aimed to examine the effectiveness of simulation-based education for the acquisition and maintenance of competence in UGRA. Methods: Studies identified in MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and ERIC were included if they assessed simulation-based UGRA teaching with outcomes measured at Kirkpatrick level 2 (knowledge and skills), 3 (transfer of learning to the workplace), or 4 (patient outcomes). Two authors independently reviewed all identified references for eligibility, abstracted data, and appraised quality. Results: After screening 176 citations and 45 full-text articles, 12 studies were included. Simulation-enhanced training improved knowledge acquisition (Kirkpatrick level 2) when compared with nonsimulation training. Seven studies measuring skill acquisition (Kirkpatrick level 2) found that simulation-enhanced UGRA training was significantly more effective than alternative teaching methods or no intervention. One study measuring transfer of learning into the clinical setting (Kirkpatrick level 3) found no difference between simulation-enhanced UGRA training and non-simulation-based training. However, this study was discontinued early because of technical challenges. Two studies examined patient outcomes (Kirkpatrick level 4), and one of these found that simulation-based UGRA training improved patient outcomes compared with didactic teaching. Conclusions: Ultrasound-guided regional anesthesia knowledge and skills significantly improved with simulation training. The acquired UGRA skills may be transferred to the clinical setting; however, further studies are required to confirm these changes translate to improved patient outcomes. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Impact of Different Ventilation Strategies on Driving Pressure, Mechanical Power, and Biological Markers During Open Abdominal Surgery in Rats.

BACKGROUND: Intraoperative mechanical ventilation may yield lung injury. To date, there is no consensus regarding the best ventilator strategy for abdominal surgery. We aimed to investigate the impact of the mechanical ventilation strategies used in 2 recent trials (Intraoperative Protective Ventilation [IMPROVE] trial and Protective Ventilation using High versus Low PEEP [PROVHILO] trial) on driving pressure ([DELTA]PRS), mechanical power, and lung damage in a model of open abdominal surgery. METHODS: Thirty-five Wistar rats were used, of which 28 were anesthetized, and a laparotomy was performed with standardized bowel manipulation. Postoperatively, animals (n = 7/group) were randomly assigned to 4 hours of ventilation with: (1) tidal volume (VT) = 7 mL/kg and positive end-expiratory pressure (PEEP) = 1 cm H2O without recruitment maneuvers (RMs) (low VT/low PEEP/RM-), mimicking the low-VT/low-PEEP strategy of PROVHILO; (2) VT = 7 mL/kg and PEEP = 3 cm H2O with RMs before laparotomy and hourly thereafter (low VT/moderate PEEP/4 RM+), mimicking the protective ventilation strategy of IMPROVE; (3) VT = 7 mL/kg and PEEP = 6 cm H2O with RMs only before laparotomy (low VT/high PEEP/1 RM+), mimicking the strategy used after intubation and before extubation in PROVHILO; or (4) VT = 14 mL/kg and PEEP = 1 cm H2O without RMs (high VT/low PEEP/RM-), mimicking conventional ventilation used in IMPROVE. Seven rats were not tracheotomized, operated, or mechanically ventilated, and constituted the healthy nonoperated and nonventilated controls. RESULTS: Low VT/moderate PEEP/4 RM+ and low VT/high PEEP/1 RM+, compared to low VT/low PEEP/RM- and high VT/low PEEP/RM-, resulted in lower [DELTA]PRS (7.1 +/- 0.8 and 10.2 +/- 2.1 cm H2O vs 13.9 +/- 0.9 and 16.9 +/- 0.8 cm H2O, respectively; P

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Targeting Hypoxia Signaling for Perioperative Organ Injury.

Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients. (C) 2017 International Anesthesia Research Society

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Avoiding Complications From Patient Positioning for Intraocular Surgery.

Collaboration of the surgical and anesthesia teams for patient positioning is essential to assure patient comfort and safety, preventing systemic and ophthalmic complications. The goals and rationales of positioning for intraocular surgery are discussed including placing the head above the heart, elevating the chin, using a head rest that is sufficiently firm, maximizing anesthesia care team access and minimizing fire risk, and taping the patient's head to the operating table to reduce unexpected movement with intraocular injury. (C) 2017 International Anesthesia Research Society

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Aortocaval Compression Syndrome: Time to Revisit Certain Dogmas.

More than 70 years ago, the phenomenon of "postural shock" in the supine position was described in healthy women in late pregnancy. Since then, avoidance of the supine position has become a key component of clinical practice. Indeed, performing pelvic tilt in mothers at term to avoid aortocaval compression is a universally adopted measure, particularly during cesarean delivery. The studies on which this practice is based are largely nonrandomized, utilized a mix of anesthetic techniques, and were conducted decades ago in the setting of avoidance of vasopressors. Recent evidence is beginning to refine our understanding of the physiologic consequences of aortocaval compression in the context of contemporary clinical practice. For example, magnetic resonance imaging of women at term in the supine and tilted positions has challenged the dogma that 15[degrees] of left tilt is sufficient to relieve inferior vena cava compression. A clinical investigation of healthy term women undergoing elective cesarean delivery with spinal anesthesia found no difference in neonatal acid-base status between women randomized to be either tilted to the left by 15[degrees] or to be in the supine position, if maternal systolic blood pressure is maintained at baseline with a crystalloid coload and prophylactic phenylephrine infusion. This review presents a fresh look at the decades of evidence surrounding this topic and proposes a reevaluation and appraisal of current guidelines regarding entrenched practices. (C) 2017 International Anesthesia Research Society

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Current Approach to Heart Failure.

No abstract available

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Whiplash Injury: Perspectives on the Development of Chronic Pain.

No abstract available

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The Expected Role of the Anesthesiologist in Delivering Bad News.

No abstract available

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Limits of Agreement With Confidence Intervals Are Necessary to Assess Comparability of Measurement Devices.

No abstract available

http://ift.tt/2f2unHs

The Evaluation of a Noninvasive Respiratory Volume Monitor in Pediatric Patients Undergoing General Anesthesia.

BACKGROUND: Pediatric patients following surgery are at risk for respiratory compromise such as hypoventilation and hypoxemia depending on their age, comorbidities, and type of surgery. Quantitative measurement of ventilation in nonintubated infants/children is a difficult and inexact undertaking. Current respiratory assessment in nonintubated patients relies on oximetry data, respiratory rate (RR) monitors, and subjective clinical assessment, but there is no objective measure of respiratory parameters that could be utilized to predict early respiratory compromise. New advances in technology and digital signal processing have led to the development of an impedance-based respiratory volume monitor (RVM, ExSpiron, Respiratory Motion, Inc, Waltham, MA). The RVM has been shown to provide accurate real-time, continuous, noninvasive measurements of tidal volume (TV), minute ventilation (MV), and RR in adult patients. In this prospective observational study, our primary aim was to determine whether the RVM accurately measures TV, RR, and MV in pediatric patients. METHODS: A total of 72 pediatric patients (27 females, 45 males), ASA I to III, undergoing general anesthesia with endotracheal intubation were enrolled. After endotracheal intubation, continuous data of MV, TV, and RR were recorded from the RVM and an in-line monitoring spirometer (NM3 monitor, Phillips Healthcare). RVM and NM3 measurements of MV, TV, and RR were compared during a 10-minute period prior to the incision ("Presurgery") and a 10-minute period after the end of surgery ("Postsurgery"). Relative errors were calculated over 1-minute segment within each 10-minute period. Bias, precision, and accuracy were calculated using Bland-Altman analyses and paired-difference equivalence tests were performed. RESULTS: Combined across the Presurgery and Postsurgery periods, the RVM's mean measurement bias (RVM - NM3 measurement) for MV was -3.8% (95% limits of agreement) (+/-1.96 SD): (-19.9% to 12.2%), for TV it was -4.9 (-21.0% to 11.3%), and for RR it was 1.1% (-4.1% to 6.2%). The mean measurement accuracies for MV, TV, and RR were 11.9%, 12.0%, and 4.2% (0.6 breaths/min), respectively. Note that lower accuracy numbers correspond to more accurate RVM measurements. The equivalence tests rejected the null hypothesis that the RVM and NM3 have different mean values and conclude with 90% power that the measurements of MV, TV, and RR from the RVM and NM3 are equivalent within +/-10%. CONCLUSIONS: Our data indicate acceptable agreement between RVM and NM3 measurements in pediatric mechanically-ventilated patients. Future studies assessing the capability of the RVM to detect respiratory compromise in other clinical settings are needed. (C) 2017 International Anesthesia Research Society

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Chronic Hiccups: An Underestimated Problem.

Persistent singultus, hiccupping that lasts for longer than 48 hours, can have a tremendous impact on a patient's quality of life. Although involved neurologic structures have been identified, the function of hiccups remains unclear-they have been controversially interpreted as a primitive reflex preventing extent swallowing of amniotic fluid in utero, an archaic gill ventilation pattern, or a fetus' preparation for independent breathing. Persistent singultus often presents as a symptom for various diseases, most commonly illnesses of the central nervous system or gastrointestinal tract; they can also be evoked by a variety of pharmacological agents. It is often impossible to define a singular cause. A wide range of treatment attempts, pharmacological and nonpharmacological, have been concerted to this date; however, chlorpromazine remains the only Food and Drug Administration-approved drug in this context. Large-scale studies on efficacy and tolerance of other therapeutic strategies are lacking. Gabapentin, baclofen, and metoclopramide have been reported to accomplish promising results in reports on the therapy of persistent singultus; they may also be effective when given in combination with other drugs, eg, proton pump inhibitors, or as conjoined therapy. As another approach of note, acupuncture treatment was able to abolish hiccups in a number of studies. When managing hiccup patients within the clinical routine, it is of importance to conduct a comprehensive and effective diagnostic workup; a well-functioning interdisciplinary team is needed to address possible causes for the symptom. Persistent singultus is a medical problem not to be underestimated; more research on options for effective treatment would be greatly needed. (C) 2017 International Anesthesia Research Society

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Degenerative Severe Aortic Stenosis in Tetralogy of Fallot: Multimodality Echocardiographic Hemodynamic Assessment.

No abstract available

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Trauma Anesthesiology as Part of the Core Anesthesiology Residency Program Training: Expert Opinion of the American Society of Anesthesiologists Committee on Trauma and Emergency Preparedness (ASA COTEP).

No abstract available

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Addition of Nasal Cannula Can Either Impair or Enhance Preoxygenation With a Bag Valve Mask: A Randomized Crossover Design Study Comparing Oxygen Flow Rates.

BACKGROUND: A critical safety component of emergency anesthesia is the avoidance of hypoxemia during the apneic phase of a rapid sequence intubation. Preoxygenation with a bag valve mask (BVM) or anesthetic circuit may be improved with supplemental oxygen by nasal cannula (NC) if there is a mask leak. In addition, NC is recommended for apneic oxygenation after induction and may be placed before preoxygenation. However, the optimum NC flow rate for preoxygenation or whether the presence of NC alone creates a mask leak remains unclear. METHODS: We performed a randomized crossover study on healthy volunteers comparing BVM alone and BVM with NC flow rates of 0 (NC-0), 5 (NC-5), 10 (NC-10), and 15 (NC-15) liters per minute (lpm). Our primary outcome was end-tidal oxygen (ETO2) after 3-minute preoxygenation. RESULTS: There was no difference in ETO2 between NC-15, NC-10, or BVM-only at 3 minutes. NC-0 and NC-5 recorded significantly lower ETO2 at all times compared with NC-15, NC-10, or BVM-only (least difference NC-5, -7% [95% confidence interval {CI}, -4% to -10%), NC-0, 16% [95% CI, 13%-19%]). There was a difference in ETO2 between NC-15 and BVM-only at 1 minute (7%; 95% CI, 5%-9%), but not at 2 or 3 minutes. There was no difference in ETO2 between NC-10 and NC-15. CONCLUSIONS: Our study found that NC at 0 and 5 lpm with a BVM is deleterious to preoxygenation and should be avoided. In addition, a lack of difference between NC-10 and BVM-only demonstrates that NC at flows of at least 10 lpm should not impair the preoxygenation process. While NC-15 may offer a benefit by reaching maximal ETO2 at 1 minute, this would need to be balanced against patient comfort. (C) 2017 International Anesthesia Research Society

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Questionable Design to Validate the ProAQT/Pulsioflex Device.

No abstract available

http://ift.tt/2hgR1fN

Managing Obstetric Emergencies and Trauma, Revised 3rd ed.

No abstract available

http://ift.tt/2f2tTRE

Alarm Limits for Intraoperative Drug Infusions: A Report From the Multicenter Perioperative Outcomes Group.

BACKGROUND: Continuous medication infusions are commonly used during surgical procedures. Alarm settings for infusion pumps are considered important for patient safety, but limits are not created in a standardized manner from actual usage data. We estimated 90th and 95th percentile infusion rates from a national database for potential use as upper limit alarm settings. METHODS: We extracted infusion rate data from 17 major hospitals using intraoperative records provided by Multicenter Perioperative Outcomes Group for adult surgery between 2008 and 2014. Seven infusions were selected for study: propofol, remifentanil, dexmedetomidine, norepinephrine, phenylephrine, nitroglycerin, and esmolol. Each dosage entry for an infusion during a procedure was included. We estimated the 50th, 90th, and 95th percentile levels for each infusion across institutions, and performed quantile regression to examine factors that might affect the percentiles rates, such as use in general anesthesia versus sedation. RESULTS: The median 90th and 95th percentile infusion rates (with interquartile range) for propofol were 150 (140-150) and 170 (150-200) [mu]g/kg/min. Quantile regression demonstrated higher 90th and 95th percentile rates during sedation for gastrointestinal endoscopy than for all surgical procedures performed under general anesthesia. For selected vasoactive medications, the corresponding median 90th and 95th percentile rates (with interquartile range) were norepinephrine 14.0 (9.8-18.1) and 18.3 (12.6-23.9) [mu]g/min, and phenylephrine 60 (55-80) and 80 (75-100) [mu]g/min. CONCLUSIONS: Alarm settings based on infusion rate percentile limits would be triggered at predictable rates; ie, the 95th percentile would be exceeded and an alarm sounded during 1 in 20 infusion rate entries. As a result, institutions could establish pump alarm settings consistent with desired alarm frequency using their own or externally validated usage data. Further study will be needed to determine the optimal percentile for infusion alarm settings. (C) 2017 International Anesthesia Research Society

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Fertility Preservation in Young Female Cancer Patients: Development and Pilot Testing of an Online Decision Aid

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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A Rare Case: Struma Ovarii in a 14-Year-Old Girl

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2vmn2JH

A comparative study of U937 cell size changes during apoptosis initiation by flow cytometry, light scattering, water assay and electronic sizing

Abstract

A decrease in flow cytometric forward light scatter (FSC) is commonly interpreted as a sign of apoptotic cell volume decrease (AVD). However, the intensity of light scattering depends not only on the cell size but also on its other characteristics, such as hydration, which may affect the scattering in the opposite way. That makes estimation of AVD by FSC problematic. Here, we aimed to clarify the relationship between light scattering, cell hydration (assayed by buoyant density) and cell size by the Coulter technique. We used human lymphoid cells U937 exposed to staurosporine, etoposide or hypertonic stress as an apoptotic model. An initial increase in FSC was found to occur in apoptotic cells treated with staurosporine and hypertonic solutions; it is accompanied by cell dehydration and is absent in apoptosis caused by etoposide that is consistent with the lack of dehydration in this case. Thus, the effect of dehydration on the scattering signal outweighs the effect of reduction in cell size. The subsequent FSC decrease, which occurred in parallel to accumulation of annexin-positive cells, was similar in apoptosis caused by all three types of inducers. We conclude that an increase, but not a decrease in light scattering, indicates the initial cell volume decrease associated with apoptotic cell dehydration.

http://ift.tt/2vYjlXH

GBM radiosensitizers: dead in the water…or just the beginning?

Abstract

The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers. However, many of  the previous radiosensitizing strategies were not based on clear pre-clinical evidence, and in many cases blood-barrier penetration was not considered. Furthermore, DNA repair inhibitors have only recenly arrived in the clinic, and likely represent potent agents for glioma radiosensitization. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization.

http://ift.tt/2vlTxYz

Randomized controlled trial of S-1 maintenance therapy in metastatic esophagogastric cancer – the multinational MATEO study

Abstract

Background

The optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer.

Methods

The Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life.

Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy.

Discussion

MATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy.

Trial registration

NCT02128243 (date of registration: 29–04-2014).

http://ift.tt/2vYaSU9

PUREAIR protocol: randomized controlled trial of intensive pulmonary rehabilitation versus standard care in patients undergoing surgical resection for lung cancer

Abstract

Background

Non-small cell lung cancer is the most common type of lung cancer. Surgery is proven to be the most effective treatment in early stages, despite its potential impact on quality of life. Pulmonary rehabilitation, either before or after surgery, is associated with reduced morbidity related symptoms and improved exercise capacity, lung function and quality of life.

Methods

We describe the study protocol for the open-label randomized controlled trial we are conducting on patients affected by primary lung cancer (stages I-II) eligible for surgical treatment. The control group receives standard care consisting in one educational session before surgery and early inpatient postoperative physiotherapy. The treatment group receives, in addition to standard care, intensive rehabilitation involving 14 preoperative sessions (6 outpatient and 8 home-based) and 39 postoperative sessions (15 outpatient and 24 home-based) with aerobic, resistance and respiratory training, as well as scar massage and group bodyweight exercise training.

Assessments are performed at baseline, the day before surgery and one month and six months after surgery. The main outcome is the long-term exercise capacity measured with the Six-Minute Walk Test; short-term exercise capacity, lung function, postoperative morbidity, length of hospital stay, quality of life (Short Form 12), mood disturbances (Hospital Anxiety and Depression Scale) and pain (Numeric Rating Scale) are also recorded and analysed. Patient compliance and treatment-related side effects are also collected. Statistical analyses will be performed according to the intention-to-treat approach. T-test for independent samples will be used for continuous variables after assessment of normality of distribution. Chi-square test will be used for categorical variables. Expecting a 10% dropout rate, assuming α of 5% and power of 80%, we planned to enrol 140 patients to demonstrate a statistically significant difference of 25 m at Six-Minute Walk Test.

Discussion

Pulmonary Resection and Intensive Rehabilitation study (PuReAIR) will contribute significantly in investigating the effects of perioperative rehabilitation on exercise capacity, symptoms, lung function and long-term outcomes in surgically treated lung cancer patients. This study protocol will facilitate interpretation of future results and wide application of evidence-based practice.

Trial registration

ClinicalTrials.gov Registry n. NCT02405273 [31.03.2015].

http://ift.tt/2vYwaRI

A randomized trial of early detection of clinically significant prostate cancer (ProScreen): study design and rationale

Abstract

The current evidence of PSA-based prostate cancer screening shows a reduction in cause-specific mortality, but with substantial overdiagnosis. Recently, new developments in detection of clinically relevant prostate cancer include multiple kallikreins as biomarkers besides PSA, and multiparametric magnetic resonance imaging (mpMRI) for biopsy decision. They offer opportunities for improving the outcomes in screening, particularly reduction in overdiagnosis and higher specificity for potentially lethal cancer. A population-based randomized screening trial will be started, with 67,000 men aged 55–67 years at entry. A quarter of the men will be allocated to the intervention arm, and invited to screening. The control arm will receive no intervention. All men in the screening arm will be offered a serum PSA determination. Those with PSA of 3 ng/ml or higher will have an additional multi-kallikrein panel and those with indications of increased risk of clinically relevant prostate cancer will undergo mpMRI. Men with a malignancy-suspect finding in MRI are referred to targeted biopsies. Screening interval is 6 years for men with baseline PSA < 1.5 ng/ml, 4 years with PSA 1.5–3.0 and 2 years if initial PSA > 3. The main outcome of the trial is prostate cancer mortality, with analysis at 10 and 15 years. The statistical power is sufficient for detecting a 28% reduction at 10 years and 22% at 15 years. The proposed study has the potential to provide the evidence to justify screening as a public health policy if mortality benefit can be sustained with substantially reduced overdiagnosis.

http://ift.tt/2f1v2Zm

Adequate sampling of multiple thyroid nodules by fine-needle aspiration

BACKGROUND

Recommendations regarding how many nodules to biopsy with thyroid fine-needle aspiration vary.

METHODS

The authors reviewed fine-needle aspiration specimens of 12,763 nodules from 10,506 patients and correlated them with the number of nodules biopsied.

RESULTS

Compared with patients in whom only a single nodule was biopsied, patients in whom multiple nodules were biopsied were found to be significantly younger, more likely female, and to have larger tumors, and those tumors were more often papillary (all P<.001). On fine-needle aspiration, patients who had multiple nodules biopsied were more often diagnosed with benign findings (P<.001), but usually had no significant difference in the risk of malignancy associated with any cytologic diagnosis. Performing biopsy in 3 nodules detected all carcinomas in the current series. Combining all cases in the literature demonstrated that performing only 3 biopsies in a patient with at least 4 suspicious nodules had a risk of malignancy of 1.2%.

CONCLUSIONS

Biopsy of 3 different nodules in patients with multiple nodules appears to lower the risk of malignancy to that of a benign fine-needle aspiration specimen. Although exceptions can occur, cytologists may be able to improve the accuracy of their diagnoses by focusing predominantly on identifying papillary carcinoma after the first 2 nodules have been biopsied. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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The evolving role of cytopathology in the era of neoadjuvant chemotherapy for the accurate pathologic diagnosis of epithelial ovarian cancer

http://ift.tt/2vfPI64

Next-generation learning and training: The Cy-TEST experience

On the basis of pioneering achievements with Cy-TEST, it is possible that a new era of learning, training, and testing in cytopathology and histopathology is coming.

http://ift.tt/2tRkMWq

A long-term survival case after surgical resection of skeletal muscle metastasis following esophagectomy for squamous cell carcinoma of the esophagus

Abstract

Cases of skeletal muscle metastasis of esophageal carcinoma are very rare, with few reports of long-term survival. We report a case of long-term survival after surgical resection of skeletal muscle metastasis. A 56-year-old man with advanced esophageal cancer and early gastric cancer underwent thoracoscopic esophagectomy, 2-field lymph node dissection, partial gastrectomy and gastric tube reconstruction. Six months later, cervical lymph node metastasis and mediastinal lymph node recurrence were found. Therefore, the patient underwent cervical lymph node dissection and adjuvant chemoradiotherapy. Two years and 3 months after the esophagectomy, a muscle metastasis was found in the left shoulder, and he underwent tumor dissection, followed by adjuvant chemotherapy for a year. There has been no sign of recurrence since, even 13 years after the esophagectomy. We believe our aggressive surgical treatment might have led to long-term survival.

http://ift.tt/2vYLE8u

Multifocal rib osteomyelitis in children: a case report and literature review

Abstract

Rib osteomyelitis is a rare disease, occurring in ~1% or less of all cases of haematogenous osteomyelitis. During the last century, 58 cases of rib osteomyelitis were reported in the literature, of which, multiple ribs were involved in only five patients. Because of its rarity and non-specific clinical signs, diagnostic of rib osteomyelitis may be delayed. We report a case of multifocal rib osteomyelitis revealed by a dorsal mass in a healthy 13-year-old female child.

http://ift.tt/2vYeQMA

Neurofibromatosis type 1 and male breast cancer: emerging risk factor?

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by the appearance of cafe au lait spots, neurofibromas and Lisch nodules. There is an established link between NF1 and the development of breast cancer in women; however, due to the rarity of both NF1 and male breast cancer, the same link has yet to be elucidated in men. The concurrent presentation of NF1 and male breast cancer is a very rare phenomenon with only a handful of case descriptions in the literature. To the best of our knowledge, there have only been four other reported cases of NF1 and male breast cancer before ours. We present one such case of a 56-year-old male with a four generation history of NF1 and a personal history of NF1 who presented with invasive ductal carcinoma of the right breast.

http://ift.tt/2vYn5s6

Ureterovaginal fistula following spontaneous vaginal delivery, repaired by vaginal ureteroneocystostomy in a low resource setting

Abstract

Ureterovaginal fistula commonly follows ureteric injury during pelvic surgery, and presents with continuous urinary incontinence in spite of normal micturition. Continuous urinary incontinence has significant impact on quality of life, thus requiring effective surgical intervention in order to restore health. We found no reported case of ureterovaginal fistula following spontaneous vaginal delivery with prolonged obstructed labour. Relevant history and simple diagnostic procedures were used for diagnosis and the patient had successful vaginal ureteroneocystostomy. This could be the first reported ureterovaginal fistula following spontaneous vaginal delivery with prolonged obstructed labour. Vaginal ureteroneocystostomy though scarcely reported, is feasible in selected cases.

http://ift.tt/2vXQMcX

Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas

BACKGROUND

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population.

METHODS

Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [K_ps] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment.

RESULTS

For patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P < .001 for an improvement from the historical rate of 17%). Evidence of PI3K/mTOR activation by immunohistochemistry for phosphorylated ribosomal S6^Ser240/244 (p-S6^Ser240/244) was associated with worse progression-free survival (PFS; hazard ratio [HR], 3.03; P = .004) and overall survival (HR, 12.7; P = .01). Tumor perfusion decreased after 6 months (median decrease in fBV, 15%; P = .03; median decrease in K_ps, 12%; P = .09), with greater decreases associated with improved PFS (HR for each 10% fBV decrease, 0.71; P = .01; HR for each 10% K_ps decrease, 0.82; P = .04).

CONCLUSIONS

Patients with recurrent LGGs demonstrated a high degree of disease stability during treatment with everolimus. PI3K/mTOR activation, as measured by immunohistochemistry for p-S6, was associated with a worse prognosis. Tumor vascular changes were observed that were consistent with the antiangiogenic effects of mTOR inhibitors. These results support further study of everolimus for LGGs. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2veZ1Dz

Feasibility and preliminary effects of resistance training and nutritional supplements during versus after radiotherapy in patients with head and neck cancer: A pilot randomized trial

BACKGROUND

Patients with head and neck cancer (HNC) experience involuntary weight loss that has a negative impact on physical function, morbidity, and survival. The objective of the current study was to evaluate the feasibility of an exercise and nutrition intervention during radiotherapy (RT) compared with after RT, and to examine preliminary effects on skeletal muscle mass.

METHODS

Patients with HNC were randomized to an exercise and nutrition intervention during RT (EN-DUR) or after RT (EN-AF). The EN-DUR intervention was conducted at a hospital and the EN-AF intervention took place at a rehabilitation center. The interventions consisted of progressive resistance training (PRT) and oral nutritional supplements (ONS). Feasibility outcomes were tracked weekly and muscle mass was measured by computed tomography scans before and after RT and at 2 months follow-up.

RESULTS

Of the 50 eligible patients, 41 (82%) agreed to participate. 90% of patients completed the EN-DUR intervention and the adherence to PRT and ONS was 81% and 57%, respectively. 52% of patients attended the EN-AF intervention and adherence to PRT and ONS was 94% and 76%, respectively. The EN-DUR demonstrated a trend toward mitigating loss of muscle mass during RT and the EN-AF demonstrated a similar trend after RT. No difference in muscle mass was detected between the groups from baseline to week 14.

CONCLUSIONS

An exercise and nutrition intervention is feasible for patients with HNC during RT, and the intervention is potentially effective in mitigating loss of muscle mass both during and after RT. Future trials should assess the feasibility and effects of extended interventions during and after treatment. Cancer 2017. © 2017 American Cancer Society.

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A call for action: Increasing enrollment of untreated patients with higher-risk myelodysplastic syndromes in first-line clinical trials

Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher-risk myelodysplastic syndromes (HR-MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real-life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24-month median survival observed with azacitidine in the landmark AZA-001 trial has not been replicated in population-based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR-MDS is significantly lower than what was observed in the AZA-001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front-line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR-MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider-scale enrollment in front-line HR-MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017. © 2017 American Cancer Society.

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Health care disparities among octogenarians and nonagenarians with stage II and III rectal cancer

BACKGROUND

Octogenarians and nonagenarians with stage II/III rectal adenocarcinomas are underrepresented in the randomized trials that have established the standard-of-care therapy of preoperative chemoradiation followed by definitive resection (ie, chemoradiation and then surgery [CRT+S]). The purpose of this study was to evaluate the impact of therapies on overall survival (OS) for patients with stage II/III rectal cancers and determine predictors of therapy within the National Cancer Data Base (NCDB).

METHODS

In the NCDB, patients who were 80 years old or older and had clinical stage II/III rectal adenocarcinoma from 2004 to 2013 were queried. Kaplan-Meier analysis, log-rank testing, logistic regression, Cox proportional hazards regression, interaction effect testing, and propensity score–matched analysis were conducted.

RESULTS

The criteria were met by 2723 patients: 14.9% received no treatment, 29.7% had surgery alone, 5.0% underwent short-course radiation and then surgery (RT+S), 45.3% underwent CRT+S, and 5.1% underwent surgery and then chemoradiation (S+CRT). African American race and residence in a less educated county were associated with not receiving treatment. Male sex, older age, worsening comorbidities, and receiving no treatment or undergoing surgery alone were associated with worse OS. There was no statistical difference in OS between RT+S, S+CRT, and CRT+S. Interaction testing found that CRT+S improved OS independently of age, comorbidity status, sex, race, and tumor stage. In the propensity score–matched analysis, CRT+S was associated with improved OS in comparison with surgery alone.

CONCLUSIONS

A significant portion of octogenarians and nonagenarians with stage II/III rectal adenocarcinomas do not receive treatment. African American race and living in a less educated community are associated with not receiving therapy. This series suggests that CRT+S is a reasonable strategy for elderly patients who can tolerate therapy. Cancer 2017. © 2017 American Cancer Society.

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Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) in pediatric and young adult patients: Results from a prospective study using limited-margin radiotherapy

BACKGROUND

Indications for and delivery of adjuvant therapies for pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) have been derived largely from adult studies; therefore, significant concern remains regarding radiation exposure to normal tissue. The authors report long-term treatment outcomes and toxicities for pediatric and young adult patients with high-grade NRSTS who were treated on a prospective trial using limited-margin radiotherapy.

METHODS

Sixty-two patients (ages 3-22 years) with predominantly high-grade NRSTS requiring radiation were treated on a phase 2 institutional study of conformal external-beam radiotherapy and/or brachytherapy using a 1.5-cm to 2-cm anatomically constrained margin. The estimated cumulative incidence of local failure, Gray's method estimated cumulative incidence of local failure, Kaplan-Meier method estimated survival, competing-risk regression model determined predictors of disease outcome, and toxicity was reported according to CTCAE v2.0.

RESULTS

At a median follow-up of 5.1 years (range, 0.2-10.9 years), 9 patients had experienced local failure. The 5-year overall cumulative incidence of local failure was 14.8% (95% confidence interval [CI], 7.2%-25%), and all but 1 local failure occurred outside the highest-dose irradiation volume. The 5-year Kaplan-Meier estimates for event-free and overall survival were 49.3% (95% CI, 36.3%-61.1%) and 67.9% (95% CI, 54.2%-78.3%), respectively. Multivariable analysis indicated that younger age was the only independent predictor of local recurrence (P = .004). The 5-year cumulative incidence of grade 3 or 4 late toxicity was 15% (95% CI, 7.2%-25.3%).

CONCLUSIONS

The delivery of limited-margin radiotherapy using conformal external-beam radiotherapy or brachytherapy provides a high rate of local tumor control without an increase in marginal failures and with acceptable treatment-related morbidity. Cancer 2017. © 2017 American Cancer Society.

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Contribution of solid organ transplant recipients to the pediatric non-hodgkin lymphoma burden in the United States

BACKGROUND

Pediatric solid organ transplant recipients have a 100 to 200 times higher risk of non-Hodgkin lymphoma (NHL) than the general pediatric population. Consequently, transplant-related NHL may contribute considerably to the pediatric NHL burden in the United States.

METHODS

A cohort study using a linkage between the US transplant registry and 16 cancer registries was conducted. Cancer incidence rates were calculated for people less than 20 years old in the transplant and general populations. Rates were applied to transplant registry and US census data to estimate pediatric NHL counts for transplant recipients and the general population.

RESULTS

During 1990-2012, an estimated 22,270 NHLs were diagnosed in US children and adolescents; they included 628 cases diagnosed in transplant recipients. Thus, 2.82% of pediatric NHL diagnoses in the general population (95% confidence interval [CI], 2.45%-3.19%) occurred in transplant recipients. Among transplant recipients, the most common subtypes were diffuse large B-cell lymphoma (DLBCL; 64.5% of cases) and Burkitt lymphoma (BL; 8.6%). For DLBCL and BL, transplant recipients contributed 7.62% (95% CI, 6.35%-8.88%) and 0.87% (95% CI, 0.51%-1.23%) of diagnoses, respectively. The proportion of NHLs that occurred in transplant recipients was highest among children less than 5 years old (4.46%; 95% CI, 3.24%-5.69%) and in more recent calendar years (3.73% in 2010-2012; 95% CI, 2.07%-5.39%). DLBCL patterns were similar, with transplant recipients contributing 19.78% of cases among children less than 5 years old (95% CI, 12.89%-26.66%) and 11.4% of cases in 2010-2012 (95% CI, 5.54%-17.28%).

CONCLUSIONS

Among children and adolescents, solid organ transplant recipients contribute a substantial fraction of NHL diagnoses, particularly DLBCL diagnoses. This fraction has increased over time. Prevention efforts targeted toward this group could reduce the overall pediatric NHL burden. Cancer 2017. © 2017 American Cancer Society.

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miR-151a induces partial EMT by regulating E-cadherin in NSCLC cells

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MeCP2, a target of miR-638, facilitates gastric cancer cell proliferation through activation of the MEK1/2–ERK1/2 signaling pathway by upregulating GIT1

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ASCT2 regulates glutamine uptake and cell growth in endometrial carcinoma

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MALT1 promotes melanoma progression through JNK/c-Jun signaling

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Patients with established cancer cachexia lack the motivation and self-efficacy to undertake regular structured exercise

Abstract

Objectives

Patients with advanced cancer frequently suffer a decline in activities associated with involuntary loss of weight and muscle mass (cachexia). This can profoundly affect function and quality of life. Although exercise participation can maintain physical and psychological function in patients with cancer, uptake is low in cachectic patients who are underrepresented in exercise studies. To understand how such patients' experiences are associated with exercise participation we investigated exercise history, self-confidence and exercise motivations in patients with established cancer cachexia, and relationships between relevant variables.

Methods

Lung and gastrointestinal cancer outpatients with established cancer cachexia (n=196) completed a questionnaire exploring exercise history and key constructs of the Theory of Planned Behaviour relating to perceived control, psychological adjustment and motivational attitudes.

Results

Patients reported low physical activity levels and few undertook regular structured exercise. Exercise self-efficacy was very low with concerns it could worsen symptoms and cause harm. Patients showed poor perceived control and a strong need for approval but received little advice from healthcare professionals. Preferences were for low intensity activities, on their own, in the home setting. Regression analysis revealed no significant factors related to the independent variables.

Conclusions

Frequently employed higher intensity, group exercise models do not address the motivational and behavioural concerns of cachectic cancer patients in this study. Developing exercise interventions which match perceived abilities and skills are required to address challenges of self-efficacy and perceived control identified. Greater engagement of health professionals with this group is required to explore potential benefits of exercise.

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KIAA1522 overexpression promotes tumorigenicity and metastasis of esophageal cancer cells through potentiating the ERK activity

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Volumetric modulated arc therapy for treatment of solid tumors: current insights

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Incidence and 5-year survival rate for head and neck cancers in Grenada compared to the African American population over the period 1991–2010

Abstract

Very little data exist on the incidence and burden of cancer in the individual Caribbean countries. Some data are available for larger areas, reported under a bigger geographical region; Latin America and the Caribbean, but many of the individual countries are not included. One of the main reasons is a lack of official cancer registries. Data are usually collected from hospital records or private physician records, and since it is not in an official registry, these data are not always accessible for inclusion in databases such as SEER and GLOBOCAN. Grenada is one of the countries that currently does not have a registry. Our aim is to report on the incidence for head and neck cancer with subcategories; hypopharynx, oropharynx, oral cavity, salivary glands, and larynx from data collected by the sole ear nose and throat specialist over a 20-year period. The age adjusted incidence per 100,000 for these cancers, whether combined or individually, is lower than that of similar populations. The incidence in males is only slightly higher than those reported in some parts of Africa. In females, only Eastern Africa is reported to have a lower incidence than that found in our study. While the incidence of oral cancers is lower than that of African Americans, the survival rate is comparable. Socioeconomic status, lack of infrastructure, and advanced stage at diagnosis appear to be closely related to the survival rate. Incidence reports suggest that incidence of head and neck cancers in individuals of African descent is lower than other populations. It is therefore not surprising that the incidence in Grenada is relatively low, although the incidence may be underestimated.

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Conception and Management of a Poorly Understood Spectrum of Dermatologic Neoplasms: Atypical Fibroxanthoma, Pleomorphic Dermal Sarcoma, and Undifferentiated Pleomorphic Sarcoma

Opinion Statement

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) tumors share many clinical, etiologic, and histologic features and likely represent components of a tumor spectrum. In dermatologic oncology, differentiating between AFX and PDS is pivotal as tumors with histological features consistent with PDS are more likely to behave in a clinically aggressive manner. Importantly, the term "pleomorphic dermal sarcoma" (PDS) is a more appropriate designation than "undifferentiated pleomorphic sarcoma" (UPS) for describing deeper, more aggressive, histologically high-grade cutaneous tumors that otherwise resemble AFX. Surgery remains the gold standard for treatment. In the setting of AFX, excision with the Mohs micrographic technique appears to offer superior tumor control rates while maintaining greater tissue preservation over wide local excision and should be considered first line. In the setting of PDS, optimal management is less clear given the paucity of available data. However, due to its greater propensity to recur and metastasize, extirpation with complete tumor margin control appears paramount. The roles of imaging and SLNB in management and clinical outcomes of AFX and PDS are unclear given the lack of available data. In reality, these tools are unlikely to be helpful in most cases of AFX. However, in the setting of PDS, emerging literature indicates that these tumors are inherently higher risk, and thus, imaging and SLNB may be helpful in select cases. Additionally, radiation therapy may be of adjuvant benefit for these tumors when clear surgical margins cannot be obtained. While traditional chemotherapy has been largely ineffectual, the recent discovery of key oncogenetic mutations has allowed for the identification of several potential molecular drug targets that may have a therapeutic role with future study. In the unfortunate setting of metastatic disease, a multidisciplinary approach is optimal. Further studies are needed to establish definitive conclusions regarding risk stratification and best management practices.

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Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

Abstract

Purpose

Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification.

Materials and methods

A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients.

Results

Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations.

Conclusion

The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.

http://ift.tt/2vkTcFt

MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8+ T cells through targeting mTOR

Abstract

MiR-15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor-infiltrating immune cells. In this study, using an orthotropic GL261 mouse glioma model, we found that miR-15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor-infiltrating CD8+ T cells. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells. Also, our in vitro experiments further confirmed that miR-15a/16^-/- CD8+ T displayed higher active phenotypes, more cytokines secretion and faster expansion, compared with WT CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR-15a/16 to negatively regulate the activation of CD8+ T cells. Taken together, these data suggest that miR-15a/16 deficiency resists the exhaustion and maintains the activation of glioma-infiltrating CD8+ T cells to alleviate glioma progression via targeting mTOR. Our findings provide evidence for the potential immunotherapy through targeting miR-15a/16 in tumor-infiltrating immune cells. This article is protected by copyright. All rights reserved.

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Prognostic role of ABO blood type in patients with extranodal natural killer/T cell lymphoma, nasal type: a triple-center study

The prognostic significance of ABO blood type for lymphoma is largely unknown. We evaluated the prognostic role of ABO blood type in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL).

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Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells

The mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer (CRC) is limited. Synthe...

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Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocations: Clinical Characteristics and Management in a Real-Life Setting: a French Retrospective Analysis (GFPC 02–14 Study)

Abstract

Background

Chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK) are rare oncogenic events found in 3–5% of non-small-cell lung cancers (NSCLC). Limited data have been published on the management of these patients outside clinical trials.

Objective

To investigate the clinical characteristics and management of patients with NSCLC harboring ALK translocations (ALK+) in a real-life setting in France.

Methods

This multicenter, observational, retrospective study included all NSCLC patients harboring ALK translocations diagnosed in participating centers between January 2012 and December 2014. Patient data include clinical characteristics, disease management, and outcomes [progression-free survival (PFS) and overall survival (OS)].

Results

The 31 participating centers reported data on 132 patients, of whom 51% (n = 67) were male. The median age was 60.1 ± 14.5 (standard deviation) years; 89% (n = 106/119) had performance status 0/1 at diagnosis; 79% (n = 103/130) were non- or former smokers; 93% (n = 120/129) had adenocarcinomas and 74%(n = 97)/19%(n = 25)/7%(n = 10) had disease stages IV/III/I-II at diagnosis, respectively; co-mutations included EGFR (n = 2), BRAF (n  = 2), KRAS (n = 1), and HER2 (n = 1). Of the patients with stage IV NSCLC (n = 97), 96% received first-line treatment [75% chemotherapy-based, 21% ALK tyrosine kinase inhibitor (TKI)], with an associated response rate (RR), disease-control rate (DCR), and PFS of 42%, 64%, and 7.5 [95% confidence interval (CI) 5.9–9.5] months, respectively; 62% received second-line treatment (28% chemotherapy, 72% ALK TKI) with an associated RR, DCR, and PFS of 43.4%, 70%, and 4.7 (95% CI 4.0–8.1) months, respectively. The 2-year OS was 56.7% (95% CI 45.5–70.4%); median OS was not reached.

Conclusion

The results of this real-life analysis suggest that the prognosis of NSCLC patients with theALK translocation may be better than that of the overall NSCLC population, but the outcomes were poorer than those of ALK+ NSCLC patients included in clinical studies.

http://ift.tt/2uQbWJJ

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Abstract

After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

http://ift.tt/2tW19AE

Nutritional Risk Factors in the Pathogenesis of Parenteral Nutrition-Associated Liver Disease

Abstract

Purpose of Review

Parenteral nutrition has been a lifesaving therapy for individuals who cannot sustain adequate oral or enteral nutrient intake to maintain fluid, electrolyte, and nutrient balance. Nonetheless, parenteral nutrition can lead to an increased risk of complications, such as parenteral nutrition-associated liver disease (PNALD). The pathogenesis of PNALD has been associated with multiple risk factors, such as longer duration, reduced small bowel length, decreased enteral intake, and bacterial infections. Nutritional risk factors also play an important role in the development of PNALD. This review presents several nutrient deficiencies and excesses that have been associated with PNALD.

Recent Findings

Deficiencies in certain nutrients (amino acids, essential fatty acids, enteral intake), excesses of certain nutrients (calories, carbohydrates, lipids), types of lipid emulsions, and mineral toxicities (aluminum, copper, manganese) have been associated with PNALD. Strategies to address PNALD require correction of these risk factors. The use of newer mixed lipid emulsions (including soybean, medium-chain triglycerides, olive oil, and fish oil) may also have less hepatotoxicity than traditional soybean oil-based lipid emulsions.

Summary

Knowledge of nutritional risk factors for PNALD will help the clinician in the systematic evaluation and treatment of these specific risk factors. Moreover, an understanding of their effects guides the balance between addressing the patient's nutritional needs and reducing the risk of PNALD.

http://ift.tt/2hfhCtB

Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

Abstract

Purpose

Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification.

Materials and methods

A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients.

Results

Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations.

Conclusion

The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.

http://ift.tt/2vkTcFt

Considerations in T Cell Therapy Product Development for B Cell Leukemia and Lymphoma Immunotherapy

Abstract

Based on laboratory and clinical research findings and investments in immunotherapy by many institutions in academia, government-funded laboratories, and industry, there is tremendous and deserved excitement in the field of cell and gene therapy. In particular, understanding of immune-mediated control of cancer has created opportunities to develop new forms of therapies based on engineered T cells. Unlike conventional drugs or biologics, the source material for these new therapies is collected from the patient or donor. The next step is commonly either enrichment to deplete unwanted cells, or methods to positively select T cells prior to polyclonal expansion or antigen-specific expansion. As the first generation of engineered T cell therapies have demonstrated proof of concept, the next stages of development will require the integration of automated technologies to enable more consistent manufacturing and the ability to produce therapies for more patients.

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The oral microbiota in patients with pancreatic cancer, patients with IPMNs, and controls: a pilot study

Abstract

Purpose

Poor oral health appears to be a risk factor for pancreatic cancer, possibly implicating the oral microbiota. In this pilot study, we evaluated the characteristics of the oral microbiota in patients with pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasms (IPMN), and healthy controls.

Methods

Forty newly diagnosed PDAC patients, 39 IPMN patients, and 58 controls, excluding current smokers and users of antibiotics, provided saliva samples. Common oral bacterial species were comprehensively surveyed by sequencing of the 16S rRNA microbial genes. We obtained measures of diversity and the mean relative proportions of individual taxa. We explored the degree to which these measures differed according to respondent characteristics based on individual interviews.

Results

PDAC cases did not differ in diversity measures from either controls or IPMN cases. PDAC cases had higher mean relative proportions of Firmicutes and related taxa, while controls had higher mean relative proportions of Proteobacteria and related taxa. Results were generally similar when comparing PDAC to IPMN cases. Among IPMNs and controls combined, younger individuals had higher levels of several taxa within the Proteobacteria. The only other variable consistently related to mean relative proportions was mouthwash use, with taxa within Firmicutes more common among users.

Conclusions

While there were no differences in diversity of the oral microbiota among these groups, there were differences in the mean relative proportions of some taxa. Characteristics of the oral microbiota are not associated with most measures of oral health.

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