Does radiotherapy prior to surgery improve long term prognosis in pediatric colorectal cancer in lower- and upper-middle income countries with limited resources? Our experience and literature review

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Yacoob Omar Carrim, Luvo Gaxa, Francisca van der Schyff, Nndweleni Meshack Bida, Fareed Omar, Zarina Lockhat
Colorectal carcinoma in children and adolescents is extremely rare, with an annual incidence <0.3 cases per million, most frequently reported in the second decade of life. It accounts for severe morbidity and poor prognosis owing to the low index of suspicion, delayed diagnosis, advanced stage at presentation and the aggressive tumor nature. Patients present with abdominal pain, vomiting, constipation, abdominal distension, rectal tenesmus, iron-deficiency anemia, change in bowel habit and weight loss. Rectal bleeding is an uncommon presentation in children. Bowel obstruction presents frequently in children compared to adults. In 90% of pediatric cases, colorectal carcinoma occurs sporadically. In 10%, predisposing conditions and syndromes are identified. We present a case study of a 12-year-old female with advanced colorectal cancer without a predisposing disease or syndrome, who received radio-chemotherapy ten weeks prior to radical abdominopelvic surgery, followed by radio-chemotherapy postoperatively, with a positive outcome.



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Downregulation of Caspase 8 in a group of Iranian breast cancer patients – A pilot study

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Masoumeh Aghababazadeh, Najmeh Dorraki, Fahimeh Afzal Javan, Asieh Sadat Fattahi, Masoumeh Gharib, Alireza Pasdar
PurposeIt is now well known that evading apoptosis, as a cancer hallmark, can lead to tumour initiation, progression and metastasis. As a result of genome wide association studies, an initiator protease in this pathway, caspase 8 (CASP8), has been found to be an important gene regarding breast cancer susceptibility. The alterations of the expression of this gene have been reported in breast cancer cell lines. Given that in previous studies expression analysis of this gene had only been done in breast cancer cell lines, in this study we aimed to evaluate the expression of this gene in breast cancer tissues versus adjacent normal tissues, using real-time quantitative method.MethodsCaspase 8 mRNA expression was quantified using comparative RT-qPCR in 27 fresh frozen breast tumours and 27 adjacent normal tissues. Moreover, relationship between the expression changes of CASP8 in tumour tissue and various clinical and pathological features were evaluated in an Iranian population.ResultsThe present study showed that expression of CASP8 was significantly reduced in tumour tissues compared to neighbouring normal tissues (p = .004). CASP8 expression was significantly correlated with the status of hormone receptors (ER and PR).ConclusionTo the best of our knowledge, this study is the first report on reduced expression of CASP8 in breast cancer versus adjacent normal tissues. Our data support previous results obtained from cell lines and therefore highlights the seminal role of the induction of CASP8 expression, as a novel therapeutic approach, in order to sensitize tumour cells to apoptotic stimuli.



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Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Pragya Singh, Sachin Kolte, Gunjesh Kumar Singh
Transitional cell carcinoma (TCC) arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay.



http://ift.tt/2AYlWpH

Does radiotherapy prior to surgery improve long term prognosis in pediatric colorectal cancer in lower- and upper-middle income countries with limited resources? Our experience and literature review

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Yacoob Omar Carrim, Luvo Gaxa, Francisca van der Schyff, Nndweleni Meshack Bida, Fareed Omar, Zarina Lockhat
Colorectal carcinoma in children and adolescents is extremely rare, with an annual incidence <0.3 cases per million, most frequently reported in the second decade of life. It accounts for severe morbidity and poor prognosis owing to the low index of suspicion, delayed diagnosis, advanced stage at presentation and the aggressive tumor nature. Patients present with abdominal pain, vomiting, constipation, abdominal distension, rectal tenesmus, iron-deficiency anemia, change in bowel habit and weight loss. Rectal bleeding is an uncommon presentation in children. Bowel obstruction presents frequently in children compared to adults. In 90% of pediatric cases, colorectal carcinoma occurs sporadically. In 10%, predisposing conditions and syndromes are identified. We present a case study of a 12-year-old female with advanced colorectal cancer without a predisposing disease or syndrome, who received radio-chemotherapy ten weeks prior to radical abdominopelvic surgery, followed by radio-chemotherapy postoperatively, with a positive outcome.



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Downregulation of Caspase 8 in a group of Iranian breast cancer patients – A pilot study

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Masoumeh Aghababazadeh, Najmeh Dorraki, Fahimeh Afzal Javan, Asieh Sadat Fattahi, Masoumeh Gharib, Alireza Pasdar
PurposeIt is now well known that evading apoptosis, as a cancer hallmark, can lead to tumour initiation, progression and metastasis. As a result of genome wide association studies, an initiator protease in this pathway, caspase 8 (CASP8), has been found to be an important gene regarding breast cancer susceptibility. The alterations of the expression of this gene have been reported in breast cancer cell lines. Given that in previous studies expression analysis of this gene had only been done in breast cancer cell lines, in this study we aimed to evaluate the expression of this gene in breast cancer tissues versus adjacent normal tissues, using real-time quantitative method.MethodsCaspase 8 mRNA expression was quantified using comparative RT-qPCR in 27 fresh frozen breast tumours and 27 adjacent normal tissues. Moreover, relationship between the expression changes of CASP8 in tumour tissue and various clinical and pathological features were evaluated in an Iranian population.ResultsThe present study showed that expression of CASP8 was significantly reduced in tumour tissues compared to neighbouring normal tissues (p = .004). CASP8 expression was significantly correlated with the status of hormone receptors (ER and PR).ConclusionTo the best of our knowledge, this study is the first report on reduced expression of CASP8 in breast cancer versus adjacent normal tissues. Our data support previous results obtained from cell lines and therefore highlights the seminal role of the induction of CASP8 expression, as a novel therapeutic approach, in order to sensitize tumour cells to apoptotic stimuli.



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Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis

Publication date: Available online 7 December 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Pragya Singh, Sachin Kolte, Gunjesh Kumar Singh
Transitional cell carcinoma (TCC) arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay.



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Comments on “Solid pseudopapillary neoplasm of the pancreas: Management and long-term outcome”

Publication date: Available online 7 December 2017
Source:European Journal of Surgical Oncology
Author(s): Xing Wang, Xubao Liu




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Reply letter to: Comments on "Solid pseudopapillary neoplasm of the pancreas: Management and long-term outcome"

Publication date: Available online 7 December 2017
Source:European Journal of Surgical Oncology
Author(s): Nir Lubezky




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Trastuzumab emtansine: determining its role in management of HER2+ breast cancer

Future Oncology, Ahead of Print.


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Biography—Q. Ping Dou

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Trastuzumab emtansine: determining its role in management of HER2+ breast cancer

Future Oncology, Ahead of Print.


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Dengue hemorrhagic fever complicated with acute liver failure: a case report

Dengue is a common arboviral infection with a clinically diverse spectrum of presentations. Although hepatic dysfunction is commonly identified in patients will dengue illness, acute liver failure is rare. The...

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Clinical examination and X-ray: an old approach to a current problem

Description

Ingesting a foreign body is not an uncommon occurrence. Most pass through the gastrointestinal tract uneventfully, and perforation is rare.1 The preoperative diagnosis, in these cases, is always very difficult and the radiological examinations are not always able to resolve the diagnostic. The mortality and the morbidity remain still high first of all for the delay in the diagnosis and the advanced age of patients.2

A 50-year-old man without relevant medical history was admitted to the emergency department with 4 days evolution of abdominal pain. The patient presented continuous abdominal pain at the left lower quadrant. There was no nausea, vomiting, alterations of bowel habits or fever.

On examination, the patient was in painful distress. Vital signs revealed tachycardia at 110 bpm, blood pressure of 120/64 mm Hg but no fever (36.8°C). Abdominal examination revealed diffuse tenderness and pain more intense at the left lower abdomen,...

http://ift.tt/2BW92X9

Necrotising pneumonia caused by non-PVL Staphylococcus aureus with 2-year follow-up

Necrotising pneumonia (NP) is a rare but life-threatening complication of pulmonary infection. It is characterised by progressive necrosis of lung parenchyma with cavitating foci evident upon radiological investigation. This article reports the case of a 52-year-old woman, immunocompetent healthcare professional presenting to Accident and Emergency with NP and Staphylococcus aureus septicaemia. The cavitating lesion was not identified on initial chest X-ray leading to a delay in antimicrobial optimisation. However, the patient went on to achieve a full symptomatic recovery in 1 month and complete radiological recovery at 2-year follow-up. Long-term prognosis for adult cases of NP currently remains undocumented. This case serves as the first piece of published evidence documenting full physiological and radiological recovery following appropriate treatment of NP in an immunocompetent adult patient.

http://ift.tt/2k96bSE

Interhemispheric subdural and subarachnoid haemorrhage in a patient with amphetamine-induced vasculitis

Description

A 27-year-old woman with a history of pulmonary embolism presented with confusion and depressed arousal after a night of alcohol and drug use. On examination, she was found to have lack of motivation and right leg weakness but had no other significant neurological findings. Trauma survey did not detect any signs of injury. CT scan of the head revealed interhemispheric subdural and subarachnoid haemorrhage with the highest volume in left frontoparietal region (figure 1). Urine toxicology showed presence of tetrahydrocannabinol and amphetamines. CT angiography demonstrated a small, incidental left supraclinoid internal carotid artery aneurysm but no other significant findings (figure 1). MRI was remarkable only for the haemorrhage and MR venogram confirmed patent venous sinuses (figure 1). Given the patient's history of drug use and the presence of amphetamines in her urine, conventional cerebral angiography was obtained to evaluate for vasculopathy. Cerebral...

http://ift.tt/2BTQypY

Fat embolism: a rare cause of perioperative renal transplant dysfunction

Fat embolism is a recognised complication of bony injury and orthopaedic surgery, commonly involving the long bones and pelvis. We report on the case of a 68-year-old renal transplant recipient who developed acute kidney injury following surgical stabilisation of metastatic carcinoma of the acetabulum and replacement of the proximal femur. A CT renal angiogram demonstrated a large fat embolus in the inferior vena cava (IVC) and left iliac veins below the level of IVC filter, with impaired renal perfusion. The risks of open or endovascular lipothrombectomy were felt to outweigh the potential benefits. The patient was managed with systemic anticoagulation and prepared for transplant failure. Subsequently, there was spontaneous improvement in urine output and 4 months postoperatively her transplant function had returned to her baseline level and this has remained stable at 1 year postsurgery.

http://ift.tt/2kcnLF0

An uncommon diagnosis for a recurrent erythematous patch in a paediatric patient

A 14-year-old girl presented with a circular erythematous patch over the left buttock for approximately 10 years, with ongoing ulceration and papules developing over the last 4 years. Punch biopsies were taken within and above the patch for diagnosis. Both revealed marked inflammatory infiltrates with atypical, irregular lymphocytes and increased mitosis. Immunostaining revealed CD8 positivity and a pan T helper cell phenotype. T cell receptor gene rearrangement analysis showed T cell clonality in both biopsies. These findings were consistent with mycosisfungoides and associated lymphomatoid papulosis. Both are rare conditions but have been associated in 5%–20% of cases. A definitive association has not yet been established; however, T cell monoclonality shows 50%–60% share a common origin. Management options are extensive with no one treatment showing superiority. Our patient received low-dose radiotherapy with good outcomes, but subsequently required further radiotherapy.

http://ift.tt/2k9649G

Development of forced normalisation psychosis with ethosuximide

A 50-year-old man with known multidrug resistant coexistent focal and generalised epilepsy was commenced on ethosuximide, with normalisation of his electroencephalogram and cessation of absence seizures. Within 3 weeks, he developed a rapidly worsening paranoid psychosis with visual and olfactory hallucinations. A month after the cessation of ethosuximide and concurrent treatment with olanzapine, his psychosis resolved and permitted reinitiation of ethosuximide at a lower dose without recurrence of psychotic symptoms.

http://ift.tt/2jty7AO

Pleural lipoma clinically mimicking the presentation of superior sulcus tumour upon initial evaluation

Here we present a case of a large pleural lipoma which presented with paresthesias of the hand. This is an unusual presentation of an uncommon tumour.

http://ift.tt/2BXLa5x

Pulmonary embolism caused by thrombin-based haemostatic matrix

Description

A 38-year-old woman underwent an outpatient L5/S1 discectomy. The procedure was complicated by intraoperative bleeding, and haemostasis was achieved using a thrombin-based haemostatic matrix (TBHM). She presented to our facility on postoperative day 5 with left-sided chest pain and dyspnoea. CT pulmonary angiography (CTPA) showed a heterogeneous filling defect with mixed attenuation and a 'pseudoair pattern' in the left main pulmonary artery (figure 1). Duplex ultrasound of the upper and lower extremities was negative for venous thrombus. An echocardiogram was normal. Pulmonary angiography showed occlusion of the basal branches of the left pulmonary artery (figure 2). Therapeutic anticoagulation with unfractionated heparin was started, and the patient was discharged home on warfarin. Repeat CT angiography 6 months later revealed no filling defect in the pulmonary arteries.

Figure 1

CT chest with contrast demonstrating the 'pseudoair' filling defect (arrow) in the left main pulmonary...

http://ift.tt/2k8tU5b

Acute pancreatitis following oesophagogastroduodenoscopy.

Acute pancreatitis is a well-recognised complication of endoscopic procedures like endoscopic retrograde cholangiopancreatography but not oesophagogastroduodenoscopy (OGD). I report a case of a 33-year-old woman, admitted with severe epigastric pain and vomiting 2 hours after an elective OGD for evaluation of chronic gastrointestinal symptoms. Pancreatitis was diagnosed on the basis of elevated lipase (40 790 U/L; normal 11–82) and findings on imaging studies. Other common causes of acute pancreatitis such as gallstones, alcohol and medications were ruled out. She had an extended hospital course because of severe disease, characterised by systemic inflammatory response syndrome, pleural effusion and ascites but was successfully managed conservatively with bowel rest, hydration and pain management. Acute pancreatitis should be considered a rare complication of OGD and should be considered in differential diagnosis for abdominal pain post OGD. Pathogenesis is likely from direct trauma to pancreas or gas insufflation.

http://ift.tt/2BW9Mvp

Hypersomatotropism induced secondary polycythaemia leading to spontaneous pituitary apoplexy resulting in cure of acromegaly and remission of polycythaemia: 'The virtuous circle

A young man with subtle clinical features suggestive of hypersomatotropism presented with acute-onset severe headache. Relevant investigations confirmed polycythaemia and growth hormone (GH)-secreting pituitary macroadenoma with apoplexy. Secondary polycythaemia and myeloproliferative disorders were ruled out. At follow-up after 3 months, resolution of polycythaemia and acromegaly was observed, evident on normal haemoglobin levels, a normocellular marrow, and normal insulin-like growth factor-1 (IGF-1) with glucose-suppressed GH levels. Direct mitogenic properties of GH-IGF-1 axis on bone marrow progenitor cells may very rarely lead to erythroid hyperplasia and subsequent polycythaemia, reversible with successful therapy of acromegaly. In this case, polycythaemia secondary to hypersomatotropism likely resulted in pituitary apoplexy with subsequent remission of both acromegaly and resultant polycythaemia.

http://ift.tt/2kaLaa5

Double duodenal perforation following foreign body ingestion

Intentional ingestion of a foreign body in adults is a rare clinical presentation. This case is one of a 27-year-old Sudanese man who presented having swallowed a ballpoint pen intentionally. Clinical examination and plain chest radiograph exhibited no signs indicative of perforation with only a raised C reactive protein identified on blood tests. Subsequent gastroscopy revealed that the pen had simultaneously perforated the duodenum at both D1 and D3 requiring removal via a laparotomy. The patient fully recovered and was discharged 2 weeks postoperatively following psychiatric input.

http://ift.tt/2k9NNZN

Novel use of a trabecular metal spacer in the treatment of a long-standing ulnar fracture non-union

The use of trabecular metal (TM) implants in spine and joint surgery is well documented. However, their use has yet to be reported as an alternative to either allograft or autograft in the management of fracture non-unions. We present our experience in using a TM implant for treating a patient with a long-standing ulnar fracture non-union. Excision of devitalised bone resulted in a 17 mm defect which the TM implant was used to infill. The defect was then bridged with a locking plate. At 2-year clinical and radiographic review, bony union and a pain-free return to full function was noted. In this case, the use of a TM implant avoided the morbidity associated with an iliac crest autograft.

http://ift.tt/2BW9vZp

One long umbilical cord, four nuchal cord loops and a true knot

Description

A 43-year-old woman G4 P2101 at 36 weeks of gestation presented to the labour floor with non-reactive fetal heart tracing and decreased fetal movement. She had a second-trimester ultrasound showing intrauterine growth retardation (IUGR). Patient had a history of hypothyroidism, two fetal demises at term and a planned preterm delivery at 34 weeks of gestation via caesarean section. Workup was negative for thrombophilia (lupus anticoagulant, anticardiolipin, anti-b2-glycoprotein, factor V Leiden, protein S, protein C, G20210 mutation, antithrombin III, antinuclear antibodies) and infectious diseases. Placental pathology following her second fetal demise revealed chorioamnionitis and necrotising funisitis with negative amniotic fluid cultures. There was no information regarding umbilical cord (UC) length or entanglements in previous pregnancies.

Given her history and the current non-reactive fetal heart tracing, the patient was taken for emergency caesarean delivery. A female infant was born with four loops of nuchal cord and a true knot (

http://ift.tt/2k9NEFJ

Catastrophic catheter-induced coronary artery vasospasm successfully rescued using intravascular ultrasound imaging guidance

A 46-year-old man underwent coronary angiography for stable angina. He developed inferior ST-segment myocardial infarction during the angiography. Intravascular ultrasound (IVUS) findings suggested coronary vasospasm. Intracoronary administration of isosorbide dinitrate restored the coronary flow. This case illustrates the essential role IVUS imaging played in establishing the diagnosis of catheter-induced coronary vasospasm.

http://ift.tt/2BUqNWR

Treating patients with brain metastases has evolved: scalp-sparing, hippocampal avoidance whole brain radiotherapy with simultaneous integrated boost

Description

A 43-year-old male with a history of receiving treatment for squamous cell carcinoma (SqCC) of lung 2 years back presented with a complaint of a single episode of self-resolving generalised tonic–clonic seizure 1 day prior. General physical and neurological examinations were unremarkable. An MRI of the brain revealed a well-defined, enhancing, space-occupying lesion (SOL) in the right temporal lobe (figure 1). He was started on oral dexamethasone, oral phenytoin (after an intravenous loading dose) and underwent a whole body ¹⁸flourodeoxyglucose positron emission tomography CT (¹⁸FDG PET-CT), which revealed increased FDG uptake in the SOL without evidence of metastatic disease elsewhere (figure 1). A diagnosis of oligometastatic SqCC lung (cTx, cNx and cM1b) was made, and the options for management were discussed with the patient.

Figure 1

Pretreatment MRI and positron emission tomography   CT (PET-CT) images. (A) T1-weighted contrast-enhanced axial image reveals a well-defined space occupying lesion in...

http://ift.tt/2k9NuhB

Lingual dyskinesia in hyperthyroidism

Description

A 28-year-old female presented to the hospital with a 3-month history of palpitation, weight loss and neck swelling. On examination, she had diffuse soft goitre, warm extremities and fine tremors of hands. In addition, she had an irregular jerky lingual and lip movements suggestive of dyskinesia (see online ). There were no signs of infiltrative ophthalmopathy or dermopathy. Neurological examination was otherwise unremarkable. A clinical diagnosis of Graves' disease was made that was biochemically confirmed by elevated T3 and T4 with suppressed tyroid stimulating hormone  (TSH) as well as diffuse increased uptake of technetium in nuclear imaging. Unlike lingual tremors associated with other neurological conditions or adverse effects of drugs, thyrotoxicosis-associated lingual dyskinesia responds very well to beta blockers.1 After 6 months of follow-up on carbimazole and propranolol therapy, her thyrotoxicosis improved, and the abnormal tongue movements had disappeared.

Learning points

Thyrotoxicosis...

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Biography—Q. Ping Dou

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Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya

Abstract

Background

Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya.

Methods

294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression.

Results

The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05–8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06–14.19).

Conclusion

This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

http://ift.tt/2j5rNCO

Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya

Abstract

Background

Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya.

Methods

294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression.

Results

The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05–8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06–14.19).

Conclusion

This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

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Can breast cancer patients with HER2 dual-equivocal tumours be managed as HER2-negative disease?

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Yiwei Tong, Xiaosong Chen, Xiaochun Fei, Lin Lin, Jiayi Wu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen
BackgroundIncreasing human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)/fluorescence in situ hybridisation (FISH) dual-equivocal breast tumours are reported after the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline update. The aim of this study is to investigate the clinico-pathologic characteristics, treatment patterns and disease outcome of these patients with HER2 dual-equivocal tumours.Patients and methodsPatients with HER2 IHC 2+ and available FISH results were retrospectively analysed from the Comprehensive Breast Health Center, Shanghai Ruijin Hospital. The 2013 ASCO/CAP guideline was applied to define HER2-positive, dual-equivocal and -negative groups. Patient characteristics, systemic treatment patterns and survival were compared among these groups. Reverse transcriptase-polymerase chain reaction-based assays were applied to test HER2 mRNA expression level.ResultsAmong 691 patients included, 133 (19.25%) were HER2 positive, 25 (3.62%) were HER2 dual-equivocal and 533 (77.13%) were HER2 negative. Univariate and multivariate analyses stated that HER2 dual-equivocal tumours shared more similarity with HER2-negative tumours, whereas HER2-positive tumours had rather different clinico-pathologic features. HER2 dual-equivocal tumours had similar HER2 mRNA levels compared with HER2-negative tumours (P = 0.26), which were much less compared with HER2-positive breast cancer. Besides, adjuvant systemic treatment patterns were comparable between HER2-negative and dual-equivocal tumours, and none of HER2 dual-equivocal patients received anti-HER2 treatment. There was no survival difference among these three groups (P = 0.43).ConclusionHER2 dual-equivocal tumours share more similarity with HER2-negative disease in terms of clinico-pathologic features, HER2 mRNA levels, adjuvant systemic treatment patterns and disease outcome, which deserves further clinical evaluation.



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Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Andreas Schneeweiss, Stephen Chia, Tamas Hickish, Vernon Harvey, Alexandru Eniu, Maeve Waldron-Lynch, Jennifer Eng-Wong, Sarah Kirk, Javier Cortés
BackgroundWe report long-term efficacy and cardiac safety outcomes in patients with HER2-positive early breast cancer treated with neoadjuvant pertuzumab plus trastuzumab with anthracycline-containing or anthracycline-free chemotherapy.MethodsDescriptive efficacy analyses were conducted in patients randomised to group A (cycles 1–6: trastuzumab [8 mg/kg loading dose and 6 mg/kg maintenance] plus pertuzumab [840 mg loading dose and 420 mg maintenance], plus 5-fluorouracil, epirubicin and cyclophosphamide [FEC] [cycles 1–3; 500 mg/m² 5-fluorouracil/100 mg/m² epirubicin/600 mg/m² cyclophosphamide] then docetaxel [cycles 4–6; 75 mg/m², escalated to 100 mg/m² if well tolerated]), B (cycles 1–3: FEC, cycles 4–6: trastuzumab plus pertuzumab plus docetaxel as mentioned previously) or C (cycles 1–6: trastuzumab plus pertuzumab plus docetaxel [75 mg/m², without dose escalation], and carboplatin [AUC 6]), five years after randomisation of the last patient. This study is registered with ClinicalTrials.gov, number NCT00976989.ResultsThree-year Kaplan–Meier survival estimates for disease-free survival (DFS) were 87% (95% confidence interval: 79–95), 88% (80–96) and 90% (82–97) in groups A–C, respectively. Progression-free survival (PFS) rates were 89% (81–96), 89% (81–96) and 87% (80–95). DFS hazard ratio for total pathological complete response (tpCR) versus no tpCR was 0.27 (0.11–0.64). During post-treatment follow-up, 2/72 (2.8%), 3/75 (4.0%) and 4/76 (5.4%) patients in groups A–C had any-grade left ventricular systolic dysfunction; eight (11.1%), 12 (16.0%) and nine (11.8%) patients experienced left ventricular ejection fraction declines ≥10% from baseline to <50%.ConclusionsLong-term DFS and PFS were similar between groups. Patients who achieved tpCR had improved DFS. No new safety signals were identified.



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Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Maeve A. Lowery, David P. Kelsen, Marinela Capanu, Sloane C. Smith, Jonathan W. Lee, Zsofia K. Stadler, Malcolm J. Moore, Hedy L. Kindler, Talia Golan, Amiel Segal, Hannah Maynard, Ellen Hollywood, MaryEllen Moynahan, Erin E. Salo-Mullen, Richard Kinh Gian Do, Alice P. Chen, Kenneth H. Yu, Laura H. Tang, Eileen M. O'Reilly
PurposeBRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC).MethodsPatients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1–2 lines of treatment, Eastern Cooperative Oncology Group 0–2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1–28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety.ResultsSixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43–77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57–1.83) and median OS was 3.1 months (95% CI 1.9–4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1).ConclusionsVeliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195).



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Enlisting the willing: A study of healthcare professional–initiated and opt-in biobanking consent reveals improvement opportunities throughout the registration process

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Elizabeth A. Fradgley, Shu Er Chong, Martine E. Cox, Christine L. Paul, Craig Gedye
Biobanking consent processes should accord with patients' preferences and be offered in a consistent and systematic manner. However, these aims can be difficult to achieve under healthcare professionals' (HCPs) time-constrained workflows, resulting in low participation rates.This current perspective provides a brief overview of HCP involvement in consent and reports new data on participant attrition at each step of the biobanking consent process as experienced by 113 patients at an Australian tertiary cancer centre. To determine attrition in this HCP-driven consent process, we reviewed medical records for the following events: inclusion of biobanking consent forms; visible patient and HCP signatures; consent status selected (decline or accept) and specimen registration with local biobank. Accessible medical records revealed the following data: 75 of 85 records included viewable forms; 22 of 85 records included patient and 19 of 85 included HCP signatures; 15 of 85 records included signed and completed forms and 3 of 85 had samples banked with annotated clinical data. We compared these data with self-reported experiences of being approached to participate by HCPs. Of the 15 participants (17.6%) who successfully completed consent, only five could recall being asked and providing consent.The low enrolment rate is a considerable lost opportunity because most patients (59%) who were not asked to participate indicated they would have consented if asked. Furthermore, in comparing self-reported experiences with medical records, we believe cancer patients' preferences for participation are mismatched with actual biobanking enrolment, which has considerable attrition at each step in the consent process.



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Are pathological high-risk features in locally advanced rectal cancer a useful selection tool for adjuvant chemotherapy?

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Marloes Swets, Peter J.K. Kuppen, Erik J. Blok, Hans Gelderblom, Cornelis J.H. van de Velde, Iris D. Nagtegaal
BackgroundSeveral histological high-risk factors are used as an indication for adjuvant therapy in stage II colon cancer. Those and other factors, including lymphatic invasion, perineural invasion (PNI), venous invasion and tumour budding are associated with decreased outcome. In this study, we evaluated the prognostic and predictive values of these biomarkers in a cohort of rectal cancer patients.Materials and methodsThe trial-based cohort consisted of 221npTNM stage II–III rectal cancer patients, included in the PROCTOR/SCRIPT trial, a multicentre randomised phase III trial. Patients treated with neoadjuvant radiotherapy and TME surgery were randomised between adjuvant chemotherapy or observation. Lymphatic invasion, PNI, extramural venous invasion, intramural venous invasion and tumour budding were determined in standard tissue slides.ResultsThe presence of PNI (HR 3.36; 95% CI 1.82–6.21), extramural vascular invasion (HR 1.93; 95% CI 1.17–3.19) and tumour budding (HR 1.83, 95% CI 1.11–3.03) was associated with a significant worse overall survival. The presence of ≥2 adverse biomarkers resulted in a stronger prediction of adverse outcome in terms of overall survival (HR 2.82; 95% CI 1.66–4.79), disease-free survival (HR 2.27; 95% CI 1.47–3.48), and distant recurrence (HR 2.51; 95% CI 1.56–4.02). None of these markers alone or combined predicted a beneficial effect of adjuvant chemotherapy.DiscussionWe confirmed that several stage-independent biomarkers were significantly associated with a decreased outcome in rectal cancer patients. More importantly, these markers did not have predictive value and are thus not useful to select for adjuvant therapy in rectal cancer.



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Reviewers 2017

Publication date: Available online 7 December 2017
Source:European Journal of Cancer





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Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III

Publication date: Available online 7 December 2017
Source:European Journal of Cancer
Author(s): Jean Jacques Grob, Dirk Schadendorf, Paul Lorigan, Paolo Ascierto, James Larkin, Paul Nathan, Caroline Robert, Axel Hauschild, Jeffrey Weber, Adil Daud, Omid Hamid, Reinhard Dummer, Johan Hansson, Christoph Hoeller, Jacob Schachter, Alexander C.J. Van Akkooi, Claus Garbe




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Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel

Abstract

Background

Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies.

Methods

miR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization. PC cell line (PC3 cell) was transfected with miR-193a-5p mimic or its inhibitor, and then cell apoptosis and the expression of its downstream genes Bach2 and HO-1 were detected by TUNEL staining and Western blotting. Luciferase reporter assay was used to detect the effect of miR-193a-5p and Bach2 on HO-1 expression. Xenograft animal model was used to test the effect of miR-193a-5p and docetaxel on PC3 xenograft growth.

Results

miR-193a-5p was upregulated in PC tissues and PC cell lines, with significant suppression of PC3 cell apoptosis induced by oxidative stress. Mechanistically, miR-193a-5p suppressed the expression of Bach2, a repressor of the HO-1 gene, by directly targeting the Bach2 mRNA 3′-UTR. Docetaxel treatment modestly decreased Bach2 expression and increased HO-1 level in PC3 cells, whereas a modest increase of HO-1 facilitated docetaxel-induced apoptosis. Notably, docetaxel-induced miR-193a-5p upregulation, which in turn inhibits Bach2 expression and thus relieves Bach2 repression of HO-1 expression, partly counteracted docetaxel-induced apoptosis, as evidenced by the increased Bcl-2 and decreased Bax expression. Accordingly, silencing of miR-193a-5p enhanced sensitization of PC3 cells to docetaxel-induced apoptosis. Finally, depletion of miR-193a-5p significantly reduced PC xenograft growth in vivo.

Conclusions

Silencing of miR-193a-5p or blockade of the miR-193a-5p-Bach2-HO-1 pathway may be a novel therapeutic approach for castration-resistant PC.

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Targeting the cross-talk between Urokinase receptor and Formyl peptide receptor type 1 to prevent invasion and trans-endothelial migration of melanoma cells

Abstract

Background

Accumulating evidence demonstrates that the Urokinase Receptor (uPAR) regulates tumor cell migration through its assembly in composite regulatory units with transmembrane receptors, and uPAR_88–92 is the minimal sequence required to induce cell motility through the Formyl Peptide Receptor type 1 (FPR1). Both uPAR and FPR1 are involved in melanoma tumor progression, suggesting that they may be targeted for therapeutic purposes. In this study, the role of the uPAR-FPR1 cross-talk to sustain melanoma cell ability to invade extracellular matrix and cross endothelial barriers is investigated. Also, the possibility that inhibition of the uPAR mediated FPR1-dependent signaling may prevent matrix invasion and transendothelial migration of melanoma cells was investigated.

Methods

Expression levels of uPAR and FPR1 were assessed by immunocytochemistry, Western Blot and qRT-PCR. Cell migration was investigated by Boyden chamber and wound-healing assays. Migration and invasion kinetics, trans-endothelial migration and proliferation of melanoma cells were monitored in real time using the xCELLigence technology. The agonist-triggered FPR1 internalization was visualized by confocal microscope. Cell adhesion to endothelium was determined by fluorometer measurement of cell-associated fluorescence or identified on multiple z-series by laser confocal microscopy. The 3D–organotypic models were set up by seeding melanoma cells onto collagen I matrices embedded dermal fibroblasts. Data were analyzed by one-way ANOVA and post-hoc Dunnett t-test for multiple comparisons.

Results

We found that the co-expression of uPAR and FPR1 confers to A375 and M14 melanoma cells a clear-cut capability to move towards chemotactic gradients, to cross extracellular matrix and endothelial monolayers. FPR1 activity is required, as cell migration and invasion were abrogated by receptor desensitization. Finally, melanoma cell ability to move toward chemotactic gradients, invade matrigel or fibroblast-embedded collagen matrices and cross endothelial monolayers are prevented by anti-uPAR_84–95 antibodies or by the RI-3 peptide which we have previously shown to inhibit the uPAR_84–95/FPR1 interaction.

Conclusions

Collectively, our findings identify uPAR and FPR1 as relevant effectors of melanoma cell invasiveness and suggest that inhibitors of the uPAR_84–95/FPR1 cross-talk may be useful for the treatment of metastatic melanoma.

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PSAT1 is regulated by ATF4 and enhances cell proliferation via the GSK3β/β-catenin/cyclin D1 signaling pathway in ER-negative breast cancer

Abstract

Background

A growing amount of evidence has indicated that PSAT1 is an oncogene that plays an important role in cancer progression and metastasis. In this study, we explored the expression and function of PSAT1 in estrogen receptor (ER)-negative breast cancer.

Method

The expression level of PSAT1 in breast cancer tissues and cells was analyzed using real-time-PCR (RT-PCR), TCGA datasets or immunohistochemistry (IHC). The overall survival of patients with ER-negative breast cancer stratified by the PSAT1 expression levels was evaluated using Kaplan-Meier analysis. The function of PSAT1 was analyzed using a series of in vitro assays. Moreover, a nude mouse model was used to evaluate the function of PSAT1 in vivo. qRT-PCR and western blot assays were used to evaluate gene and protein expression, respectively, in the indicated cells. In addition, we demonstrated that PSAT1 was activated by ATF4 by chromatin immunoprecipitation (ChIP) assays.

Results

mRNA expression of PSAT1 was up-regulated in ER-negative breast cancer. A tissue microarray that included 297 specimens of ER-negative breast cancer was subjected to an immunohistochemistry assay, which demonstrated that PSAT1 was overexpressed and predicted a poor clinical outcome of patients with this disease. Our data showed that PSAT1 promoted cell proliferation and tumorigenesis in vitro and in vivo. We further found that PSAT1 induced up-regulation of cyclin D1 via the GSK3β/β-catenin pathway, which eventually led to the acceleration of cell cycle progression. Furthermore, ATF4 was also overexpressed in ER-negative breast cancers, and a positive correlation between the ATF4 and PSAT1 mRNA levels was observed in ER-negative breast cancers. We further demonstrated that knockdown of ATF4 by siRNA reduced PSAT1 expression. Finally, chromatin immunoprecipitation (ChIP) assays showed that PSAT1 was a target of ATF4.

Conclusions

PSAT1, which is overexpressed in ER-negative breast cancers, is activated by ATF4 and promotes cell cycle progression via regulation of the GSK3β/β-catenin/cyclin D1 pathway.

http://ift.tt/2zZGsT9

Targeting the cross-talk between Urokinase receptor and Formyl peptide receptor type 1 to prevent invasion and trans-endothelial migration of melanoma cells

Abstract

Background

Accumulating evidence demonstrates that the Urokinase Receptor (uPAR) regulates tumor cell migration through its assembly in composite regulatory units with transmembrane receptors, and uPAR_88–92 is the minimal sequence required to induce cell motility through the Formyl Peptide Receptor type 1 (FPR1). Both uPAR and FPR1 are involved in melanoma tumor progression, suggesting that they may be targeted for therapeutic purposes. In this study, the role of the uPAR-FPR1 cross-talk to sustain melanoma cell ability to invade extracellular matrix and cross endothelial barriers is investigated. Also, the possibility that inhibition of the uPAR mediated FPR1-dependent signaling may prevent matrix invasion and transendothelial migration of melanoma cells was investigated.

Methods

Expression levels of uPAR and FPR1 were assessed by immunocytochemistry, Western Blot and qRT-PCR. Cell migration was investigated by Boyden chamber and wound-healing assays. Migration and invasion kinetics, trans-endothelial migration and proliferation of melanoma cells were monitored in real time using the xCELLigence technology. The agonist-triggered FPR1 internalization was visualized by confocal microscope. Cell adhesion to endothelium was determined by fluorometer measurement of cell-associated fluorescence or identified on multiple z-series by laser confocal microscopy. The 3D–organotypic models were set up by seeding melanoma cells onto collagen I matrices embedded dermal fibroblasts. Data were analyzed by one-way ANOVA and post-hoc Dunnett t-test for multiple comparisons.

Results

We found that the co-expression of uPAR and FPR1 confers to A375 and M14 melanoma cells a clear-cut capability to move towards chemotactic gradients, to cross extracellular matrix and endothelial monolayers. FPR1 activity is required, as cell migration and invasion were abrogated by receptor desensitization. Finally, melanoma cell ability to move toward chemotactic gradients, invade matrigel or fibroblast-embedded collagen matrices and cross endothelial monolayers are prevented by anti-uPAR_84–95 antibodies or by the RI-3 peptide which we have previously shown to inhibit the uPAR_84–95/FPR1 interaction.

Conclusions

Collectively, our findings identify uPAR and FPR1 as relevant effectors of melanoma cell invasiveness and suggest that inhibitors of the uPAR_84–95/FPR1 cross-talk may be useful for the treatment of metastatic melanoma.

http://ift.tt/2A1BtRQ

FAM198B is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer. Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAMB198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis and tumor growth was examined by in vitro cellular assays and in vivo mouse models. Additionally, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis was used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analysis were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression. Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation and anchorage-independent growth and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK). Interestingly Deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability. Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma.

http://ift.tt/2A3AxwF

The Impact of Smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations - the Lung Cancer Mutation Consortium (LCMC2)

PURPOSE Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. PATIENTS AND METHODS Sixteen U.S. institutions enrolled 1367 lung cancer patients in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and immunohistochemistry. RESULTS The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1 or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared to those with such mutations not receiving targeted therapy; and 1.0 year compared to those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR ALK/ROS1, when compared to 75 never smokers with the same alterations. In addition, co-existing TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations. CONCLUSION Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment.

http://ift.tt/2nFJr1j

First-in-human phase I study of single-agent vanucizumab, a first-in-class bi-specific anti-Ang-2/anti-VEGF antibody, in adult patients with advanced solid tumors

Purpose: Vanucizumab is an investigational anti-angiogenic, first-in-class, bi-specific monoclonal antibody targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating bi-weekly (q2w; 3-30 mg/kg) or weekly (qw; 10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally-located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg q2w dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related Grade ≥3 toxicities. Toxicity was generally higher with qw than q2w dosing. A maximum tolerated dose of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K^TRANS (measured by dynamic contrast-enhanced-MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2000 mg q2w dose (phamacokinetically equivalent to 30 mg/kg q2w) was recommended for further investigation. Conclusion: Bi-weekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging anti-tumor activity in this heterogeneous population.

http://ift.tt/2kz9oP6

Merkel cell carcinoma in the age of immunotherapy: Facts and hopes

Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/'exhausted' and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials, involving three PD-1 pathway blocking agents (avelumab, pembrolizumab, and nivolumab) indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, ~50% of MCC patients do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden anti-tumor immune responses in these patients. Here we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade.

http://ift.tt/2j5lcbH

FAM198B is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer. Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAMB198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis and tumor growth was examined by in vitro cellular assays and in vivo mouse models. Additionally, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis was used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analysis were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression. Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation and anchorage-independent growth and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK). Interestingly Deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability. Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma.

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The Impact of Smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations - the Lung Cancer Mutation Consortium (LCMC2)

PURPOSE Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. PATIENTS AND METHODS Sixteen U.S. institutions enrolled 1367 lung cancer patients in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and immunohistochemistry. RESULTS The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1 or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared to those with such mutations not receiving targeted therapy; and 1.0 year compared to those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR ALK/ROS1, when compared to 75 never smokers with the same alterations. In addition, co-existing TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations. CONCLUSION Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment.

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First-in-human phase I study of single-agent vanucizumab, a first-in-class bi-specific anti-Ang-2/anti-VEGF antibody, in adult patients with advanced solid tumors

Purpose: Vanucizumab is an investigational anti-angiogenic, first-in-class, bi-specific monoclonal antibody targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating bi-weekly (q2w; 3-30 mg/kg) or weekly (qw; 10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally-located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg q2w dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related Grade ≥3 toxicities. Toxicity was generally higher with qw than q2w dosing. A maximum tolerated dose of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K^TRANS (measured by dynamic contrast-enhanced-MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2000 mg q2w dose (phamacokinetically equivalent to 30 mg/kg q2w) was recommended for further investigation. Conclusion: Bi-weekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging anti-tumor activity in this heterogeneous population.

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Merkel cell carcinoma in the age of immunotherapy: Facts and hopes

Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/'exhausted' and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials, involving three PD-1 pathway blocking agents (avelumab, pembrolizumab, and nivolumab) indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, ~50% of MCC patients do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden anti-tumor immune responses in these patients. Here we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade.

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CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis

Abstract

Background

In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism.

Methods

Using the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus – polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites.

Results

We provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5^+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5^−/− cells, that exhibit reduced glycolytic metabolism.

Conclusions

These findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.

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CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis

Abstract

Background

In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism.

Methods

Using the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus – polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites.

Results

We provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5^+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5^−/− cells, that exhibit reduced glycolytic metabolism.

Conclusions

These findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.

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Improved Tumor Penetration and Single-Cell Targeting of Antibody Drug Conjugates Increases Anticancer Efficacy and Host Survival

Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small molecule payload and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADC is poorly understood. Here we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, co-administration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared to T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo, yet improves the effectiveness of T-DM1 in vivo. Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. Additionally, this technique characterized cellular pharmacokinetics with heterogeneous delivery after one day, degradation and payload release by two days, and in vitro cell killing and in vivo tumor shrinkage 2-3 days later. This work demonstrates that the intratumoral distribution of ADC - independent of payload dose or plasma clearance - plays a major role in ADC efficacy.

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Radiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF-1R activation

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1). Subsequently, RT-activated CAF promoted survival of CRC cells as well as a metabolic switch favoring glutamine consumption through IGF-1 receptor (IGF-1R) activation. RT followed by IGF-1R neutralization in orthotopic CRC models reduced the number of mice with organ metastases. Activation of the downstream IGF-1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from RC patients after neoadjuvant chemoRT. Taken together, our data support the notion that paracrine IGF-1/IGF-1R signaling initiated by RT-activated CAF worsen CRC progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.

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SIRT6 is a target of regulation by UBE3A that contributes to liver tumorigenesis in an ANXA2-dependent manner

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.

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Aptamer-conjugated extracellular nanovesicles for targeted drug delivery

Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins and nucleic acids that contribute to intercellular communication. ENV have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes, however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of ~107 cells grafted with lipidated ligands can generate cancer cell-targeting ENV and can be prepared in ~1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.

http://ift.tt/2BgrD32

Tumor-associated fatigue in cancer patients develops independently of interleukin-1 signaling

Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central pro-inflammatory cytokine, interleukin-1 (IL-1). The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of Il1b in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of Il1b in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depressive-like behaviors, or energy balance. Decreased wheel running occurred prior to Il1b detection in the brain, when systemic inflammation was minimal. Further, mice null for two components of IL-1β signaling, the type 1 interleukin-1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of 4 additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together our results show that brain IL-1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression.

http://ift.tt/2AlGlph

Intensity modulated radiation therapy and surgery for Management of Retroperitoneal Sarcomas: a single-institution experience

Abstract

Background

Peri-operative radiation of retroperitoneal sarcomas (RPS) is an important component of multidisciplinary treatment. All retrospective series thus far included patients treated with older radiation therapy (RT) techniques including 2D and 3DRT. Intensity modulated radiation therapy (IMRT) allows for selective dose escalation while sparing adjacent organs. We therefore report the first series of patients with RPS treated solely with IMRT, surgery and chemotherapy. We hypothesized that IMRT would permit safe dose escalation and superior rates of local control (LC) in this high-risk patient population.

Methods

Thirty patients with RPS treated with curative intent between 2006 and 2015 were included in this retrospective study. RT was administered either pre- or post-operatively and IMRT was used in all patients. Statistical comparisons, LC, distant metastasis (DM), and overall survival (OS) were calculated by Kaplan-Meier analysis and univariate Cox regression.

Results

Median follow-up time after completion of RT was 36 months (range 1.4-112). Median tumor size was 14 cm (range 3.6 - 28 cm). The most prevalent histologies were liposarcoma in 10 (33%) patients and leiomyosarcoma in 10 (33%) with 21 patients (70%) having high-grade disease. Twenty-eight (93%) patients had surgical resection with 47% having positive margins. Chemotherapy was administered in 9 (30%) patients. RT was delivered pre-operatively in 11 (37%) patients, and post-operatively in 19 (63%) with 60% of patients receiving a simultaneous integrated boost. Pre-operative median RT dose to the high-risk area was 55 Gy (range, 43–66 Gy) while median post-operative dose was 60.4 Gy (range, 45-66.6 Gy). There was one acute grade 3 and one late grade 3 toxicity and no grade 4 or 5 toxicities. Three year actuarial LC, freedom from DM, and OS rates were 84%, 64%, and 68% respectively. Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04). Pre-operative RT was associated with improved LC (p = 0.1) with a 5-year actuarial LC of 100%. Administration of chemotherapy, timing of RT, histology or grade was not predictive of OS.

Conclusions

Patients with RPS treated with peri-operative IMRT at our institution had excellent local control and low incidences of toxicity.

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SIRT6 is a target of regulation by UBE3A that contributes to liver tumorigenesis in an ANXA2-dependent manner

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential and invasiveness of cells. In mouse models of hepatocellular carcinoma, SIRT6 downregulation and consequent induction of ANXA2 were critical for UBE3A-mediated tumorigenesis. Furthermore, in clinical specimens, increased UBE3A levels correlated with reduced SIRT6 levels and elevated ANXA2 levels in increasing tumor grades. Overall, our findings show how the tumor suppressor SIRT6 is regulated in hepatocellular carcinoma and establish the mechanism underlying UBE3A-mediated tumorigenesis in this disease.

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Aptamer-conjugated extracellular nanovesicles for targeted drug delivery

Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins and nucleic acids that contribute to intercellular communication. ENV have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes, however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of ~107 cells grafted with lipidated ligands can generate cancer cell-targeting ENV and can be prepared in ~1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.

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Tumor-associated fatigue in cancer patients develops independently of interleukin-1 signaling

Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central pro-inflammatory cytokine, interleukin-1 (IL-1). The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of Il1b in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of Il1b in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depressive-like behaviors, or energy balance. Decreased wheel running occurred prior to Il1b detection in the brain, when systemic inflammation was minimal. Further, mice null for two components of IL-1β signaling, the type 1 interleukin-1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of 4 additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together our results show that brain IL-1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression.

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Intensity modulated radiation therapy and surgery for Management of Retroperitoneal Sarcomas: a single-institution experience

Abstract

Background

Peri-operative radiation of retroperitoneal sarcomas (RPS) is an important component of multidisciplinary treatment. All retrospective series thus far included patients treated with older radiation therapy (RT) techniques including 2D and 3DRT. Intensity modulated radiation therapy (IMRT) allows for selective dose escalation while sparing adjacent organs. We therefore report the first series of patients with RPS treated solely with IMRT, surgery and chemotherapy. We hypothesized that IMRT would permit safe dose escalation and superior rates of local control (LC) in this high-risk patient population.

Methods

Thirty patients with RPS treated with curative intent between 2006 and 2015 were included in this retrospective study. RT was administered either pre- or post-operatively and IMRT was used in all patients. Statistical comparisons, LC, distant metastasis (DM), and overall survival (OS) were calculated by Kaplan-Meier analysis and univariate Cox regression.

Results

Median follow-up time after completion of RT was 36 months (range 1.4-112). Median tumor size was 14 cm (range 3.6 - 28 cm). The most prevalent histologies were liposarcoma in 10 (33%) patients and leiomyosarcoma in 10 (33%) with 21 patients (70%) having high-grade disease. Twenty-eight (93%) patients had surgical resection with 47% having positive margins. Chemotherapy was administered in 9 (30%) patients. RT was delivered pre-operatively in 11 (37%) patients, and post-operatively in 19 (63%) with 60% of patients receiving a simultaneous integrated boost. Pre-operative median RT dose to the high-risk area was 55 Gy (range, 43–66 Gy) while median post-operative dose was 60.4 Gy (range, 45-66.6 Gy). There was one acute grade 3 and one late grade 3 toxicity and no grade 4 or 5 toxicities. Three year actuarial LC, freedom from DM, and OS rates were 84%, 64%, and 68% respectively. Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04). Pre-operative RT was associated with improved LC (p = 0.1) with a 5-year actuarial LC of 100%. Administration of chemotherapy, timing of RT, histology or grade was not predictive of OS.

Conclusions

Patients with RPS treated with peri-operative IMRT at our institution had excellent local control and low incidences of toxicity.

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A Rare Case of a Metastatic Gastrointestinal Stromal Tumor (GIST): a Case Report and Review of the Literature

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A Rare Case of a Metastatic Gastrointestinal Stromal Tumor (GIST): a Case Report and Review of the Literature

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First-Line Osimertinib Beneficial in Advanced NSCLC [News in Brief]

In the FLAURA trial, drug improves survival for a subset of patients with higher incidence of EGFR-mutated disease.

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Clinical Indicators of the Need for Telemetry Postoperative Monitoring in Patients With Suspected Obstructive Sleep Apnea Undergoing Total Knee Arthroplasty

Background and Objectives Obstructive sleep apnea is associated with increased complication rates postoperatively. Current literature does not provide adequate guidance on management of these patients. This study used the STOP-Bang questionnaire to diagnose patients with possible obstructive sleep apnea (score ≥3). We hypothesized that a STOP-Bang score of 3 or greater would significantly correlate with the number of oxygen desaturation episodes during the first 48 hours after total knee arthroscopy. Methods The STOP-Bang questionnaire was administered to 110 patients preoperatively. All patients underwent spinal-epidural anesthesia with a saphenous nerve block and sedation and were connected to the Nellcor OxiMax N-600x pulse oximeter for 48 hours postoperatively. Results Final analysis included 98 patients. There was no significant difference in the total number of desaturation events between STOP-Bang groups (score

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Intrathecal Morphine for Laparoscopic Segmental Colonic Resection as Part of an Enhanced Recovery Protocol: A Randomized Controlled Trial

Background and Objectives Management of postoperative pain after laparoscopic segmental colonic resections remains controversial. We compared 2 methods of analgesia within an Enhanced Recovery After Surgery (ERAS) program. The goal of the study was to investigate whether administration of intrathecal bupivacaine/morphine would lead to an enhanced recovery. Methods A single-center, randomized, double-blind controlled trial was performed (NL43488.101.13). Patients scheduled for laparoscopic segmental intestinal resections were considered. Exclusion criteria were patients in whom contraindications to spinal anesthesia were present, conversion to open surgery, and gastric and rectal surgery. The intervention group received single-shot intrathecal bupivacaine/morphine (12.5 mg/300 μg), with an altered dose for older patients. The control group received a sham procedure and a bolus of piritramide (0.1 mg/kg). Both groups received standardized general anesthesia and a patient-controlled intravenous analgesia pump as postoperative analgesia. All patients were treated according to an ERAS protocol. A decrease in days to "fit for discharge" was the primary outcome. Results Fifty-six patients were enrolled. Intervention group patients were fit for discharge earlier (median of 3 vs 4 days, P = 0.044). Furthermore, there was a significant decrease in opioid use and lower pain scores on the first postoperative day in the intervention group. There were no differences in adverse events (except for more pruritus), time to mobilization, fluid administration, or patient satisfaction. Conclusions This randomized controlled trial shows that intrathecal morphine is a more effective method of postoperative analgesia in laparoscopic surgery than intravenous opioids within an ERAS program. Recovery is faster and less painful with intrathecal morphine. Other studies have confirmed these results, although data on faster recovery are new and require confirmation in future trials. Clinical Trial Registration This study was registered at ClinicalTrials.gov, identifier NCT02284282). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Accepted for publication September 13, 2017. Address correspondence to: Mark V. Koning, MD, Korenschoofstraat 173, 3513 DE Utrecht, the Netherlands (e-mail: markkoning66@hotmail.com). The authors declare no conflict of interest. Copyright © 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Improving patient safety during procedural sedation via respiratory volume monitoring: A randomized controlled trial

Assess the utility of a respiratory volume monitor (RVM) to reduce the incidence of low minute ventilation events in procedural sedation.

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Motivation for Launching a Cancer Metastasis Inhibition (CMI) Program

Abstract

Metastatic cancers impose significant burdens on patients, affecting quality of life, morbidity, and mortality. Even during remission, microscopic metastases can lurk, but few therapies directly target tumor cell metastasis. Agents that interfere with this process would represent a new paradigm in cancer management, changing the 'waiting game' into a time of active prevention. These therapies could take multiple forms based on the pathways involved in the metastatic process. For example, a phenome-wide association study showed that a single nucleotide polymorphism in the gene TBXA2R is associated with increased metastasis in multiple primary cancers (P = 0.003), suggesting clinical applicability of TBXA2R antagonists. Emerging data related to the role of platelets in metastasis are concordant with our sense that these pathways present significant opportunities for therapeutic development. However, before real progress can be made toward clinical targeting of the metastatic process, foundational work is needed to define informative measures of critical elements such as circulating tumor cells and tumor DNA, and circulatory vs. lymphatic spread. These challenges require an expansion of team science and composition to obtain competitive funding. At our academic medical center, we have implemented a Cancer Metastasis Inhibition (CMI) program investigating this approach across multiple cancers.

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Early Metabolic Change after Induction Chemotherapy Predicts Histologic Response and Prognosis in Patients with Esophageal Cancer: Secondary Analysis of a Randomized Trial

Abstract

Background

Early metabolic response after preoperative induction chemotherapy (IC) appears to predict histologic response and prognosis in esophageal cancer (EC), but the usefulness of this approach needs further development.

Objective

We evaluated metabolic response after one cycle of IC using positron emission tomography (PET) to correlate PET response and outcomes.

Patients and Methods

We retrospectively analyzed PET data from a randomized phase 2 trial (NCT00525915) of chemoradiation and surgery with or without IC for the treatment of EC. PET was performed at baseline, after one cycle of IC, and 5–7 weeks after chemoradiation. The relationship between PET response (≥35% reduction in standardized uptake value [SUV]) after IC and treatment response was analyzed.

Results

In 63 patients who received IC, the mean initial SUV_max prior to treatment was 11.9 ± 8.04 and mean SUV_max after one cycle of IC was 6.47 ± 4.45. The mean SUV reduction after IC was 39.3%. Eleven of 37 PET responders achieved a pathologic complete response (pCR), but only two of 22 PET non-responders did (univariate logistic regression; odds ratio: 4.25, 95% confidence interval: 0.83–21.77; p = 0.08). PET responders to IC had significantly longer overall survival (OS) than PET nonresponders (log-rank p = 0.009). PET response after chemoradiation was not correlated with OS (log-rank p = 0.15).

Conclusion

Early PET response after IC is prognostic, but subsequent PET changes (for example, after chemoradiation) are not prognostic. Early PET response might have the potential of predicting pCR.

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miR-200c as a Predictive Biomarker for 5-Fluorouracil Chemosensitivity in Colorectal Cancer

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miR-200c as a Predictive Biomarker for 5-Fluorouracil Chemosensitivity in Colorectal Cancer

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Diagnosis of EML4-ALK Translocation With FISH, Immunohistochemistry, and Real-time Polymerase Chain Reaction in Patients With Non–Small Cell Lung Cancer

Objective: To assess anaplastic lymphoma kinase (ALK) rearrangement detection with immunohistochemistry (IHC) and real-time polymerase chain reaction (RT-qPCR) in comparison with fluorescence in situ hybridization (FISH). Methods: Tumor tissue samples from 230 patients with advanced non–small cell lung cancer (NSCLC) were analyzed by FISH to detect ALK rearrangements. Additional IHC tests using 5A4 clone and RT-qPCR (variants 1 to 5) were performed in 63 and 48 patients, respectively. Results: Thirteen percent of FISH tests were not evaluable. From the remaining tests (n=200), 18 (9.0%) were ALK positive (ALK+). ALK+ patients were significantly younger at the time of diagnosis (below 55 y, 14.3% vs. 5.5%, P=0.035), were light smokers (tobacco index

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Potential Role of Single Nucleotide Polymorphisms of XRCC1, XRCC3, and RAD51 in Predicting Acute Toxicity in Rectal Cancer Patients Treated With Preoperative Radiochemotherapy

Objectives: To investigate the association between polymorphisms of DNA repair genes and xenobiotic with acute adverse effects in locally advanced rectal cancer patients treated with neoadjuvant radiochemotherapy. Methods: Sixty-seven patients were analyzed for the current study. Genotypes in DNA repair genes XRCC1 (G28152A), XRCC3 (A4541G), XRCC3 (C18067T), RAD51 (G315C), and GSTP1 (A313G) were determined by pyrosequencing technology. Results: The observed grade ≥3 acute toxicity rates were 23.8%. Chemotherapy and radiotherapy were interrupted for 46 and 14 days, respectively, due to critical complications. Four patients were hospitalized, 6 patients had been admitted to the ER, and 5 patients received invasive procedures (2 bladder catheters, 2 blood transfusions, and 1 growth factor therapy). RAD51 correlated with acute severe gastrointestinal toxicity in heterozygosity (Aa) and homozygosity (AA) (P=0.036). Grade ≥3 abdominal/pelvis pain toxicity was higher in the Aa group (P=0.017) and in the Aa+AA group (P=0.027) compared with homozygous (aa) patients. Acute skin toxicity of any grade occurred in 55.6% of the mutated patients versus 22.8% in the wild-type group (P=0.04) for RAD51. XRCC1 correlated with skin toxicity of any grade in the Aa+AA group (P=0.03) and in the Aa group alone (P=0.044). Grade ≥3 urinary frequency/urgency was significantly higher in patients with AA (P=0.01), Aa (P=0.022), and Aa+AA (P=0.031) for XRCC3 compared with aa group. Conclusions: Our study suggested that RAD51, XRCC1, and XRCC3 polymorphisms may be predictive factors for radiation-induced acute toxicity in rectal cancer patients treated with preoperative combined therapy.

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Do Prostate Cancer Patients With Markedly Elevated PSA Benefit From Radiation Therapy?: A Population-based Study

Objectives: Patients with clinically localized prostate cancer but markedly elevated prostate-specific antigen (PSA) are often treated with systemic agents alone. We hypothesized that they would benefit from radiation therapy. Methods: We utilized the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with nonmetastatic prostate cancer from 2004 to 2008. Patients treated surgically or with brachytherapy were excluded. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Propensity score was used to adjust for the nonrandomized assignment of local therapies. Results: A total of 75,539 nonmetastatic prostate cancer patients were identified who received either radiotherapy or no local treatment. Median age was 70 years. Median follow-up of alive subjects was 60 months, with an interquartile range of 47 to 77 months. Estimated 4-year overall survival of entire population was 88%. Significant prognostic variables for overall survival on multivariate analysis included age, grade, PSA level, T stage, and use of radiation therapy. Use of radiation therapy was the most powerful predictor of both cause-specific and overall survival (HR=0.41 and 0.46, respectively, P

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The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas

Objectives: Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). Materials and Methods: Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan–Meyer, and Cox regression were used for statistical analyses. Results: Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). Conclusions: This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.

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