Chronic pain following median sternotomy is common after cardiac surgery. If left untreated, chronic sternal pain can reduce quality of life, affecting sleep, mood, activity level, and overall satisfaction. This has a significant societal effect given the large number of cardiac surgeries annually. Although a number of pathophysiologic processes and risk factors are assumed to contribute, the exact cause and major risk factors remain unknown. Moreover, the treatment of chronic poststernotomy pain is often inadequate, relying on opioids and other medications that provide minimal benefit to the patient and have significant adverse effects. Indeed, little is known regarding the prevention of chronic pain development following sternotomy. This review aims to present the current, limited data regarding the incidence, risk factors, treatment, and prevention of chronic poststernotomy pain and to identify areas of future research to improve management of this common complaint following cardiac surgery. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 21 Σεπτεμβρίου 2017
The Spread of Ultrasound-Guided Injectate From the Adductor Canal to the Genicular Branch of the Posterior Obturator Nerve and the Popliteal Plexus: A Cadaveric Study.
Background and Objectives: The popliteal nerve plexus contributes to afferent knee-pain conduction. It is mainly formed by genicular branches from the posterior obturator and the tibial nerves, innervating the intra-articular and posterior knee region. A subinguinal obturator nerve block alleviates pain after total knee arthroplasty. Reduced hip adductor motor function could be avoided by a posterior obturator nerve block inside the popliteal fossa. The aim of this study was to evaluate the spread of dye after a distal adductor canal (AC) injection to the popliteal fossa and coloring of the popliteal plexus and the genicular branch of the posterior obturator nerve by dissection. We also assessed the spread of dye into the popliteal fossa after a distal femoral triangle injection. Methods: Ten milliliters of dye was injected into the distal part of the AC in 10 cadaver sides and into the distal part of the femoral triangle in 3 sides. Dissection was used to assess the spread of the injectate and coloring of the popliteal plexus and the genicular branch of the posterior obturator nerve, as well as the saphenous and medial vastus nerves. Results: The popliteal plexus and the genicular branch of the posterior obturator nerve were dyed in all 10 dissections after AC injections. No dye spread into the popliteal fossa after femoral triangle injections. Conclusions: Injection of 10 mL of dye into the distal part of the AC spreads into the popliteal fossa and colors the popliteal plexus and the genicular branch of the posterior obturator nerve. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.
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Osteonecrosis of the jaw and survival of patients with cancer: a nationwide cohort study in Denmark
Abstract
Osteonecrosis of the jaw (ONJ) is an adverse effect of bone-targeted therapies, which are used to prevent symptomatic skeletal events following bone malignancy. We examined the association between ONJ and survival among cancer patients treated with bone-targeted agents. Using nationwide registries and databases in Denmark, we identified 184 cancer patients with incident ONJ between 2010 and 2015, and a comparison cohort of 1067 cancer patients without ONJ and with a history of hospital-administered treatment with bisphosphonates or denosumab initiating from cancer diagnosis. At the date of confirmed ONJ diagnosis, the comparison cohort was matched to the ONJ patients on age, cancer site, year of cancer diagnosis, and stage at diagnosis. The patients were followed up for survival until emigration or 15 June 2016. We computed overall survival and estimated mortality rate ratios adjusted for sex, and for the presence of distant metastases and other comorbidity at start of follow-up. A match was found for 149 of the 184 ONJ patients. The 1- and 3-year survival among all 184 cancer patients with ONJ was 70% (95% confidence interval [CI]: 63%–76%) and 42% (95% CI: 34%–51%), respectively. Among the matched patients, ONJ was associated with an adjusted mortality rate ratio of 1.31 (95% CI: 1.01–1.71). ONJ was associated with reduced survival among cancer patients treated with bone-targeted agents. ONJ may be a marker of advanced disease or of survival-related lifestyle characteristics.
In this nationwide cohort study, the authors examined the association between osteonecrosis of the jaw (ONJ) and survival among cancer patients treated with bone-targeted agents. ONJ was associated with reduced survival. The reason for the association is likely ONJ being a marker of advanced disease or of survival-related lifestyle characteristics.
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Osteonecrosis of the jaw and survival of patients with cancer: a nationwide cohort study in Denmark
Abstract
Osteonecrosis of the jaw (ONJ) is an adverse effect of bone-targeted therapies, which are used to prevent symptomatic skeletal events following bone malignancy. We examined the association between ONJ and survival among cancer patients treated with bone-targeted agents. Using nationwide registries and databases in Denmark, we identified 184 cancer patients with incident ONJ between 2010 and 2015, and a comparison cohort of 1067 cancer patients without ONJ and with a history of hospital-administered treatment with bisphosphonates or denosumab initiating from cancer diagnosis. At the date of confirmed ONJ diagnosis, the comparison cohort was matched to the ONJ patients on age, cancer site, year of cancer diagnosis, and stage at diagnosis. The patients were followed up for survival until emigration or 15 June 2016. We computed overall survival and estimated mortality rate ratios adjusted for sex, and for the presence of distant metastases and other comorbidity at start of follow-up. A match was found for 149 of the 184 ONJ patients. The 1- and 3-year survival among all 184 cancer patients with ONJ was 70% (95% confidence interval [CI]: 63%–76%) and 42% (95% CI: 34%–51%), respectively. Among the matched patients, ONJ was associated with an adjusted mortality rate ratio of 1.31 (95% CI: 1.01–1.71). ONJ was associated with reduced survival among cancer patients treated with bone-targeted agents. ONJ may be a marker of advanced disease or of survival-related lifestyle characteristics.
In this nationwide cohort study, the authors examined the association between osteonecrosis of the jaw (ONJ) and survival among cancer patients treated with bone-targeted agents. ONJ was associated with reduced survival. The reason for the association is likely ONJ being a marker of advanced disease or of survival-related lifestyle characteristics.
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Posteriorly dislocated capsular tension ring leading to rhegmatogenous retinal detachment
Description
A 54-year-old woman presented with sudden diminution of vision in her left eye 4 months before. Medical history revealed that she underwent a phacoemulsification 1 year before in the left eye and 4 years before in the right eye. Snellen visual acuity in the right eye was 20/20 while she was just able to count fingers at 1 m in the left eye. She had a divergent squint of 30 prism dioptres in the left eye. The right eye had a well-centred foldable posterior chamber intraocular lens (PCIOL) in the capsular bag, while the left eye had a rigid polymethyl methacrylate (PMMA) PCIOL in the sulcus with a large posterior capsular defect (figure 1A). On fundus examination of the left eye, we found a total rhegmatogenous retinal detachment with a large punched-out toxoplasma scar at the macula, three retinal horseshoe tears superonasally at the equator (figure 2B) and a...
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Splenic calcification in systemic lupus erythematosus
Description
A 39-year-old woman with known systemic lupus erythematosus (SLE) nephropathy, antiphospholipid syndrome and chronic renal failure was evaluated for renal transplant. She was asymptomatic; nevertheless, the abdominal ultrasonogram showed splenic calcification (figure 1). The chest radiograph showed faint lesions suggestive of (L) hypochondrial calcification (figure 2). The tuberculin skin test result revealed induration of 3 mm. She had no history of treatment for tuberculosis or brucellosis. The angiotensin-converting enzyme was normal at 19 U/L (normal range 29–112 U/L). A CT scan of the abdomen and pelvis showed a bulky spleen that contained numerous small and differently sized smooth calcific foci probably related to granulomatous disease. No calcification was seen in the liver (figure 3A, B). There were no definite or suspicious pulmonary nodules seen on a whole body fluorodeoxyglucose positron-emission tomography (PET) scan. Similarly, numerous tiny splenic calcifications with no abnormal metabolic activity were detected...
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Diaphyseal tuberculosis - a rare manifestation
DESCRIPTION
A 2 year old child presented with low-grade fever, progressive pain and swelling of right leg for the past 3 months. There was no history of injury, chronic cough, respiratory symptoms, weight loss or arthritis. Child's father had been treated for pulmonary tuberculosis 1 year back. On examination, there was a firm, diffuse, tender swelling over the medial aspect of middle one-third of right tibia and matted inguinal lymphadenopathy. Rest of the systemic examination was not contributory. A clinical diagnosis of diaphyseal bone tumour or chronic infective osteomyelitis was considered.
Investigations showed erythrocyte sedimentation rate 46 mm in first hour, haemoglobin 96 g/L and 20 mm induration after Mantoux test and normal chest radiograph. Radiograph of the right tibia showed a lytic intramedullary bone lesion (Figure 1A–B). MRI confirmed an intramedullary lytic lesion with cortical breach and thickening (figure 1C). Histopathology showed caseous necrosis, granuloma formation, Langhans giant cells...
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Cholesterol embolism: its always a good idea to look into the eye
Description
Atheroembolism is a rare but feared complication of arteriography, causing a myriad of signs and symptoms including livedo reticularis, abdominal pain, cyanosis of the toes and renal injury. The main cause is a rupture of atherosclerotic plaque in vessel walls and its embolisation to small diameter vessels affecting more frequently skin and kidneys.1 Here, we present a 69-year-old Hispanic male with medical history of hypertension, type 2 diabetes mellitus and unstable angina status post drug-eluting stent in the left anterior descending coronary artery placement 10 days prior to admission, who arrived to the emergency department with intense diffuse sharp abdominal pain, nausea, vomiting, oliguria and lower extremity pain. Physical examination disclosed livedo reticularis in lower extremities (figure 1), tender abdomen with decreased bowel sounds and funduscopy positive for a Hollenhorst crystal observed in right inferotemporal quadrant (figure 2) and increased creatinine and...
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Infected enteric duplication cyst
Description
An 8-month-old female infant presented with a 2-day history of vomiting, diarrhoea and fever. Physical examination revealed a painful right abdomen. Laboratory tests showed a C-reactive protein of 140 mg/L (normal: <6 mg/L) and a white blood cell count of 12.8x109/L (normal: 4–15x109/L). Ultrasound of the abdomen revealed a paracolic cystic mass of 1.4x5 cm with septations from the lower part of the liver into the right fossa with no signs of volvulus or intussusception (figure 1). Abdominal CT confirmed the cystic mass and revealed signs of infection. MRI of the abdomen suggested an enteric duplication cyst as the most likely diagnosis (figure 2).
Figure 1
Ultrasound: encapsulated tubular mass with predominant hypoechoic heterogeneous echogenicity under the right lobe of the liver.
Figure 2
MRI coronal T1-weighted image with intravenous contrast: tubular cystic mass with thick wall ventral and lateral...
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An airway traffic jam: a plastic traffic cone masquerading as bronchial carcinoma
Tracheobronchial foreign body (TFB) aspiration is a common occurrence in children compared with adults. Long-standing cases of TFB aspiration during childhood presenting in an adult have rarely been reported. We report the unique case of an endobronchial Playmobil traffic cone that went undetected for 40 years and presented as a suspected bronchogenic carcinoma. This was subsequently removed successfully with flexible bronchoscopy. To our knowledge this is the first case of a TFB that was overlooked this length of time.
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Comparison of volumetric-modulated arc therapy using simultaneous integrated boosts (SIB-VMAT) of 45 Gy/55 Gy in 25 fractions with conventional radiotherapy in preoperative chemoradiation for rectal cancers: a propensity score case-matched analysis
The aim of this retrospective study was to compare volumetric-modulated arc therapy using simultaneous integrated boosts (SIB-VMAT) of 45 Gy/55 Gy in 25 fractions with three-dimensional conformal radiotherapy ...
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Computed tomography in children with community-acquired pneumonia
Abstract
Diagnostic imaging plays a significant role in both the diagnosis and treatment of complications of pneumonia in children and chest radiography is the imaging modality of choice. Computed tomography (CT) on the other hand, is not currently a first-line imaging tool for children with suspected uncomplicated community-acquired pneumonia and is largely reserved for when complications of pneumonia are suspected or there is difficulty in differentiating pneumonia from other pathology. This review outlines the situations where CT needs to be considered in children with pneumonia, describes the imaging features of the parenchymal and pleural complications of pneumonia, discusses how CT may have a wider role in developing countries where human immunodeficiency virus (HIV) and tuberculosis are prevalent, makes note of the role of CT scanning for identifying missed foreign body aspiration and, lastly, addresses radiation concerns.
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Comparison of volumetric-modulated arc therapy using simultaneous integrated boosts (SIB-VMAT) of 45 Gy/55 Gy in 25 fractions with conventional radiotherapy in preoperative chemoradiation for rectal cancers: a propensity score case-matched analysis
The aim of this retrospective study was to compare volumetric-modulated arc therapy using simultaneous integrated boosts (SIB-VMAT) of 45 Gy/55 Gy in 25 fractions with three-dimensional conformal radiotherapy ...
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Computed tomography in children with community-acquired pneumonia
Abstract
Diagnostic imaging plays a significant role in both the diagnosis and treatment of complications of pneumonia in children and chest radiography is the imaging modality of choice. Computed tomography (CT) on the other hand, is not currently a first-line imaging tool for children with suspected uncomplicated community-acquired pneumonia and is largely reserved for when complications of pneumonia are suspected or there is difficulty in differentiating pneumonia from other pathology. This review outlines the situations where CT needs to be considered in children with pneumonia, describes the imaging features of the parenchymal and pleural complications of pneumonia, discusses how CT may have a wider role in developing countries where human immunodeficiency virus (HIV) and tuberculosis are prevalent, makes note of the role of CT scanning for identifying missed foreign body aspiration and, lastly, addresses radiation concerns.
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X-linked ichthyosis associated with psychosis and behavioral abnormalities: a case report
X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and ...
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Breast cancer metastases to the thyroid gland – an uncommon sentinel for diffuse metastatic disease: a case report and review of the literature
Metastases to the thyroid are rare. The most common primary cancer to metastasize to the thyroid is renal cell carcinoma, followed by malignancies of the gastrointestinal tract, lungs, and skin, with breast ca...
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Treatment of oesophageal cancer – Stressing the patient perspective
Source:European Journal of Cancer, Volume 84
Author(s): Florian Lordick
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First-line treatment in metastatic colorectal cancer: Important or crucial?
Source:European Journal of Cancer, Volume 84
Author(s): David Malka, Federico Rotolo, Valérie Boige
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ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer
In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity and teratoma formation by Lu-iPSC, and diminished clonogenicity and malignant growth of SCLC cells in-vivo. Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis, and highlight ASXL3 as a novel candidate target for SCLC therapy.
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miR-130a deregulates PTEN and stimulates tumor growth
H-RasV12 oncogene has been shown to promote autophagic cell death. Here we provide evidence of a contextual role for H-RasV12 in cell death that is varied by its effects on miR-130a. In E1A-immortalized murine embryo fibroblasts, acute expression of H-RasV12 promoted apoptosis but not autophagic cell death. miRNA screens in this system showed that miR-130a was strongly downregulated by H-RasV12 in this model system. Enforced expression of miR-130a increased cell proliferation in part via repression of PTEN. Consistent with this effect, miR-130a overexpression in human breast cancer cells promoted Akt phosphorylation, cell survival and tumor growth. In clinical specimens of multiple human cancers, expression of miR-130 family members correlated inversely with PTEN expression. Overall, our results defined miR-130a as an oncogenic microRNA that targets PTEN to drive malignant cell survival and tumor growth.
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Diabetes treatments and risks of adverse breast cancer outcomes among early stage breast cancer patients: A SEER-Medicare analysis
The widely prescribed diabetes medicine metformin has been reported to lower the risk of incident breast cancer, but it is unclear if it affects malignant progression after diagnosis. In this study, we conducted a retrospective cohort study using the linked Surveillance, Epidemiology and End-Results (SEER)-Medicare database. Women were included in the study if they were aged 66-80 years, newly diagnosed with stage I or II breast cancer, and enrolled in Medicare Parts A, B, and D during 2007-2011. Information on dispensed diabetes-related medications was obtained from Medicare Part D claims data. Our primary outcomes were second breast cancer events (SBCE), breast cancer recurrence, and breast cancer death. Time-varying Cox proportional hazard models were used to estimate hazard ratios and their 95% confidence intervals (CI). Among 14,766 women included in the study, 791 experienced SBCE, 627 had a recurrence, and 237 died from breast cancer. Use of metformin (n=2,558) was associated with 28% (95% CI: 0.57-0.92), 31% (95% CI: 0.53-0.90), and 49% (95% CI: 0.33-0.78) lower risks of a SBCE, breast cancer recurrence, and breast cancer death. Use of sulfonylureas or insulin was associated with 1.49 (95% CI: 1.00-2.23) and 2.58-fold (95%CI: 1.72-3.90) higher risks of breast cancer death. Further research may be warranted to determine if metformin is a preferred treatment for diabetes among breast cancer survivors and whether it benefits breast cancer patients without diabetes.
http://ift.tt/2xs3wLI
ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer
In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity and teratoma formation by Lu-iPSC, and diminished clonogenicity and malignant growth of SCLC cells in-vivo. Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis, and highlight ASXL3 as a novel candidate target for SCLC therapy.
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miR-130a deregulates PTEN and stimulates tumor growth
H-RasV12 oncogene has been shown to promote autophagic cell death. Here we provide evidence of a contextual role for H-RasV12 in cell death that is varied by its effects on miR-130a. In E1A-immortalized murine embryo fibroblasts, acute expression of H-RasV12 promoted apoptosis but not autophagic cell death. miRNA screens in this system showed that miR-130a was strongly downregulated by H-RasV12 in this model system. Enforced expression of miR-130a increased cell proliferation in part via repression of PTEN. Consistent with this effect, miR-130a overexpression in human breast cancer cells promoted Akt phosphorylation, cell survival and tumor growth. In clinical specimens of multiple human cancers, expression of miR-130 family members correlated inversely with PTEN expression. Overall, our results defined miR-130a as an oncogenic microRNA that targets PTEN to drive malignant cell survival and tumor growth.
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Diabetes treatments and risks of adverse breast cancer outcomes among early stage breast cancer patients: A SEER-Medicare analysis
The widely prescribed diabetes medicine metformin has been reported to lower the risk of incident breast cancer, but it is unclear if it affects malignant progression after diagnosis. In this study, we conducted a retrospective cohort study using the linked Surveillance, Epidemiology and End-Results (SEER)-Medicare database. Women were included in the study if they were aged 66-80 years, newly diagnosed with stage I or II breast cancer, and enrolled in Medicare Parts A, B, and D during 2007-2011. Information on dispensed diabetes-related medications was obtained from Medicare Part D claims data. Our primary outcomes were second breast cancer events (SBCE), breast cancer recurrence, and breast cancer death. Time-varying Cox proportional hazard models were used to estimate hazard ratios and their 95% confidence intervals (CI). Among 14,766 women included in the study, 791 experienced SBCE, 627 had a recurrence, and 237 died from breast cancer. Use of metformin (n=2,558) was associated with 28% (95% CI: 0.57-0.92), 31% (95% CI: 0.53-0.90), and 49% (95% CI: 0.33-0.78) lower risks of a SBCE, breast cancer recurrence, and breast cancer death. Use of sulfonylureas or insulin was associated with 1.49 (95% CI: 1.00-2.23) and 2.58-fold (95%CI: 1.72-3.90) higher risks of breast cancer death. Further research may be warranted to determine if metformin is a preferred treatment for diabetes among breast cancer survivors and whether it benefits breast cancer patients without diabetes.
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Improvements in Clinical Practice for Fertility Preservation Among Young Cancer Patients: Results from Bundled Interventions
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Geographic Access to Cancer Care and Mortality Among Adolescents
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Improvements in Clinical Practice for Fertility Preservation Among Young Cancer Patients: Results from Bundled Interventions
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Geographic Access to Cancer Care and Mortality Among Adolescents
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial
We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.
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Prognostic factors for tube feeding dependence after curative (chemo-) radiation in head and neck cancer: A systematic review of literature
Tube feeding dependence is a commonly observed debilitating side-effect of curative (chemo-) radiation in head and neck cancer patients that severely affects quality of life. Prevention of this side-effect can be obtained using advanced radiation techniques, such as IMRT. For radiotherapy treatment plan optimization, it has become increasingly important to develop prediction models that enable clinicians to predict the risk of tube feeding dependence for individual patients. To develop such a tool, information regarding the most relevant prognostic factors for tube feeding dependence is necessary.
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Evolution in sentinel lymph node biopsy in breast cancer
Source:Critical Reviews in Oncology/Hematology
Author(s): Si-Qi Qiu, Guo-Jun Zhang, Liesbeth Jansen, Jakob de Vries, Carolien P. Schröder, Elisabeth G.E. de Vries, Gooitzen M. van Dam
Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer.
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Evolution in sentinel lymph node biopsy in breast cancer
Source:Critical Reviews in Oncology/Hematology
Author(s): Si-Qi Qiu, Guo-Jun Zhang, Liesbeth Jansen, Jakob de Vries, Carolien P. Schröder, Elisabeth G.E. de Vries, Gooitzen M. van Dam
Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer.
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Significance of glucocorticoid receptor expression in patients with non-small cell lung cancer treated with pemetrexed-based chemotherapy
Abstract
Background
Pemetrexed is the preferred chemotherapy agent in the management of non-squamous non-small cell lung cancer (non-sq-NSCLC), but lacks biomarkers predicting its efficacy. Dexamethasone, one of the premedications of pemetrexed, may downregulate p53 through the glucocorticoid receptor (GR). The purpose of our study was to explore the effect of GR in peripheral blood mononuclear cells (PBMC) and its role in predicting pemetrexed efficacy.
Methods
In all, 122 patients with stage IV non-sq-NSCLC who received first-line pemetrexed-containing chemotherapy were retrospectively reviewed. The expression of GR in PBMC was measured before treatment with pemetrexed using real-time PCR was used to detect the levels of GRα and GRβ.
Results
The response rate for all patients was 38.5%, with a median progression-free survival (PFS) of 5.9 months and overall survival (OS) of 14.3 months. In univariate analyses, patients with a low GRα/GRβ ratio in PBMC had higher RR, better PFS, and better OS than those with a high GRα/GRβ ratio (RR: 48.2 vs. 30.3%, p = 0.043; mPFS: 6.9 vs. 4.0 months, p < 0.001; mOS: 18.7 vs. 12.2 months, p = 0.005). The baseline GRα/GRβ ratio was an independent factor for RR (odds ratio [OR] = 0.451, 95% CI 0.208–0.978; p = 0.044), PFS (HR = 1.584, 95% CI 1.094–2.295; p = 0.015), and OS (HR = 1.761, 95% CI 1.195–2.595; p = 0.004).
Conclusions
Baseline GRα/GRβ ratio in PBMC may play a role in predicting the efficacy of first-line pemetrexed-containing chemotherapy in stage IV non-sq NSCLC patients.
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Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition
Abstract
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.
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Superactive human leptin antagonist (SHLA), triple Lan1 and quadruple Lan2 leptin mutein as a promising treatment for human folliculoma
Abstract
Purpose
There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.
Methods
We evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).
Results
ObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.
Conclusion
These results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment.
Graphical abstract
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Significance of glucocorticoid receptor expression in patients with non-small cell lung cancer treated with pemetrexed-based chemotherapy
Abstract
Background
Pemetrexed is the preferred chemotherapy agent in the management of non-squamous non-small cell lung cancer (non-sq-NSCLC), but lacks biomarkers predicting its efficacy. Dexamethasone, one of the premedications of pemetrexed, may downregulate p53 through the glucocorticoid receptor (GR). The purpose of our study was to explore the effect of GR in peripheral blood mononuclear cells (PBMC) and its role in predicting pemetrexed efficacy.
Methods
In all, 122 patients with stage IV non-sq-NSCLC who received first-line pemetrexed-containing chemotherapy were retrospectively reviewed. The expression of GR in PBMC was measured before treatment with pemetrexed using real-time PCR was used to detect the levels of GRα and GRβ.
Results
The response rate for all patients was 38.5%, with a median progression-free survival (PFS) of 5.9 months and overall survival (OS) of 14.3 months. In univariate analyses, patients with a low GRα/GRβ ratio in PBMC had higher RR, better PFS, and better OS than those with a high GRα/GRβ ratio (RR: 48.2 vs. 30.3%, p = 0.043; mPFS: 6.9 vs. 4.0 months, p < 0.001; mOS: 18.7 vs. 12.2 months, p = 0.005). The baseline GRα/GRβ ratio was an independent factor for RR (odds ratio [OR] = 0.451, 95% CI 0.208–0.978; p = 0.044), PFS (HR = 1.584, 95% CI 1.094–2.295; p = 0.015), and OS (HR = 1.761, 95% CI 1.195–2.595; p = 0.004).
Conclusions
Baseline GRα/GRβ ratio in PBMC may play a role in predicting the efficacy of first-line pemetrexed-containing chemotherapy in stage IV non-sq NSCLC patients.
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Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition
Abstract
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.
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Superactive human leptin antagonist (SHLA), triple Lan1 and quadruple Lan2 leptin mutein as a promising treatment for human folliculoma
Abstract
Purpose
There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.
Methods
We evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).
Results
ObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.
Conclusion
These results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment.
Graphical abstract
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Consumption of alcohol and cardiovascular disease mortality: a 16 year follow-up of 115,592 Norwegian men and women aged 40–44 years
Abstract
We tested whether teetotalism explains the upturn in cardiovascular risk for non-drinkers and whether wine is a more favorable alcohol type. We studied 115,592 men and women aged 40–44 years who participated in the age 40 program in Norway in 1994–1999 and were followed for an average of 16 years with 550 cardiovascular deaths. Self-reported number of glasses of beer, wine and spirits during 14 days was transformed to alcohol units/day. One unit is approximately 8 grams of pure alcohol. The mean and median number of alcohol units/day were 0.70 and 0.46. Teetotallers had higher risk of dying from cardiovascular disease than alcohol consumers, multivariate adjusted hazard ratio (95% CI) 1.97 (1.52–2.56). The use of alcohol-related deaths as endpoint substantiated a selection of previous alcohol users to the teetotal group. Without teetotallers there was no association between alcohol consumption and cardiovascular disease mortality. However, the multivariate adjusted hazard ratio per one unit/day of wine was 0.76 (0.58–0.99). The corresponding figures for beer and spirits were 1.04 (0.94–1.15) and 0.98 (0.75–1.29). The upturn in risk for non-drinkers could be explained by a higher risk for teetotallers who likely included previous alcohol users or teetotalers who started to drink during follow-up. Wine gave the most favorable risk estimates.
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Integrated network analysis to explore the key genes regulated by parathyroid hormone receptor 1 in osteosarcoma
Abstract
Background
As an invasive malignant tumor, osteosarcoma (OS) has high mortality. Parathyroid hormone receptor 1 (PTHR1) contributes to maintaining proliferation and undifferentiated state of OS. This study is designed to reveal the action mechanisms of PTHR1 in OS.
Methods
Microarray dataset GSE46861, which included six PTHR1 knockdown OS samples and six control OS samples, was obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and then performed with enrichment analysis separately using the limma package and DAVID online tool. Then, protein-protein interaction (PPI) network and module analyses were conducted using Cytoscape software. Using the WebGestalt tool, microRNAs (miRNAs) were predicted for the DEGs involved in the PPI network. Following this, transcription factors (TFs) were predicted and an integrated network was constructed by Cytoscape software.
Results
There were 871 DEGs in the PTHR1 knockdown OS samples compared with the control OS samples. Besides, upregulated ZFPM2 was involved in the miRNA-DEG regulatory network. Moreover, TF LEF1 was predicted for the miRNA-DEG regulatory network of the downregulated genes. In addition, LEF1, NR4A2, HAS2, and RHOC had higher degrees in the integrated network.
Conclusions
ZFPM2, LEF1, NR4A2, HAS2, and RHOC might be potential targets of PTHR1 in OS.
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Integrated network analysis to explore the key genes regulated by parathyroid hormone receptor 1 in osteosarcoma
Abstract
Background
As an invasive malignant tumor, osteosarcoma (OS) has high mortality. Parathyroid hormone receptor 1 (PTHR1) contributes to maintaining proliferation and undifferentiated state of OS. This study is designed to reveal the action mechanisms of PTHR1 in OS.
Methods
Microarray dataset GSE46861, which included six PTHR1 knockdown OS samples and six control OS samples, was obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and then performed with enrichment analysis separately using the limma package and DAVID online tool. Then, protein-protein interaction (PPI) network and module analyses were conducted using Cytoscape software. Using the WebGestalt tool, microRNAs (miRNAs) were predicted for the DEGs involved in the PPI network. Following this, transcription factors (TFs) were predicted and an integrated network was constructed by Cytoscape software.
Results
There were 871 DEGs in the PTHR1 knockdown OS samples compared with the control OS samples. Besides, upregulated ZFPM2 was involved in the miRNA-DEG regulatory network. Moreover, TF LEF1 was predicted for the miRNA-DEG regulatory network of the downregulated genes. In addition, LEF1, NR4A2, HAS2, and RHOC had higher degrees in the integrated network.
Conclusions
ZFPM2, LEF1, NR4A2, HAS2, and RHOC might be potential targets of PTHR1 in OS.
http://ift.tt/2xUmjRj
Guidelines for the use of chest radiographs in community-acquired pneumonia in children and adolescents
Abstract
National guidance from the United Kingdom and the United States on community-acquired pneumonia in children states that chest radiographs are not recommended routinely in uncomplicated cases. The main reason in the ambulatory setting is that there is no evidence of a substantial impact on clinical outcomes. However clinical practice and adherence to guidance is multifactorial and includes the clinical context (developed vs. developing world), the confidence of the attending physician, the changing incidence of complications (according to the success of immunisation programs), the availability of alternative imaging (and its relationship to perceived risks of radiation) and the reliability of the interpretation of imaging. In practice, chest radiographs are performed frequently for suspected pneumonia in children. Time pressures facing clinicians at the front line, difficulties in distinguishing which children require admission, restricted bed numbers for admissions, imaging-resource limitations, perceptions regarding risk from procedures, novel imaging modalities and the probability of other causes for the child's presentation all need to be factored into a guideline. Other drivers that often weigh in, depending on the setting, include cost-effectiveness and the fear of litigation. Not all guidelines designed for the developed world can therefore be applied to the developing world, and practice guidelines require regular review in the context of new information. In addition, radiologists must improve radiographic diagnosis of pneumonia, reach consensus on the interpretive terminology that clarifies their confidence regarding the presence of pneumonia and act to replace one imaging technique with another whenever there is proof of improved accuracy or reliability.
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Community-acquired pneumonia in children — a changing spectrum of disease
Abstract
Pneumonia remains the leading cause of death in children outside the neonatal period, despite advances in prevention and management. Over the last 20 years, there has been a substantial decrease in the incidence of childhood pneumonia and pneumonia-associated mortality. New conjugate vaccines against Haemophilus influenzae type b and Streptococcus pneumoniae have contributed to decreases in radiologic, clinical and complicated pneumonia cases and have reduced hospitalization and mortality. The importance of co-infections with multiple pathogens and the predominance of viral-associated disease are emerging. Better access to effective preventative and management strategies is needed in low- and middle-income countries, while new strategies are needed to address the residual burden of disease once these have been implemented.
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Preliminary report from the World Health Organisation Chest Radiography in Epidemiological Studies project
Abstract
Childhood pneumonia is among the leading infectious causes of mortality in children younger than 5 years of age globally. Streptococcus pneumoniae (pneumococcus) is the leading infectious cause of childhood bacterial pneumonia. The diagnosis of childhood pneumonia remains a critical epidemiological task for monitoring vaccine and treatment program effectiveness. The chest radiograph remains the most readily available and common imaging modality to assess childhood pneumonia. In 1997, the World Health Organization Radiology Working Group was established to provide a consensus method for the standardized definition for the interpretation of pediatric frontal chest radiographs, for use in bacterial vaccine efficacy trials in children. The definition was not designed for use in individual patient clinical management because of its emphasis on specificity at the expense of sensitivity. These definitions and endpoint conclusions were published in 2001 and an analysis of observer variation for these conclusions using a reference library of chest radiographs was published in 2005. In response to the technical needs identified through subsequent meetings, the World Health Organization Chest Radiography in Epidemiological Studies (CRES) project was initiated and is designed to be a continuation of the World Health Organization Radiology Working Group. The aims of the World Health Organization CRES project are to clarify the definitions used in the World Health Organization defined standardized interpretation of pediatric chest radiographs in bacterial vaccine impact and pneumonia epidemiological studies, reinforce the focus on reproducible chest radiograph readings, provide training and support with World Health Organization defined standardized interpretation of chest radiographs and develop guidelines and tools for investigators and site staff to assist in obtaining high-quality chest radiographs.
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Guidelines for the use of chest radiographs in community-acquired pneumonia in children and adolescents
Abstract
National guidance from the United Kingdom and the United States on community-acquired pneumonia in children states that chest radiographs are not recommended routinely in uncomplicated cases. The main reason in the ambulatory setting is that there is no evidence of a substantial impact on clinical outcomes. However clinical practice and adherence to guidance is multifactorial and includes the clinical context (developed vs. developing world), the confidence of the attending physician, the changing incidence of complications (according to the success of immunisation programs), the availability of alternative imaging (and its relationship to perceived risks of radiation) and the reliability of the interpretation of imaging. In practice, chest radiographs are performed frequently for suspected pneumonia in children. Time pressures facing clinicians at the front line, difficulties in distinguishing which children require admission, restricted bed numbers for admissions, imaging-resource limitations, perceptions regarding risk from procedures, novel imaging modalities and the probability of other causes for the child's presentation all need to be factored into a guideline. Other drivers that often weigh in, depending on the setting, include cost-effectiveness and the fear of litigation. Not all guidelines designed for the developed world can therefore be applied to the developing world, and practice guidelines require regular review in the context of new information. In addition, radiologists must improve radiographic diagnosis of pneumonia, reach consensus on the interpretive terminology that clarifies their confidence regarding the presence of pneumonia and act to replace one imaging technique with another whenever there is proof of improved accuracy or reliability.
http://ift.tt/2xijqIY
Community-acquired pneumonia in children — a changing spectrum of disease
Abstract
Pneumonia remains the leading cause of death in children outside the neonatal period, despite advances in prevention and management. Over the last 20 years, there has been a substantial decrease in the incidence of childhood pneumonia and pneumonia-associated mortality. New conjugate vaccines against Haemophilus influenzae type b and Streptococcus pneumoniae have contributed to decreases in radiologic, clinical and complicated pneumonia cases and have reduced hospitalization and mortality. The importance of co-infections with multiple pathogens and the predominance of viral-associated disease are emerging. Better access to effective preventative and management strategies is needed in low- and middle-income countries, while new strategies are needed to address the residual burden of disease once these have been implemented.
http://ift.tt/2fkjW2e
Preliminary report from the World Health Organisation Chest Radiography in Epidemiological Studies project
Abstract
Childhood pneumonia is among the leading infectious causes of mortality in children younger than 5 years of age globally. Streptococcus pneumoniae (pneumococcus) is the leading infectious cause of childhood bacterial pneumonia. The diagnosis of childhood pneumonia remains a critical epidemiological task for monitoring vaccine and treatment program effectiveness. The chest radiograph remains the most readily available and common imaging modality to assess childhood pneumonia. In 1997, the World Health Organization Radiology Working Group was established to provide a consensus method for the standardized definition for the interpretation of pediatric frontal chest radiographs, for use in bacterial vaccine efficacy trials in children. The definition was not designed for use in individual patient clinical management because of its emphasis on specificity at the expense of sensitivity. These definitions and endpoint conclusions were published in 2001 and an analysis of observer variation for these conclusions using a reference library of chest radiographs was published in 2005. In response to the technical needs identified through subsequent meetings, the World Health Organization Chest Radiography in Epidemiological Studies (CRES) project was initiated and is designed to be a continuation of the World Health Organization Radiology Working Group. The aims of the World Health Organization CRES project are to clarify the definitions used in the World Health Organization defined standardized interpretation of pediatric chest radiographs in bacterial vaccine impact and pneumonia epidemiological studies, reinforce the focus on reproducible chest radiograph readings, provide training and support with World Health Organization defined standardized interpretation of chest radiographs and develop guidelines and tools for investigators and site staff to assist in obtaining high-quality chest radiographs.
http://ift.tt/2flj91h
Consumption of alcohol and cardiovascular disease mortality: a 16 year follow-up of 115,592 Norwegian men and women aged 40–44 years
Abstract
We tested whether teetotalism explains the upturn in cardiovascular risk for non-drinkers and whether wine is a more favorable alcohol type. We studied 115,592 men and women aged 40–44 years who participated in the age 40 program in Norway in 1994–1999 and were followed for an average of 16 years with 550 cardiovascular deaths. Self-reported number of glasses of beer, wine and spirits during 14 days was transformed to alcohol units/day. One unit is approximately 8 grams of pure alcohol. The mean and median number of alcohol units/day were 0.70 and 0.46. Teetotallers had higher risk of dying from cardiovascular disease than alcohol consumers, multivariate adjusted hazard ratio (95% CI) 1.97 (1.52–2.56). The use of alcohol-related deaths as endpoint substantiated a selection of previous alcohol users to the teetotal group. Without teetotallers there was no association between alcohol consumption and cardiovascular disease mortality. However, the multivariate adjusted hazard ratio per one unit/day of wine was 0.76 (0.58–0.99). The corresponding figures for beer and spirits were 1.04 (0.94–1.15) and 0.98 (0.75–1.29). The upturn in risk for non-drinkers could be explained by a higher risk for teetotallers who likely included previous alcohol users or teetotalers who started to drink during follow-up. Wine gave the most favorable risk estimates.
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Consumption of alcohol and cardiovascular disease mortality: a 16 year follow-up of 115,592 Norwegian men and women aged 40–44 years
Abstract
We tested whether teetotalism explains the upturn in cardiovascular risk for non-drinkers and whether wine is a more favorable alcohol type. We studied 115,592 men and women aged 40–44 years who participated in the age 40 program in Norway in 1994–1999 and were followed for an average of 16 years with 550 cardiovascular deaths. Self-reported number of glasses of beer, wine and spirits during 14 days was transformed to alcohol units/day. One unit is approximately 8 grams of pure alcohol. The mean and median number of alcohol units/day were 0.70 and 0.46. Teetotallers had higher risk of dying from cardiovascular disease than alcohol consumers, multivariate adjusted hazard ratio (95% CI) 1.97 (1.52–2.56). The use of alcohol-related deaths as endpoint substantiated a selection of previous alcohol users to the teetotal group. Without teetotallers there was no association between alcohol consumption and cardiovascular disease mortality. However, the multivariate adjusted hazard ratio per one unit/day of wine was 0.76 (0.58–0.99). The corresponding figures for beer and spirits were 1.04 (0.94–1.15) and 0.98 (0.75–1.29). The upturn in risk for non-drinkers could be explained by a higher risk for teetotallers who likely included previous alcohol users or teetotalers who started to drink during follow-up. Wine gave the most favorable risk estimates.
http://ift.tt/2yt6U7e
Immune-Related Adverse Events and Nivolumab Efficacy in NSCLC
This medical record review evaluates the relation of immune-related adverse events to nivolumab efficacy in non–small-cell lung cancer.
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Delayed Adjacent Chemotherapy and Survival After Lung Cancer Surgery—Reply
In Reply We agree that observational comparison of outcomes across populations is dependent on the distribution of all attributes with the potential to affect the outcome of interest. For attributes that are captured by the database (eg, age, comorbidity, stage), a number of strategies were used to create balance (propensity matching) or adjust for imbalances (Cox proportional hazards). For attributes that are not captured by the database (eg, performance status [PS], smoking status), one must first hypothesize as to whether an imbalance is likely. First, we identified populations by a common event that tends to create balance in unmeasured attributes. All patients had undergone and survived lung cancer surgery. This would suggest that all patients had a reasonable PS (in the study by Kawaguchi et al, 75% of patients who underwent surgery had a PS of 0). Whereas PS and smoking have not been examined in relationship to the timing of adjuvant chemotherapy in lung cancer per se, neither has been associated with delays for other tumor types. Therefore, we believe that imbalances, should they exist for smoking and PS, would likely be subtle.
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Improving Treatment for Patients With Gastroesophageal Cancer
Optimal multimodality treatment followed by surgical resection results in cure for less than half of patients with operable adenocarcinoma of the lower esophagus or gastroesophageal junction. This is true whether the adjunctive therapy is neoadjuvant chemotherapy, perioperative chemotherapy, or neoadjuvant chemoradiotherapy. Therefore, it is reasonable to question whether additional treatment beyond current standards of care might increase the proportion of patients cured. In this issue of JAMA Oncology, Mokdad and colleagues, in a propensity score–matched analysis based on a large National Cancer Database cohort, examine the effects of adjuvant chemotherapy following chemoradiotherapy and surgery for resectable gastroesophageal adenocarcinoma. They found that patients treated with adjuvant chemotherapy had improved overall survival compared with those who did not receive adjuvant treatment (median overall survival, 40 vs 34 months; hazard ratio, 0.79; 95% CI, 0.72-0.88; P < .001). Based on these findings, a randomized clinical trial of adjuvant chemotherapy vs observation following neoadjuvant chemoradiotherapy and surgical resection is proposed to provide a definitive answer to this question.
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Delayed Adjacent Chemotherapy and Survival After Lung Cancer Surgery
To the Editor In their recent article in JAMA Oncology, Salazar et al found that patients with non–small cell lung cancer treated with delayed chemotherapy, defined as chemotherapy administered after 56 days, had better outcomes, with hazard ratio of 0.664 (95% CI, 0.623-0.707; P < .001) compared with patients who received surgery alone. The authors listed multiple valid limitations to their study, including the retrospective nature of the National Cancer Database data that they used.
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HIV Status and Anal Cancer Outcomes in the Post-HAART Era
This study uses data from the Veterans Affairs database to examine the association of HIV status with outcomes in patients with anal cancer.
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Enhancing Interpretability of Cancer Clinical Trial Results
This comparative clinical study discusses problems with conventional trial design and analysis and presents alternatives to the hazard ratio using a recent immunotherapy study as an illustrative example.
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Adjuvant Chemotherapy After Gastroesophageal Cancer Surgery
This propensity score–matched analysis uses National Cancer Database data on patients with gastroesophageal adenocarcinoma who received preoperative chemoradiotherapy and resection to explore whether adjuvant chemotherapy confers a survival benefit compared with observation.
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ITIH5 induces a shift in TGF-β superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death
Abstract
ITIH5 has been proposed being a novel tumor suppressor in various tumor entities including breast cancer. Recently, ITIH5 was furthermore identified as metastasis suppressor gene in pancreatic carcinoma. In this study we aimed to specify the impact of ITIH5 on metastasis in breast cancer. Therefore, DNA methylation of ITIH5 promoter regions was assessed in breast cancer metastases using the TCGA portal and methylation-specific PCR. We reveal that the ITIH5 upstream promoter region is particularly responsible for ITIH5 gene inactivation predicting shorter survival of patients. Notably, methylation of this upstream ITIH5 promoter region was associated with increased progression, e.g. abundantly found in distant metastases. In vitro, stably ITIH5-overexpressing MDA-MB-231 breast cancer clones were used to analyze cell invasion and to identify novel ITIH5-downstream targets. Indeed, ITIH5 re-expression suppresses invasive growth of MDA-MB-231 breast cancer cells while modulating expression of genes involved in metastasis including Endoglin (ENG), an accessory TGF-β receptor, which was furthermore co-expressed with ITIH5 in primary breast tumors. By performing in vitro stimulation of TGF-β signaling using TGF-β1 and BMP-2 we show that ITIH5 triggered a TGF-β superfamily signaling switch contributing to downregulation of targets like Id1, known to endorse metastasis. Moreover, ITIH5 predicts longer overall survival only in those breast tumors that feature high ENG expression or inversely regulated ID1 suggesting a clinical and functional impact of an ITIH5-ENG axis for breast cancer progression. Hence, we provide evidence that ITIH5 may represent a novel modulator of TGF-β superfamily signaling involved in suppressing breast cancer metastasis. This article is protected by copyright. All rights reserved
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MiR-182 inhibits the epithelial to mesenchymal transition and metastasis of lung cancer cells by targeting the Met gene
Abstract
Background: The microRNA miR-182, belonging to the miR-183 family, is one of the most frequently studied cancer-related oncogenic miRNAs that is dysregulated in various cancer tissues, and it plays a crucial role in tumorigenesis and tumor progression. Studies revealed that miR-182 might function as an oncogenic or tumor suppressor miRNA in different tissues. However, the role of miR-182 in the development of lung cancer remains largely unknown.
Methods: miR-182 expression in tumor samples from 58 patients, normal lung tissue samples, and lung cancer cell lines were evaluated by qRT-PCR. Survival curves were analyzed using the Kaplan-Meier method and compared with a log-rank test.
Results: Our study demonstrated that miR-182 is frequently downregulated in metastatic NSCLC cells compared with primary tumor tissues. Over-expression of miR-182 significantly inhibited the migration and invasion of lung cancer cells and promoted the expression of the epithelial marker (E-cadherin) in addition to reducing the levels of Snail in lung cancer cells. Further studies demonstrated that miR-182 negatively regulated Met via direct binding to the Met 3'-untranslated region (3'-UTR). Furthermore, we found that miR-182 suppressed the phosphorylation of AKT and the nuclear accumulation of Snail, a transcription factor that promotes the epidermal to mesenchymal transition (EMT). Moreover, miR-182 could repress cell migration, invasion and EMT of lung cancer cells induced by hepatocyte growth factor (HGF).
Conclusions: miR-182 might suppress the EMT and metastasis via inactivation of Met/AKT/Snail in non-small cell lung cancer (NSCLC) cells, which implicates miR-182 may be useful as a new therapeutic target in NSCLC. This article is protected by copyright. All rights reserved
http://ift.tt/2w91bSE
ITIH5 induces a shift in TGF-β superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death
Abstract
ITIH5 has been proposed being a novel tumor suppressor in various tumor entities including breast cancer. Recently, ITIH5 was furthermore identified as metastasis suppressor gene in pancreatic carcinoma. In this study we aimed to specify the impact of ITIH5 on metastasis in breast cancer. Therefore, DNA methylation of ITIH5 promoter regions was assessed in breast cancer metastases using the TCGA portal and methylation-specific PCR. We reveal that the ITIH5 upstream promoter region is particularly responsible for ITIH5 gene inactivation predicting shorter survival of patients. Notably, methylation of this upstream ITIH5 promoter region was associated with increased progression, e.g. abundantly found in distant metastases. In vitro, stably ITIH5-overexpressing MDA-MB-231 breast cancer clones were used to analyze cell invasion and to identify novel ITIH5-downstream targets. Indeed, ITIH5 re-expression suppresses invasive growth of MDA-MB-231 breast cancer cells while modulating expression of genes involved in metastasis including Endoglin (ENG), an accessory TGF-β receptor, which was furthermore co-expressed with ITIH5 in primary breast tumors. By performing in vitro stimulation of TGF-β signaling using TGF-β1 and BMP-2 we show that ITIH5 triggered a TGF-β superfamily signaling switch contributing to downregulation of targets like Id1, known to endorse metastasis. Moreover, ITIH5 predicts longer overall survival only in those breast tumors that feature high ENG expression or inversely regulated ID1 suggesting a clinical and functional impact of an ITIH5-ENG axis for breast cancer progression. Hence, we provide evidence that ITIH5 may represent a novel modulator of TGF-β superfamily signaling involved in suppressing breast cancer metastasis. This article is protected by copyright. All rights reserved
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MiR-182 inhibits the epithelial to mesenchymal transition and metastasis of lung cancer cells by targeting the Met gene
Abstract
Background: The microRNA miR-182, belonging to the miR-183 family, is one of the most frequently studied cancer-related oncogenic miRNAs that is dysregulated in various cancer tissues, and it plays a crucial role in tumorigenesis and tumor progression. Studies revealed that miR-182 might function as an oncogenic or tumor suppressor miRNA in different tissues. However, the role of miR-182 in the development of lung cancer remains largely unknown.
Methods: miR-182 expression in tumor samples from 58 patients, normal lung tissue samples, and lung cancer cell lines were evaluated by qRT-PCR. Survival curves were analyzed using the Kaplan-Meier method and compared with a log-rank test.
Results: Our study demonstrated that miR-182 is frequently downregulated in metastatic NSCLC cells compared with primary tumor tissues. Over-expression of miR-182 significantly inhibited the migration and invasion of lung cancer cells and promoted the expression of the epithelial marker (E-cadherin) in addition to reducing the levels of Snail in lung cancer cells. Further studies demonstrated that miR-182 negatively regulated Met via direct binding to the Met 3'-untranslated region (3'-UTR). Furthermore, we found that miR-182 suppressed the phosphorylation of AKT and the nuclear accumulation of Snail, a transcription factor that promotes the epidermal to mesenchymal transition (EMT). Moreover, miR-182 could repress cell migration, invasion and EMT of lung cancer cells induced by hepatocyte growth factor (HGF).
Conclusions: miR-182 might suppress the EMT and metastasis via inactivation of Met/AKT/Snail in non-small cell lung cancer (NSCLC) cells, which implicates miR-182 may be useful as a new therapeutic target in NSCLC. This article is protected by copyright. All rights reserved
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The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas
BACKGROUND
Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the current study was to identify novel somatically mutated genes in UCSs.
METHODS
We whole exome sequenced paired tumor and nontumor DNAs from 14 UCSs and orthogonally validated 464 somatic variants using Sanger sequencing. Fifteen genes that were somatically mutated in at least 2 tumor exomes were Sanger sequenced in another 39 primary UCSs.
RESULTS
Overall, among 53 UCSs in the current study, the most frequently mutated of these 15 genes were tumor protein p53 (TP53) (75.5%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (34.0%), protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A) (18.9%), F-box and WD repeat domain containing 7 (FBXW7) (18.9%), chromodomain helicase DNA binding protein 4 (CHD4) (17.0%), and forkhead box A2 (FOXA2) (15.1%). FOXA2 has not previously been implicated in UCSs and was predominated by frameshift and nonsense mutations. One UCS with a FOXA2 frameshift mutation expressed truncated FOXA2 protein by immunoblotting. Sequencing of FOXA2 in 160 primary endometrial carcinomas revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid, and 11.1% of mixed endometrial carcinomas, the majority of which were frameshift mutations.
CONCLUSIONS
Collectively, the findings of the current study provide compelling genetic evidence that FOXA2 is a pathogenic driver gene in the etiology of primary uterine cancers, including UCSs. Cancer 2017. © 2017 American Cancer Society.
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Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor–mutant lung cancers and brain metastases
BACKGROUND
In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)–mutant lung cancers with untreated brain metastases.
METHODS
Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors).
RESULTS
Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue.
CONCLUSIONS
Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2017. © 2017 American Cancer Society.
from Cancer via ola Kala on Inoreader http://ift.tt/2xx3d2w
via IFTTT
Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor–mutant lung cancers and brain metastases
BACKGROUND
In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)–mutant lung cancers with untreated brain metastases.
METHODS
Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors).
RESULTS
Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue.
CONCLUSIONS
Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2017. © 2017 American Cancer Society.
http://ift.tt/2xx3d2w
The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas
BACKGROUND
Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the current study was to identify novel somatically mutated genes in UCSs.
METHODS
We whole exome sequenced paired tumor and nontumor DNAs from 14 UCSs and orthogonally validated 464 somatic variants using Sanger sequencing. Fifteen genes that were somatically mutated in at least 2 tumor exomes were Sanger sequenced in another 39 primary UCSs.
RESULTS
Overall, among 53 UCSs in the current study, the most frequently mutated of these 15 genes were tumor protein p53 (TP53) (75.5%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (34.0%), protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A) (18.9%), F-box and WD repeat domain containing 7 (FBXW7) (18.9%), chromodomain helicase DNA binding protein 4 (CHD4) (17.0%), and forkhead box A2 (FOXA2) (15.1%). FOXA2 has not previously been implicated in UCSs and was predominated by frameshift and nonsense mutations. One UCS with a FOXA2 frameshift mutation expressed truncated FOXA2 protein by immunoblotting. Sequencing of FOXA2 in 160 primary endometrial carcinomas revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid, and 11.1% of mixed endometrial carcinomas, the majority of which were frameshift mutations.
CONCLUSIONS
Collectively, the findings of the current study provide compelling genetic evidence that FOXA2 is a pathogenic driver gene in the etiology of primary uterine cancers, including UCSs. Cancer 2017. © 2017 American Cancer Society.
http://ift.tt/2fkCO15
Successful Treatment of Cardiac Angiosarcoma Associated with Disseminated Intravascular Coagulation with Nab-Paclitaxel: A Case Report and Review of the Literature
Angiosarcoma of the heart is an uncommon soft tissue sarcoma. A few cases of disseminated intravascular coagulation (DIC) associated with angiosarcoma occurring in various organs, but not the heart, have been reported. Although taxane is commonly used in the treatment of metastatic angiosarcoma, data on the efficacy of nab-paclitaxel for angiosarcoma are limited. Here, we report probably the first case of a patient with primary cardiac angiosarcoma with coexisting DIC who was successfully treated with nab-paclitaxel. A 62-year-old female with chief complaints of nausea and shortness of breath was diagnosed as having cardiac angiosarcoma with liver metastases. Four months after the resection of her primary tumor, the hepatic metastatic lesions progressed rapidly accompanied by new metastatic lesions in the right iliac bone and signs of DIC. She received nab-paclitaxel as first-line chemotherapy. A response of stable disease was achieved after 2 treatment cycles and DIC was successfully controlled for at least 4 months. This report suggests potential utility of nab-paclitaxel for angiosarcoma complicated with DIC. We also review the literature for all cases of angiosarcoma with DIC reported so far.
Case Rep Oncol 2017;10:863–870
http://ift.tt/2fDnCt3
Liquid Biopsy Prevents Inaccurate Her2 Status Determination by in situ Hybridization in a Patient with Invasive Ductal Adenocarcinoma of the Breast: Case Report
Utilization of circulating tumor DNA as a novel and noninvasive test for diagnosis confirmation, therapy selection, and cancer surveillance is a rapidly growing area of interest. In the wake of FDA approval of a liquid biopsy test, it is important for clinicians to acknowledge the obvious clinical utility of liquid biopsy for cancer management throughout the course of the disease. This case report describes a female with invasive ductal adenocarcinoma of the breast, where liquid biopsy was instrumental for her cancer characterization and personalized therapy selection.
Case Rep Oncol 2017;10:857–862
http://ift.tt/2xhj2dZ
Preanalytical blood sample workup for cell-free DNA analysis using Droplet Digital PCR for future molecular cancer diagnostics
Abstract
In current molecular cancer diagnostics, using blood samples of cancer patients for the detection of genetic alterations in plasma (cell-free) circulating tumor DNA (ctDNA) is an emerging practice. Since ctDNA levels in blood are low, highly sensitive Droplet Digital PCR (ddPCR) can be used for detecting rare mutational targets. In order to perform ddPCR on blood samples, a standardized procedure for processing and analyzing blood samples is necessary to facilitate implementation into clinical practice. Therefore, we assessed the technical sample workup procedure for ddPCR on blood plasma samples. Blood samples from healthy individuals, as well as lung cancer patients were analyzed. We compared different methods and protocols for sample collection, storage, centrifugation, isolation, and quantification. Cell-free DNA (cfDNA) concentrations of several wild-type targets and BRAF and EGFR-mutant ctDNA concentrations quantified by ddPCR were primary outcome measurements. Highest cfDNA concentrations were measured in blood collected in serum tubes. No significant differences in cfDNA concentrations were detected between various time points of up to 24 h until centrifugation. Highest cfDNA concentrations were detected after DNA isolation with the Quick cfDNA Serum & Plasma Kit, while plasma isolation using the QIAamp Circulating Nucleic Acid Kit yielded the most consistent results. DdPCR results on cfDNA are highly dependent on multiple factors during preanalytical sample workup, which need to be addressed during the development of this diagnostic tool for cancer diagnostics in the future.
Droplet Digital PCR (ddPCR) is an emerging technique for analysis of cell-free DNA in cancer diagnostics. We investigated different methods and procedures used during preanalytical workup of blood samples.
http://ift.tt/2xjRvGp
Prognostic and predictive role of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy
Abstract
The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG-PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed-based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first-line pemetrexed-based chemotherapy, and evaluated by FDG-PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were correlated with FDG-PET parameters, such as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG-PET in a large series of MPM patients treated with first-line pemetrexed-based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut-off values to define early metabolic response supported the role of FDG-PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.
Our data confirmed the prognostic role of baseline FDG-PET in a large series of MPM patients: baseline SUVmax and TLG statistically significantly correlate with PFS and OS in all population. In patients without pleurodesis, the FDG-PET is able to predict treatment response: both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses have a statistically significant lower risk of PD and death.
http://ift.tt/2yfZqnm
Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors
Abstract
Although oncolytic adenoviruses are promising cancer therapy agents, for effective oncolytic activity, viruses need to specifically infect and effectively replicate in cancer cells but not in normal cells. We have previously identified a pancreatic cancer-targeting ligand, SYENFSA (SYE), by screening an adenovirus library displaying random peptides against human pancreatic cancer cells and reported that a survivin promoter-regulated adenovirus, displaying the SYE ligand (AdSur-SYE), provided effective oncolysis of pancreatic ductal adenocarcinoma (PDAC) in a preclinical study. As we examined the infectivity of AdSur-SYE in human surgical specimens of various pancreatic tumors, we unexpectedly found that AdSur-SYE showed high gene transduction efficiency for pancreatic neuroendocrine tumors (PNETs) as well as for PDAC, 9.1- and 6.2-fold, respectively, compared to that of the nontargeting virus (AdSur). The infectivity of both vectors was almost the same in other cancers and organs such as the pancreas. Immunostaining indicated that the cells infected with AdSur-SYE were PNET cells but not stromal cells. AdSur-SYE showed a significantly higher oncolytic potency than that of AdSur in human PNET cell lines, and intratumoral infection with AdSur-SYE completely diminished subcutaneous tumors in a murine model, in which AdSur-SYE effectively proliferated and spread. AdSur-SYE exerted a stronger oncolytic effect in primary PNET cells cocultured with mouse embryonic fibroblasts than AdSur did. Thus, AdSur-SYE shows promise as a next-generation therapy for PNET.
We have previously identified a pancreatic cancer-targeting peptide ligand and demonstrated that a survivin promoter-regulated adenovirus, displaying the ligand, provided effective oncolysis of pancreatic ductal adenocarcinoma in a preclinical study. In this study, we found that this adenovirus showed an even higher gene transduction efficiency and oncolytic potency for pancreatic neuroendocrine tumors in vitro, in a mouse model, and using clinical specimens of various human cancers. The data suggest that the virus, AdSur-SYE, is a promising next-generation therapy agent for pancreatic neuroendocrine tumors.
http://ift.tt/2xkmj9T
Effect of socioeconomic status on stage at diagnosis of lung cancer in a hospital-based multicenter retrospective clinical epidemiological study in China, 2005–2014
Abstract
There is inconsistent evidence of associations between socioeconomic status (SES) and lung cancer stage in non-Chinese populations up to now. We set out to determine how SES affects stage at diagnosis at both individual and area levels, from a hospital-based multicenter 10-year (2005–2014) retrospective clinical epidemiological study of 7184 primary lung cancer patients in mainland China. Individual-level SES data were measured based on two indicators from case report forms of the study: an individual's education and occupation. Seven census indicator variables were used as surrogates for the area-level SES with principal component analysis (PCA). Multivariate analysis was undertaken using binary logistic regressions and multinomial logit model to describe the association and explore the effect across tertiles on stage after adjusting for demographic variables. There was a significant stepwise gradient of effect across different stages in the highest tertile of area-level SES, comparing with the lowest tertile of area-level SES (ORs, 0.77, 0.67, and 0.29 for stage II, III, and IV). Patients with higher education were less likely to have stage IV lung cancer, comparing with the illiterate group (ORs, 0.52, 0.63, 0.71, 0.64 for primary school, middle school, high school, college degree or above subgroup, respectively). Findings suggest that the most socioeconomically deprived areas may be associated with a higher risk of advanced-stage lung cancer, and increasing educational level may be correlated with a lower risk to be diagnosed at advanced stage in both men and women.
To date, the role of socioeconomic status (SES), either at the individual or community level, in shaping lung cancer risk has been only measured in non-Chinese populations, and the association is inconsistent. This is the first study to consider, simultaneously, measures of SES at the individual and area levels in China, in which the most socioeconomically deprived areas is associated with a higher risk of advanced-stage lung cancer compared with the least deprived areas.
http://ift.tt/2yfNxxC
miR-206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9
Abstract
miR-206 plays an important role in regulating the growth of multiple cancer cells. Cyclin-dependent kinase 9 (CDK9) stimulates the production of abundant prosurvival proteins, leading to impaired apoptosis of cancer cells. However, it is unknown whether CDK9 is involved in the miR-206-mediated growth suppression of hepatocellular carcinoma (HCC) cells. In this study, we found that the expression level of miR-206 was significantly lower in HCC cell lines than that in normal hepatic cell line (L02). Meanwhile, CDK9 was upregulated in HCC cell lines. Moreover, miR-206 downregulated CDK9 in HCC cells via directly binding to its mRNA 3′ UTR, which resulted in a decrease of RNA PolII Ser2 phosphorylation and Mcl-1 level. Additionally, miR-206 suppressed the cell proliferation, and induced cell cycle arrest and apoptosis. Similarly, silence or inhibition of CDK9 also repressed the cell proliferation, and induced cell cycle arrest and apoptosis. Taken together, the results demonstrated that miR-206 inhibited the growth of HCC cells through targeting CDK9, suggesting that the miR-206-CDK9 pathway may be a novel target for the treatment of HCC.
miR-206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9. These data indicated that miR-206 plays its anti-HCC effect via, at least partially, targeting the CDK9 signaling pathway, suggesting that miR206-CDK9 pathway may be a novel potential target for the treatment of HCC.
http://ift.tt/2xjNiT8
Efficacy of biological response modifier lentinan with chemotherapy for advanced cancer: a meta-analysis
Abstract
Lentinan is a common biological response modifier. This study was sought to evaluate the efficacy of adjuvant lentinan combined with chemotherapy for advanced cancer. A meta-analysis of published prospective controlled trials investigating the effects of lentinan for kinds of advanced cancer was performed. Sensitivity analysis, inverted funnel plots, and trial sequence analysis were conducted to explore the reliability and stability of results. Seventeen clinical studies were identified containing 1423 patients. Twelve trials included gastrointestinal cancer (GIC), three trials included lung cancer (LC), and two trials included the two cancers. There was a increase in survival rate in 1 year (risk ratios [RR], 1.46, P = 0.001) and overall response rate including both complete and partial response (RR, 1.28, P = 0.005). There was also a reduction in progressive disease (RR, 0.57, P = 0.0005), nonsevere adverse events (RR, 0.88, P = 0.004), and severe adverse events (RR, 0.73, P = 0.007). Similar results were shown in the two subgroups of GIC and LC. Limited trials reported the data of median overall survival and time to treatment failure, and the data were insufficient for quantitative analysis, and no significant difference were found in 2-year survival rate. Adjuvant lentinan used with chemotherapy achieved improvements in 1-year survival rate, response rate, and adverse events in advanced cancer. The effect seemed to be similar irrespective of cancer type. However, its sustained efficacy on survival was still unclear.
Lentinan is a common biological response modifier. This study used meta-analysis method and found adjuvant lentinan with chemotherapy achieved improvements in 1-year survival rate, response rate, and adverse events in advanced cancer. The effect seemed to be similar irrespective of cancer type.
http://ift.tt/2yfZkw0
Nonsteroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk: results from the EPICAP study
Abstract
Chronic inflammation may play a role in prostate cancer carcinogenesis. In that context, our objective was to investigate the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in prostate cancer risk based on the EPICAP data. EPICAP is a population-based case–control study carried out in 2012–2013 (département of Hérault, France) that enrolled 819 men aged less than 75 years old newly diagnosed for prostate cancer and 879 controls frequency matched to the cases on age. Face to face interviews gathered information on several potential risk factors including NSAIDs use. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using unconditional logistic regression models. All-NSAIDs use was inversely associated with prostate cancer: OR 0.77, 95% CI 0.61–0.98, especially in men using NSAIDs that preferentially inhibit COX-2 activity (OR 0.48, 95% CI 0.28–0.79). Nonaspirin NSAIDs users had a decreased risk of prostate cancer (OR 0.72, 95% CI 0.53–0.99), particularly among men with an aggressive prostate cancer (OR 0.49, 95% CI 0.27–0.89) and in men with a personal history of prostatitis (OR 0.21, 95% CI 0.07–0.59). Our results are in favor of a decreased risk of prostate cancer in men using NSAIDs, particularly for men using preferential anti-COX-2 activity. The protective effect of NSAIDs seems to be more pronounced in aggressive prostate cancer and in men with a personal history of prostatitis, but this needs further investigations to be confirmed.
Our results showed a decreased risk of prostate cancer in men using NSAIDs, especially with frequent, current, and chronic use. This effect is particularly observed in men using nonaspirin NSAIDs, and especially with preferential anti-COX-2 activity. Protective effect of NSAIDs seemed to be more pronounced in aggressive prostate cancer and in situation of chronic inflammation mediated by a personal history of prostatitis.
http://ift.tt/2xjNfGW
Metabolomic and transcriptomic profiling of hepatocellular carcinomas in Hras12V transgenic mice
Abstract
Activation of the Ras/MAPK pathway is prevalently involved in the occurrence and development of hepatocellular carcinoma (HCC). However, its effects on the deregulated cellular metabolic processes involved in HCC in vivo remain unknown. In this study, a mouse model of HCC induced by hepatocyte-specific expression of the Hras12V oncogene was investigated using an integrative analysis of metabolomics and transcriptomics data. Consistent with the phenotype of abundant lipid droplets in HCC, the lipid biosynthesis in HCC was significantly enhanced by (1) a sufficient supply of acetyl-CoA from enhanced glycolysis and citrate shuttle activity; (2) a sufficient supply of NADPH from enhanced pentose phosphate pathway (PPP) activity; (3) upregulation of key enzymes associated with lipid biosynthesis; and (4) downregulation of key enzymes associated with bile acid biosynthesis. In addition, glutathione (GSH) was significantly elevated, which may result from a sufficient supply of 5-oxoproline and L-glutamate as well as an enhanced reduction in the process of GSSG being turned into GSH by NADPH. The high level of GSH along with elevated Bcl2 and Ucp2 expression may contribute to a normal level of reactive oxygen species (ROS) in HCC. In conclusion, our results suggest that the lipid metabolism, glycolysis, PPP, tricarboxylic acid (TCA) cycle, citrate shuttle activity, bile acid synthesis, and redox homeostasis in the HCC induced by ras oncogene are significantly perturbed, and these altered metabolic processes may play crucial roles in the carcinogenesis, development, and pathological characteristics of HCC.
This study provides integrative analysis of metabolomics and transcriptomics data for mouse HCC induced by the ras oncogene. The enhanced glycolysis, citrate shuttle, pentose phosphate pathway, and expression of lipid biosynthesis-associated key enzymes play central roles in the accumulation of lipid droplets in HCC. Enhanced cholesterol biosynthesis and attenuated bile acid biosynthesis play important roles in cholesterol accumulation in HCC. High levels of GSH and elevated Bcl2 and Ucp2 expression may contribute to a normal level of ROS in HCC.
http://ift.tt/2yfR7rR
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