The management of solely intracanalicular acoustic neurinoma (iAN) includes observation, microsurgical resection and radiation therapy. Treatment goals are long-term tumor control, hearing preservation and con...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 20 Απριλίου 2017
Long-term follow-up after stereotactic radiosurgery of intracanalicular acoustic neurinoma
Long-term follow-up after stereotactic radiosurgery of intracanalicular acoustic neurinoma
The management of solely intracanalicular acoustic neurinoma (iAN) includes observation, microsurgical resection and radiation therapy. Treatment goals are long-term tumor control, hearing preservation and con...
http://ift.tt/2osFhWM
Management of a case of myopic foveoschisis with phakic intraocular lens (pIOL) in situ: intraoperative challenges
We describe the case of a 30-year-old man with pathological myopia with a phakic intraocular lens (IOL) (Visian ICL V4c model; STAAR, Monrovia, California, USA) in situ having complaints of metamorphopsia in the left eye with documented myopic foveoschisis on swept-source optical coherence tomography (DRI OCT Triton; Topcon, Tokyo, Japan). The patient underwent pars plana vitrectomy with internal limiting membrane peeling. This report discusses the intraoperative challenges occurring as a result of increased optical aberrations in the presence of a phakic IOL.
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Exogenous Cushing's syndrome due to a Chinese herbalists prescription of ointment containing dexamethasone
Eczema in children is a chronic disabling condition. The impact of this condition on the lives of families is often underestimated by conventional physicians. As a consequence parents may investigate complementary treatment options. Close monitoring by a paediatrician is essential, considering that a variety of adverse effects can occur during the use of complementary treatment. We present a 5-year-old girl with eczema. She visited a Chinese herbalist who prescribed an ointment. The parents noticed that the eczema resolved fast, itching decreased and she was finally sleeping well. However, her behaviour changed and appetite increased. Undetectable levels of serum cortisol were found, which was indicative of exogenous Cushing's syndrome. Analysis of the ointment revealed the presence of dexamethasone. Hydrocortisone substitution and subsequently a reduction schedule were implemented, after which endogenous cortisol production recovered after 4 months. Physicians should be aware that unregistered herbal medicine can contain potent drugs such as glucocorticoids.
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Synergistic anti-cancer effects of epigenetic drugs on medulloblastoma cells
Abstract
Purpose
Medulloblastomas are aggressive brain malignancies. While considerable progress has been made in the treatment of medulloblastoma patients with respect to overall survival, these patients are still at risk of developing neurologic and cognitive deficits as a result of anti-cancer therapies. It is hypothesized that targeted molecular therapies represent a better treatment option for medulloblastoma patients. Therefore, the aim of the present study was to test a panel of epigenetic drugs for their effect on medulloblastoma cells under mild hypoxic conditions that reflect the physiological concentrations of oxygen in the brain.
Methods
Protein levels of histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) in medulloblastoma-derived cells (Daoy and D283 Med), as well as in developing and differentiated brain cells, were determined and compared. Class I and II histone deacetylase inhibitors (HDACi) and a DNMT inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC), were applied to Daoy and D283 Med cells, and their effects were studied using viability, apoptosis and cancer sphere assays.
Results
We found that in HDAC1 and DNMT1 overexpressing medulloblastoma-derived cells, cell death was induced under various epigenetic drug conditions tested. At low HDACi concentrations, however, a pro-proliferative effect was observed. Parthenolide, a drug that affects cancer stem cells, was found to be efficient in inducing cell death in both cell lines tested. In contrast, we found that Daoy cells were more resistant to 5-aza-dC than D283 Med cells. When suberoylanilide hydroxamic acid (SAHA) and parthenolide were individually applied to both cell lines in combination with 5-aza-dC, a synergistic effect on cell survival was observed.
Conclusions
Our current results suggest that the application of HDACi in combination with drugs that target DNMT may represent a promising option for the treatment of medulloblastoma.
http://ift.tt/2opMpmQ
Synergistic anti-cancer effects of epigenetic drugs on medulloblastoma cells
Abstract
Purpose
Medulloblastomas are aggressive brain malignancies. While considerable progress has been made in the treatment of medulloblastoma patients with respect to overall survival, these patients are still at risk of developing neurologic and cognitive deficits as a result of anti-cancer therapies. It is hypothesized that targeted molecular therapies represent a better treatment option for medulloblastoma patients. Therefore, the aim of the present study was to test a panel of epigenetic drugs for their effect on medulloblastoma cells under mild hypoxic conditions that reflect the physiological concentrations of oxygen in the brain.
Methods
Protein levels of histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) in medulloblastoma-derived cells (Daoy and D283 Med), as well as in developing and differentiated brain cells, were determined and compared. Class I and II histone deacetylase inhibitors (HDACi) and a DNMT inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC), were applied to Daoy and D283 Med cells, and their effects were studied using viability, apoptosis and cancer sphere assays.
Results
We found that in HDAC1 and DNMT1 overexpressing medulloblastoma-derived cells, cell death was induced under various epigenetic drug conditions tested. At low HDACi concentrations, however, a pro-proliferative effect was observed. Parthenolide, a drug that affects cancer stem cells, was found to be efficient in inducing cell death in both cell lines tested. In contrast, we found that Daoy cells were more resistant to 5-aza-dC than D283 Med cells. When suberoylanilide hydroxamic acid (SAHA) and parthenolide were individually applied to both cell lines in combination with 5-aza-dC, a synergistic effect on cell survival was observed.
Conclusions
Our current results suggest that the application of HDACi in combination with drugs that target DNMT may represent a promising option for the treatment of medulloblastoma.
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A protocol for a cluster-randomized controlled trial of a self-help psycho-education programme to reduce diagnosis delay in women with breast cancer symptoms in Indonesia
Abstract
Background
Breast cancer (BC) is the most frequent cancer occurring in women across the world. Its mortality rate in low-middle income countries (LMICs) is higher than in high-income countries (HICs), and in Indonesia BC is the leading cause of cancer deaths among women. Delay in breast cancer diagnosis negatively impacts cancer prognosis. Only about 30% of patients who come to the hospital to check on their breast abnormalities, continue thorough examination to biopsy to get a diagnosis based on the results of anatomical pathology. Many Indonesian women with breast cancer were already in an advanced stage when starting treatment. Therefore, delay in diagnosis is a serious problem that needs to be addressed. The present study will investigate whether our newly developed self-help psycho-educational programme, "PERANTARA", for women with breast cancer symptoms is effective to reduce patient diagnosis delay in Indonesia.
Methods
A cluster-randomized controlled trial will be conducted in 106 patients in four hospitals in Bandung, West Java, Indonesia. Data will be collected at baseline (pre-assessment), 7 days after the intervention (post-assessment), and at 3 months (follow-up assessments). The primary outcome is delay in diagnosis and treatment. Secondary outcomes are breast cancer knowledge, anxiety and depression, and quality of life. Exploratively, adherence with treatment will be measured too. Data will be analysed by hierarchical linear modelling (HLM) to assess differential change over time.
Discussion
If proven effective, PERANTARA will be evaluated and implemented in a diversity of settings for local cares (such as in POSYANDU, PUSKESMAS) that provide health education/psycho-education for women with breast symptoms.
Trial registration
ISRCTN12570738. Date: November 19th, 2016.
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Prevalence and prognostic implications of psychological distress in patients with gastric cancer
Abstract
Background
The aim of this study was to investigate the prevalence and prognostic significance of psychological distress in gastric cancer patients.
Methods
The study population included 229 gastric cancer patients visiting Yonsei Cancer Center between November 2009 and March 2011. The distress was measured by available tools including the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies–Depression Scale (CES-D). Patients with psychological distress were defined as those who scored above the cut-off values in both the MDT and either one of the HADS or CES-D.
Results
The median age of patients was 56 (range, 20 to 86) and 97 (42.4%) patients were with stage IV disease status at enrollment. The overall prevalence of psychological distress was 33.6% (95% CI: 27.5–39.8%) in 229 gastric cancer patients. In multiple logistic regression analysis, lower education level (odds ratio [OR] 2.39; 95% confidence interval [CI] 1.11–5.17, P = 0.026) and higher disease stage (OR 2.72; 95% CI 1.47–5.03, P = 0.001) were associated with psychological distress. In stage I-III disease, patients with psychological distress had worse disease-free survival (DFS) (5-year DFS rate: 60% vs 76%, P = 0.49) compared with those without psychological distress. In stage IV disease (n = 97), patients with psychological distress showed poorer overall survival than those without psychological distress (median OS (Overall Survival): 12.2 vs. 13.8 months, P = 0.019).
Conclusion
Psychological distress is common in patients with all stages of gastric cancer and is associated with worse outcomes.
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A protocol for a cluster-randomized controlled trial of a self-help psycho-education programme to reduce diagnosis delay in women with breast cancer symptoms in Indonesia
Abstract
Background
Breast cancer (BC) is the most frequent cancer occurring in women across the world. Its mortality rate in low-middle income countries (LMICs) is higher than in high-income countries (HICs), and in Indonesia BC is the leading cause of cancer deaths among women. Delay in breast cancer diagnosis negatively impacts cancer prognosis. Only about 30% of patients who come to the hospital to check on their breast abnormalities, continue thorough examination to biopsy to get a diagnosis based on the results of anatomical pathology. Many Indonesian women with breast cancer were already in an advanced stage when starting treatment. Therefore, delay in diagnosis is a serious problem that needs to be addressed. The present study will investigate whether our newly developed self-help psycho-educational programme, "PERANTARA", for women with breast cancer symptoms is effective to reduce patient diagnosis delay in Indonesia.
Methods
A cluster-randomized controlled trial will be conducted in 106 patients in four hospitals in Bandung, West Java, Indonesia. Data will be collected at baseline (pre-assessment), 7 days after the intervention (post-assessment), and at 3 months (follow-up assessments). The primary outcome is delay in diagnosis and treatment. Secondary outcomes are breast cancer knowledge, anxiety and depression, and quality of life. Exploratively, adherence with treatment will be measured too. Data will be analysed by hierarchical linear modelling (HLM) to assess differential change over time.
Discussion
If proven effective, PERANTARA will be evaluated and implemented in a diversity of settings for local cares (such as in POSYANDU, PUSKESMAS) that provide health education/psycho-education for women with breast symptoms.
Trial registration
ISRCTN12570738. Date: November 19th, 2016.
http://ift.tt/2pJR6LZ
Prevalence and prognostic implications of psychological distress in patients with gastric cancer
Abstract
Background
The aim of this study was to investigate the prevalence and prognostic significance of psychological distress in gastric cancer patients.
Methods
The study population included 229 gastric cancer patients visiting Yonsei Cancer Center between November 2009 and March 2011. The distress was measured by available tools including the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies–Depression Scale (CES-D). Patients with psychological distress were defined as those who scored above the cut-off values in both the MDT and either one of the HADS or CES-D.
Results
The median age of patients was 56 (range, 20 to 86) and 97 (42.4%) patients were with stage IV disease status at enrollment. The overall prevalence of psychological distress was 33.6% (95% CI: 27.5–39.8%) in 229 gastric cancer patients. In multiple logistic regression analysis, lower education level (odds ratio [OR] 2.39; 95% confidence interval [CI] 1.11–5.17, P = 0.026) and higher disease stage (OR 2.72; 95% CI 1.47–5.03, P = 0.001) were associated with psychological distress. In stage I-III disease, patients with psychological distress had worse disease-free survival (DFS) (5-year DFS rate: 60% vs 76%, P = 0.49) compared with those without psychological distress. In stage IV disease (n = 97), patients with psychological distress showed poorer overall survival than those without psychological distress (median OS (Overall Survival): 12.2 vs. 13.8 months, P = 0.019).
Conclusion
Psychological distress is common in patients with all stages of gastric cancer and is associated with worse outcomes.
http://ift.tt/2osotPA
Brodie abscess of the femoral capital epiphysis in a 2-year-old child caused by Kingella kingae
We report the case of a Brodie abscess of the femoral capital epiphysis from which Kingella kingae was isolated. This is to the best of our knowledge the first report of a Brodie abscess of the femoral capital epiphysis from which K. kingae was isolated.
http://ift.tt/2oamKlY
Delayed LGI1 seropositivity in voltage-gated potassium channel (VGKC)-complex antibody limbic encephalitis
We utilise a clinical case to highlight why exclusion of voltage-gated potassium channel (VGKC)-complex autoantibody testing in serological evaluation of patients may delay or miss the diagnosis. A 68-year-old man presented with increasing involuntary movements consistent with faciobrachial dystonic seizures (FBDS). Initial evaluation demonstrated VGKC antibody seropositivity with leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) seronegativity. Aggressive immunotherapy with methylprednisolone and plasmapheresis was started early in the course of his presentation. Following treatment with immunotherapy, the patient demonstrated clinical improvement. Repeat serum evaluation 4 months posthospitalisation remained seropositive for VGKC-complex antibodies, with development of LGI1 autoantibody seropositivity. VGKC-complex and LGI1 antibodies remained positive 12 months posthospitalisation. Our findings suggest that clinical symptoms can predate the detection of the antibody. We conclude that when suspicion for autoimmune encephalitis is high in the setting of VGKC autoantibody positivity, regardless of LGI1 or CASPR2 seropositivity, early immunotherapy and repeat testing should be considered.
http://ift.tt/2osA6Gd
Syndrome of inappropriate antidiuretic hormone accompanied by bilateral hypothalamic and anterior thalamic lesions with serum antiaquaporin 4 antibody
We described a rare case of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and severe unconsciousness accompanied by bilateral hypothalamic and anterior thalamic lesions with positive serum antiaquaporin 4 (AQP4) antibody. A 29-year-old man was admitted to our hospital due to the subacute progression of an unconscious state. He was observed to be hyponatraemic secondary to SIADH. Brain MRI showed bilateral hypothalamic and anterior thalamic lesions. Anti-AQP4 antibody was detected in his serum. After the administration of intravenous methylprednisolone pulse therapy, his symptoms improved with complete recovery from SIADH and regression of the hypothalamic and anterior thalamic lesions. The patient was transferred to another hospital for rehabilitation with 20 mg/day of oral prednisolone 127 days after admission. This case highlights the importance of testing for anti-AQP4 antibody in patients with unexplainable SIADH, subacute progressive unconsciousness and bilateral hypothalamic and anterior thalamic lesions.
http://ift.tt/2oajiI5
Transoesophageal three-dimensional echocardiographic diagnosis of Barlows disease
Description
A 67-year-old man with a year history of palpitations and dyspnoea presented to the physician's office. His blood pressure was 140/80 mm Hg and pulse was 80 beats/min. Heart auscultation revealed a loud systolic click followed by a holosystolic murmur. The ECG showed sinus rhythm, P wave +/– in V1 and P wave duration 140 ms in DII. The Holter monitoring showed atrial extrasystoles and an episode of atrial tachycardia (figure 1A).
Figure 1
(A) The Holter monitoring showed atrial extrasystoles and an episode of atrial tachycardia. (B) M-mode echocardiogram showed late systolic sagging of the mitral valve. (C) Transoesophageal echocardiogram showed clearly the prolapsing mitral leaflets and severe mitral regurgitation. (D,E) Three-dimensional echocardiographic imaging demonstrated bileaflet prolapse. Mitral model showed prolapse of the P1, P2, P3 and A1, A2, A3.
The transthoracic echocardiogram M-mode showed late systolic sagging of the mitral...
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A case of glioblastoma resected immediately after administering bevacizumab: consideration on histopathological findings and safety of surgery
Abstract
Surgery after administering bevacizumab should be carefully considered particularly because of wound healing concerns. A 27-year-old man presented with multiple tumor recurrences after gross total removal of a left temporal oligodendroglioma (1p/19q-noncodeleted). Whole brain radiotherapy with concomitant temozolomide and bevacizumab was immediately prescribed; however, the patient's condition deteriorated because of brain herniation. Three days after administering bevacizumab, an emergency tumor removal with external decompression and a ventriculo-peritoneal shunt was performed. The surgery and postoperative clinical course were uneventful. On histopathological examination, the tumor showed findings such as tumor vessel thrombosis, numerous interstitial red blood cells, and cells with degraded, fragmented nuclei possibly suggesting apoptosis, which could be attributable to bevacizumab. Performing craniotomy shortly after administering bevacizumab is not recommended; however, it can still be safely performed as long as surgery and wound management is carefully performed. Vessel thrombosis might be among the mechanisms of action of bevacizumab.
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Review of stereotactic radiosurgery for intradural spine tumors
CNS Oncology April 2017, Vol. 6, No. 2, Pages 131-138.
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Immunotherapy and targeted therapy in brain metastases: emerging options in precision medicine
CNS Oncology April 2017, Vol. 6, No. 2, Pages 139-151.
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Prognostic value of pre- and post-treatment health-related quality of life in predicting survival of patients with brain metastases
CNS Oncology April 2017, Vol. 6, No. 2, Pages 119-129.
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Adult pilocytic astrocytoma of conus medullaris: clinical considerations and review of the literature
CNS Oncology April 2017, Vol. 6, No. 2, Pages 107-110.
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Our panel of experts highlights the most important research articles across the spectrum of topics relevant to the field of CNS oncology
CNS Oncology April 2017, Vol. 6, No. 2, Pages 85-87.
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CNS hemangioblastomatosis in a patient without von Hippel–Lindau disease
CNS Oncology April 2017, Vol. 6, No. 2, Pages 101-105.
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BRAF-V600E mutant papillary craniopharyngioma dramatically responds to combination BRAF and MEK inhibitors
CNS Oncology April 2017, Vol. 6, No. 2, Pages 95-99.
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Review of stereotactic radiosurgery for intradural spine tumors
CNS Oncology April 2017, Vol. 6, No. 2, Pages 131-138.
http://ift.tt/2pJM6qJ
Immunotherapy and targeted therapy in brain metastases: emerging options in precision medicine
CNS Oncology April 2017, Vol. 6, No. 2, Pages 139-151.
http://ift.tt/2oWB7aD
Prognostic value of pre- and post-treatment health-related quality of life in predicting survival of patients with brain metastases
CNS Oncology April 2017, Vol. 6, No. 2, Pages 119-129.
http://ift.tt/2pJJokY
Adult pilocytic astrocytoma of conus medullaris: clinical considerations and review of the literature
CNS Oncology April 2017, Vol. 6, No. 2, Pages 107-110.
http://ift.tt/2oWGjuV
Our panel of experts highlights the most important research articles across the spectrum of topics relevant to the field of CNS oncology
CNS Oncology April 2017, Vol. 6, No. 2, Pages 85-87.
http://ift.tt/2pJPeTi
CNS hemangioblastomatosis in a patient without von Hippel–Lindau disease
CNS Oncology April 2017, Vol. 6, No. 2, Pages 101-105.
http://ift.tt/2oWNh32
BRAF-V600E mutant papillary craniopharyngioma dramatically responds to combination BRAF and MEK inhibitors
CNS Oncology April 2017, Vol. 6, No. 2, Pages 95-99.
http://ift.tt/2pJJZTO
Psychosocial Outcomes in Active Treatment through Survivorship
Abstract
Objective
To understand potential differences in psychosocial outcomes from active treatment to survivorship.
Methods
Using the Medical Expenditure Panel Survey Experiences with Cancer Survivorship Supplement (n = 1,360) we examined and compared psychosocial outcomes among respondents in active treatment with survivors by year(s) since treatment ended. Survey-weighted regression models were used to test associations between year(s) since treatment and depressive symptoms (PHQ-2), psychological distress (K-6) and cancer-specific worry related to recurrence.
Results
Unadjusted estimates showed no significant differences in depressive symptoms or psychological distress between those in active treatment and cancer survivors at any time post-treatment. In contrast, the prevalence of cancer-specific worry was lowest among survivors more than 5 years since treatment (10%), slightly higher among those with less than 1 year since treatment (15%) and highest among those in active treatment (32%). In models controlled for socio-demographic and health-related covariates, the year(s) since treatment ended was inversely associated with the odds of cancer-specific worry but was not associated with depressive symptoms or psychological distress.
Conclusions
In this population-based sample, worry about cancer recurrence may diminish with years since treatment ended, while depressive symptoms and distress are persistent across the trajectory. These findings highlight unmet psychosocial needs among cancer survivors and demonstrate the importance of targeted interventions across the survivorship continuum.
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Psychosocial Outcomes in Active Treatment through Survivorship
Abstract
Objective
To understand potential differences in psychosocial outcomes from active treatment to survivorship.
Methods
Using the Medical Expenditure Panel Survey Experiences with Cancer Survivorship Supplement (n = 1,360) we examined and compared psychosocial outcomes among respondents in active treatment with survivors by year(s) since treatment ended. Survey-weighted regression models were used to test associations between year(s) since treatment and depressive symptoms (PHQ-2), psychological distress (K-6) and cancer-specific worry related to recurrence.
Results
Unadjusted estimates showed no significant differences in depressive symptoms or psychological distress between those in active treatment and cancer survivors at any time post-treatment. In contrast, the prevalence of cancer-specific worry was lowest among survivors more than 5 years since treatment (10%), slightly higher among those with less than 1 year since treatment (15%) and highest among those in active treatment (32%). In models controlled for socio-demographic and health-related covariates, the year(s) since treatment ended was inversely associated with the odds of cancer-specific worry but was not associated with depressive symptoms or psychological distress.
Conclusions
In this population-based sample, worry about cancer recurrence may diminish with years since treatment ended, while depressive symptoms and distress are persistent across the trajectory. These findings highlight unmet psychosocial needs among cancer survivors and demonstrate the importance of targeted interventions across the survivorship continuum.
http://ift.tt/2pJIzIY
Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis
BRCA1 mutated breast cancers are commonly diagnosed as negative for classical hormone receptors i.e. estrogen receptor, progesterone receptor and/or Her2. Due to these common targets b...
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Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2
Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK...
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What are colorectal cancer survivors’ preferences for dietary advice? A best-worst discrete choice experiment
Abstract
Purpose
Studies on healthy lifestyle interventions in survivors of colorectal cancer have been disappointing, demonstrating only modest changes. This study aims to quantify people's preferences for different aspects of dietary intervention.
Method
A best-worst discrete choice experiment was designed and incorporated into a questionnaire including participants' characteristics and a self-assessment of lifestyle.
Results
The response rate was 68% and 179 questionnaires were analysed. When analysing aggregate preferences, the modes of information provision selected as the most preferred were "face-to-face" (willingness to pay (WTP) £63.97, p ≤ 0.001) and "telephone" (WTP £62.36, p < 0.001) discussions whereas group discussions were preferred least (WTP −£118.96, p ≤ 0.001). Scenarios that included hospitals were most preferred (WTP £17.94, p = 0.031), and the favoured provider was bowel cancer nurses (WTP £75.11, p ≤ 0.001). When investigating preference heterogeneity, three sub-groups were identified: Firstly, "technophiles" preferring email (WTP £239.60, p ≤ 0.001) were male, were younger and had fewer risk factors. Secondly, a "one-to-one" group had strong preference for interventions over the telephone or at their local doctors and were older (WTP £642.13, p ≤ 0.001). Finally, a "person-centred" group preferred face-to-face individual or group sessions (WTP £358.79, p < 0.001) and had a high risk lifestyle.
Conclusion
For survivors of colorectal cancer, there is not one approach that suits all when it comes to providing dietary advice.
Implications for Cancer Survivors
This is important information to consider when planning healthy lifestyle interventions which include dietary advice for survivors of colorectal cancer. Aligning services to individuals' preferences has the potential to improve patient experience and outcomes by increasing uptake of healthy lifestyle advice services and promoting a more tailored approach to dietary modifications, acknowledging sub-groups of people within the total population of colorectal cancer survivors.
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What are colorectal cancer survivors’ preferences for dietary advice? A best-worst discrete choice experiment
Abstract
Purpose
Studies on healthy lifestyle interventions in survivors of colorectal cancer have been disappointing, demonstrating only modest changes. This study aims to quantify people's preferences for different aspects of dietary intervention.
Method
A best-worst discrete choice experiment was designed and incorporated into a questionnaire including participants' characteristics and a self-assessment of lifestyle.
Results
The response rate was 68% and 179 questionnaires were analysed. When analysing aggregate preferences, the modes of information provision selected as the most preferred were "face-to-face" (willingness to pay (WTP) £63.97, p ≤ 0.001) and "telephone" (WTP £62.36, p < 0.001) discussions whereas group discussions were preferred least (WTP −£118.96, p ≤ 0.001). Scenarios that included hospitals were most preferred (WTP £17.94, p = 0.031), and the favoured provider was bowel cancer nurses (WTP £75.11, p ≤ 0.001). When investigating preference heterogeneity, three sub-groups were identified: Firstly, "technophiles" preferring email (WTP £239.60, p ≤ 0.001) were male, were younger and had fewer risk factors. Secondly, a "one-to-one" group had strong preference for interventions over the telephone or at their local doctors and were older (WTP £642.13, p ≤ 0.001). Finally, a "person-centred" group preferred face-to-face individual or group sessions (WTP £358.79, p < 0.001) and had a high risk lifestyle.
Conclusion
For survivors of colorectal cancer, there is not one approach that suits all when it comes to providing dietary advice.
Implications for Cancer Survivors
This is important information to consider when planning healthy lifestyle interventions which include dietary advice for survivors of colorectal cancer. Aligning services to individuals' preferences has the potential to improve patient experience and outcomes by increasing uptake of healthy lifestyle advice services and promoting a more tailored approach to dietary modifications, acknowledging sub-groups of people within the total population of colorectal cancer survivors.
http://ift.tt/2oWMP5a
Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors
Purpose<br /> Bronchial and gastroenteropancreatic neuroendocrine tumors (NETs) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for therapy with Lutetium-177-labeled somatostatin analogs. We have treated over 1200 patients with peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival and toxicity of this therapy. <p>Patients and methods<br /> For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq) 177Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.</p> <p>Results<br /> The objective response rate (ORR) of the total group of patients was 39%. Stable disease (SD) was reached in 43% of patients. Progression free survival (PFS) and overall survival (OS) for all NET patients were 29 months (95% CI 26-33 months) and 63 months (95% CI 55-72 months). Long-term toxicity included acute leukemia in 4 patients (0.7%) and myelodysplastic syndrome in 9 patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.</p> <p>Conclusion <br /> PRRT with 177Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with 177Lu-DOTATATE is safe with few side-effects and shows a good response rates with PFS of 29 months and OS of 63 months.
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In vivo detection of EGFRvIII in glioblastoma via perfusion magnetic resonance imaging signature consistent with deep peritumoral infiltration: the {varphi} index
Purpose: <br />The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor's spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma non-invasively, using routine clinically-acquired imaging.<br /><br />Experimental Design: <br />We found peritumoral infiltration and vascularization patterns being related to EGFRvIII status. We therefore constructed a quantitative within-patient peritumoral heterogeneity index (PHI/-index), by contrasting perfusion patterns of immediate and distant peritumoral edema. Application of -index in preoperative perfusion scans of independent discovery (n=64) and validation (n=78) cohorts, revealed the generalizability of this EGFRvIII imaging signature.<br /><br />Results: <br />Analysis in both cohorts demonstrated that the obtained signature is highly accurate (89.92%), specific (92.35%) and sensitive (83.77%), with significantly distinctive ability (p=4.0033x10-10, AUC=0.8869). Findings indicated a highly infiltrative-migratory phenotype for EGFRvIII+ tumors, which displayed similar perfusion patterns throughout peritumoral edema. Contrarily, EGFRvIII- tumors displayed perfusion dynamics consistent with peritumorally-confined vascularization, suggesting potential benefit from extensive peritumoral resection/radiation.<br /><br />Conclusions:<br />This EGFRvIII signature is potentially suitable for clinical translation, since obtained from analysis of clinically-acquired images. Use of within-patient heterogeneity measures, rather than population-based associations, renders -index potentially resistant to inter-scanner variations. Overall, our findings enable non-invasive evaluation of EGFRvIII for patient selection for targeted therapy, stratification into clinical trials, personalized treatment planning, and potentially treatment-response evaluation.
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PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison
Purpose: PD-L1 expression in the pre-treatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications. <br /><br />Experimental Design: PD-L1 immunohistochemistry (IHC) was performed on thirty-four formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3 and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies. <br /><br />Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2=0.81-0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2>0.78, all clones). <br /><br />Conclusions: The 5H1, SP142, 28-8, 22C3 and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays.
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The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications
Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10-5-10-6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents, while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions.
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Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors
Purpose<br /> Bronchial and gastroenteropancreatic neuroendocrine tumors (NETs) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for therapy with Lutetium-177-labeled somatostatin analogs. We have treated over 1200 patients with peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival and toxicity of this therapy. <p>Patients and methods<br /> For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq) 177Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq) 177Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.</p> <p>Results<br /> The objective response rate (ORR) of the total group of patients was 39%. Stable disease (SD) was reached in 43% of patients. Progression free survival (PFS) and overall survival (OS) for all NET patients were 29 months (95% CI 26-33 months) and 63 months (95% CI 55-72 months). Long-term toxicity included acute leukemia in 4 patients (0.7%) and myelodysplastic syndrome in 9 patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.</p> <p>Conclusion <br /> PRRT with 177Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with 177Lu-DOTATATE is safe with few side-effects and shows a good response rates with PFS of 29 months and OS of 63 months.
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In vivo detection of EGFRvIII in glioblastoma via perfusion magnetic resonance imaging signature consistent with deep peritumoral infiltration: the {varphi} index
Purpose: <br />The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor's spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma non-invasively, using routine clinically-acquired imaging.<br /><br />Experimental Design: <br />We found peritumoral infiltration and vascularization patterns being related to EGFRvIII status. We therefore constructed a quantitative within-patient peritumoral heterogeneity index (PHI/-index), by contrasting perfusion patterns of immediate and distant peritumoral edema. Application of -index in preoperative perfusion scans of independent discovery (n=64) and validation (n=78) cohorts, revealed the generalizability of this EGFRvIII imaging signature.<br /><br />Results: <br />Analysis in both cohorts demonstrated that the obtained signature is highly accurate (89.92%), specific (92.35%) and sensitive (83.77%), with significantly distinctive ability (p=4.0033x10-10, AUC=0.8869). Findings indicated a highly infiltrative-migratory phenotype for EGFRvIII+ tumors, which displayed similar perfusion patterns throughout peritumoral edema. Contrarily, EGFRvIII- tumors displayed perfusion dynamics consistent with peritumorally-confined vascularization, suggesting potential benefit from extensive peritumoral resection/radiation.<br /><br />Conclusions:<br />This EGFRvIII signature is potentially suitable for clinical translation, since obtained from analysis of clinically-acquired images. Use of within-patient heterogeneity measures, rather than population-based associations, renders -index potentially resistant to inter-scanner variations. Overall, our findings enable non-invasive evaluation of EGFRvIII for patient selection for targeted therapy, stratification into clinical trials, personalized treatment planning, and potentially treatment-response evaluation.
http://ift.tt/2o9Txrr
PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison
Purpose: PD-L1 expression in the pre-treatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications. <br /><br />Experimental Design: PD-L1 immunohistochemistry (IHC) was performed on thirty-four formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3 and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies. <br /><br />Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2=0.81-0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2>0.78, all clones). <br /><br />Conclusions: The 5H1, SP142, 28-8, 22C3 and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays.
http://ift.tt/2pIVpUQ
The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications
Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10-5-10-6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents, while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions.
http://ift.tt/2o9TvQl
Master Transcriptional Regulators in Cancer: Discovery via Reverse Engineering Approaches and Subsequent Validation
Reverse engineering of transcriptional networks using gene expression data enables identification of genes that underpin the development and progression of different cancers. Methods to this end have been available for over a decade and, with a critical mass of transcriptomic data in the oncology arena having been reached, they are ever more applicable. Extensive and complex networks can be distilled into a small set of key master transcriptional regulators (MTR), genes that are very highly connected and have been shown to be involved in processes of known importance in disease. Interpreting and validating the results of standardized bioinformatic methods is of crucial importance in determining the inherent value of MTRs. In this review, we briefly describe how MTRs are identified and focus on providing an overview of how MTRs can and have been validated for use in clinical decision making in malignant diseases, along with serving as tractable therapeutic targets. Cancer Res; 77(9); 1–5. ©2017 AACR.
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Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection
Considerable advances in cancer-specific optical imaging have improved the precision of tumor resection. In comparison to traditional imaging modalities, this technology is unique in its ability to provide real-time feedback to the operating surgeon. Given the significant clinical implications of optical imaging, there is an urgent need to standardize surgical navigation tools and contrast agents to facilitate swift regulatory approval. Because fluorescence-enhanced surgery requires a combination of both device and drug, each may be developed in conjunction, or separately, which are important considerations in the approval process. This report is the result of a one-day meeting held on May 4, 2016 with officials from the National Cancer Institute, the FDA, members of the American Society of Image-Guided Surgery, and members of the World Molecular Imaging Society, which discussed consensus methods for FDA-directed human testing and approval of investigational optical imaging devices as well as contrast agents for surgical applications. The goal of this workshop was to discuss FDA approval requirements and the expectations for approval of these novel drugs and devices, packaged separately or in combination, within the context of optical surgical navigation. In addition, the workshop acted to provide clarity to the research community on data collection and trial design. Reported here are the specific discussion items and recommendations from this critical and timely meeting. Cancer Res; 77(9); 1–10. ©2017 AACR.
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Whither Radioimmunotherapy: To Be or Not To Be?
Therapy of cancer with radiolabeled monoclonal antibodies has produced impressive results in preclinical experiments and in clinical trials conducted in radiosensitive malignancies, particularly B-cell lymphomas. Two "first-generation," directly radiolabeled anti-CD20 antibodies, 131iodine-tositumomab and 90yttrium-ibritumomab tiuxetan, were FDA-approved more than a decade ago but have been little utilized because of a variety of medical, financial, and logistic obstacles. Newer technologies employing multistep "pretargeting" methods, particularly those utilizing bispecific antibodies, have greatly enhanced the therapeutic efficacy of radioimmunotherapy and diminished its toxicities. The dramatically improved therapeutic index of bispecific antibody pretargeting appears to be sufficiently compelling to justify human clinical trials and reinvigorate enthusiasm for radioimmunotherapy in the treatment of malignancies, particularly lymphomas. Cancer Res; 77(9); 1–6. ©2017 AACR.
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Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone
Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention.
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Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-kappaB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation, and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC.
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Micellar delivery of miR-34a modulator rubone and paclitaxel in resistant prostate cancer
Treatment of prostate cancer with paclitaxel (PTX) often fails due to development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that co-delivery of PTX and 2′-hydroxy-2,4,4′,5,6′-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes PTX-resistant prostate cancer cells, killing both cancer stem-like cells (CSCs) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. PTX and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70 ± 0.10% and 5.34 ± 0.02% for PTX and rubone, respectively, controlling a drug release of 60.20 ± 2.67% and 60.62 ± 4.35% release of PTX and rubone at 24 h. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing PTX concentration. Co-incubation with a miR-34a inhibitor diminished the effect of rubone. PTX IC50 in PC3 and PC3-TXR cells was 55.6 and 2580 nM, respectively, but decreased to 49.8 and 93.2 nM when treated in combination with rubone, demonstrating a reversal of PTX resistance by rubone. Systemic administration of micelles carrying PTX and rubone inhibited orthotopic prostate tumor growth in nude mice, compared to monotherapy, by reversing the expression of miR-34a, SIRT1, Cyclin D1 and E-cadherin. In summary, our results showed how rubone acts as an efficient small molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of PTX in PTX-resistant prostate cancer.
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Immune gene expression is associated with genomic aberrations in breast cancer
The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the 3 major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER positive, 207 HER2 positive, and 191 triple negative (TNBC) cancers from TCGA. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, neoantigen, and CNV loads in TNBC and HER2+ cancers. In ER+ cancers, mutation load, neoantigen load, and CNV load weakly but positively associated with immune infiltration, which reached significance for overall mutation load only. No highly recurrent single gene or pathway level mutations associated with immune infiltration. High immune gene expression and lower clonal heterogeneity in TNBC and HER2+ cancers suggest an immune pruning effect and equilibrium between immune surveillance and clonal expansion. Thus, immune checkpoint inhibitors may tip the balance in favor of immune surveillance in these cancers.
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Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion
New magnetic resonance (MR) molecular imaging techniques offer the potential for non-invasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a 3D dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low and high grade tumors in the TRAMP transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1 and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans, attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL. This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials.
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Epithelial-to-mesenchymal Transition contributes to Immunosuppression in Breast Carcinomas
The Epithelial-to-mesenchymal transition (EMT) is a cell-biological program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. It is, unclear, however, whether activation of EMT in carcinoma cells can change their susceptibility to immune attack. We demonstrate here that mammary tumor cells arising from more epithelial carcinoma cell lines expressed high levels of MHC-I, low levels of PD-L1 and contained within their stroma CD8+ T cells and M1 (anti-tumor) macrophages. In contrast, tumors arising from more-mesenchymal carcinoma cell lines exhibiting EMT markers expressed low levels of MHC-I, high levels of PD-L1 and contained within their stroma regulatory T cells, M2 (pro-tumor) macrophages and exhausted CD8+ T cells. Moreover, the more mesenchymal carcinoma cells within a tumor retained the ability to protect their more epithelial counterparts from immune attack. Lastly, epithelial tumors were more susceptible to elimination by immunotherapy than corresponding mesenchymal tumors. Our results identify immune cells and immunomodulatory markers that can be potentially targeted to enhance the susceptibility of immunosuppressive tumors to various therapeutic regimens.
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EGFR mediates responses to small molecule drugs targeting oncogenic fusion kinases
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells, mouse models and human clinical specimens before onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to co-target EGFR to reduce risks of developing drug resistance.
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Selective glucocorticoid receptor modulators (SGRMs) delay castrate-resistant prostate cancer growth
Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here we report that two novel non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect AR signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective non-steroidal SGRMs potently inhibit GR activity and PC growth despite AR pathway inhibition demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC.
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Mechanisms of Pinometostat (EPZ-5676) Treatment Emergent Resistance in MLL Rearranged Leukemia
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well characterized leukemic genes. Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment emergent resistance (TER) in cell lines confirmed to have MLL-r. TER was achieved in five MLL-r cell lines, KOPN-8, MOLM-13, MV4-11, NOMO-1, and SEM. Two of the cell lines, KOPN-8 and NOMO-1 were thoroughly characterized to understand the mechanisms involved in pinometostat resistance. Unlike many other targeted therapies, resistance does not appear to be achieved through drug-induced selection of mutations of the target itself. Instead, we identified both drug efflux transporter dependent and independent mechanisms of resistance to pinometostat. In KOPN-8 TER cells, increased expression of the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the primary mechanism of drug resistance. In contrast, resistance in NOMO-1 cells occurs through a mechanism other than upregulation of a specific efflux pump. RNA-seq analysis performed on both parental and resistant KOPN-8 and NOMO-1 cell lines supported two unique candidate pathway mechanisms that may explain the pinometostat resistance observed in these cell lines. These results are the first demonstration of TER models of the DOT1L inhibitor pinometostat and may provide useful tools for investigating clinical resistance.
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Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.
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Master Transcriptional Regulators in Cancer: Discovery via Reverse Engineering Approaches and Subsequent Validation
Reverse engineering of transcriptional networks using gene expression data enables identification of genes that underpin the development and progression of different cancers. Methods to this end have been available for over a decade and, with a critical mass of transcriptomic data in the oncology arena having been reached, they are ever more applicable. Extensive and complex networks can be distilled into a small set of key master transcriptional regulators (MTR), genes that are very highly connected and have been shown to be involved in processes of known importance in disease. Interpreting and validating the results of standardized bioinformatic methods is of crucial importance in determining the inherent value of MTRs. In this review, we briefly describe how MTRs are identified and focus on providing an overview of how MTRs can and have been validated for use in clinical decision making in malignant diseases, along with serving as tractable therapeutic targets. Cancer Res; 77(9); 1–5. ©2017 AACR.
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Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection
Considerable advances in cancer-specific optical imaging have improved the precision of tumor resection. In comparison to traditional imaging modalities, this technology is unique in its ability to provide real-time feedback to the operating surgeon. Given the significant clinical implications of optical imaging, there is an urgent need to standardize surgical navigation tools and contrast agents to facilitate swift regulatory approval. Because fluorescence-enhanced surgery requires a combination of both device and drug, each may be developed in conjunction, or separately, which are important considerations in the approval process. This report is the result of a one-day meeting held on May 4, 2016 with officials from the National Cancer Institute, the FDA, members of the American Society of Image-Guided Surgery, and members of the World Molecular Imaging Society, which discussed consensus methods for FDA-directed human testing and approval of investigational optical imaging devices as well as contrast agents for surgical applications. The goal of this workshop was to discuss FDA approval requirements and the expectations for approval of these novel drugs and devices, packaged separately or in combination, within the context of optical surgical navigation. In addition, the workshop acted to provide clarity to the research community on data collection and trial design. Reported here are the specific discussion items and recommendations from this critical and timely meeting. Cancer Res; 77(9); 1–10. ©2017 AACR.
http://ift.tt/2p1mSDw
Whither Radioimmunotherapy: To Be or Not To Be?
Therapy of cancer with radiolabeled monoclonal antibodies has produced impressive results in preclinical experiments and in clinical trials conducted in radiosensitive malignancies, particularly B-cell lymphomas. Two "first-generation," directly radiolabeled anti-CD20 antibodies, 131iodine-tositumomab and 90yttrium-ibritumomab tiuxetan, were FDA-approved more than a decade ago but have been little utilized because of a variety of medical, financial, and logistic obstacles. Newer technologies employing multistep "pretargeting" methods, particularly those utilizing bispecific antibodies, have greatly enhanced the therapeutic efficacy of radioimmunotherapy and diminished its toxicities. The dramatically improved therapeutic index of bispecific antibody pretargeting appears to be sufficiently compelling to justify human clinical trials and reinvigorate enthusiasm for radioimmunotherapy in the treatment of malignancies, particularly lymphomas. Cancer Res; 77(9); 1–6. ©2017 AACR.
http://ift.tt/2pILwXk
Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone
Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention.
http://ift.tt/2p1kZGS
Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-kappaB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation, and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC.
http://ift.tt/2pIVlVp
Micellar delivery of miR-34a modulator rubone and paclitaxel in resistant prostate cancer
Treatment of prostate cancer with paclitaxel (PTX) often fails due to development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that co-delivery of PTX and 2′-hydroxy-2,4,4′,5,6′-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes PTX-resistant prostate cancer cells, killing both cancer stem-like cells (CSCs) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. PTX and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70 ± 0.10% and 5.34 ± 0.02% for PTX and rubone, respectively, controlling a drug release of 60.20 ± 2.67% and 60.62 ± 4.35% release of PTX and rubone at 24 h. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing PTX concentration. Co-incubation with a miR-34a inhibitor diminished the effect of rubone. PTX IC50 in PC3 and PC3-TXR cells was 55.6 and 2580 nM, respectively, but decreased to 49.8 and 93.2 nM when treated in combination with rubone, demonstrating a reversal of PTX resistance by rubone. Systemic administration of micelles carrying PTX and rubone inhibited orthotopic prostate tumor growth in nude mice, compared to monotherapy, by reversing the expression of miR-34a, SIRT1, Cyclin D1 and E-cadherin. In summary, our results showed how rubone acts as an efficient small molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of PTX in PTX-resistant prostate cancer.
http://ift.tt/2p1fGY0
Immune gene expression is associated with genomic aberrations in breast cancer
The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the 3 major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER positive, 207 HER2 positive, and 191 triple negative (TNBC) cancers from TCGA. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, neoantigen, and CNV loads in TNBC and HER2+ cancers. In ER+ cancers, mutation load, neoantigen load, and CNV load weakly but positively associated with immune infiltration, which reached significance for overall mutation load only. No highly recurrent single gene or pathway level mutations associated with immune infiltration. High immune gene expression and lower clonal heterogeneity in TNBC and HER2+ cancers suggest an immune pruning effect and equilibrium between immune surveillance and clonal expansion. Thus, immune checkpoint inhibitors may tip the balance in favor of immune surveillance in these cancers.
http://ift.tt/2pISuM6
Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion
New magnetic resonance (MR) molecular imaging techniques offer the potential for non-invasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a 3D dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low and high grade tumors in the TRAMP transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1 and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans, attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL. This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials.
http://ift.tt/2p1oT2H
Epithelial-to-mesenchymal Transition contributes to Immunosuppression in Breast Carcinomas
The Epithelial-to-mesenchymal transition (EMT) is a cell-biological program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. It is, unclear, however, whether activation of EMT in carcinoma cells can change their susceptibility to immune attack. We demonstrate here that mammary tumor cells arising from more epithelial carcinoma cell lines expressed high levels of MHC-I, low levels of PD-L1 and contained within their stroma CD8+ T cells and M1 (anti-tumor) macrophages. In contrast, tumors arising from more-mesenchymal carcinoma cell lines exhibiting EMT markers expressed low levels of MHC-I, high levels of PD-L1 and contained within their stroma regulatory T cells, M2 (pro-tumor) macrophages and exhausted CD8+ T cells. Moreover, the more mesenchymal carcinoma cells within a tumor retained the ability to protect their more epithelial counterparts from immune attack. Lastly, epithelial tumors were more susceptible to elimination by immunotherapy than corresponding mesenchymal tumors. Our results identify immune cells and immunomodulatory markers that can be potentially targeted to enhance the susceptibility of immunosuppressive tumors to various therapeutic regimens.
http://ift.tt/2pINxTg
EGFR mediates responses to small molecule drugs targeting oncogenic fusion kinases
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells, mouse models and human clinical specimens before onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to co-target EGFR to reduce risks of developing drug resistance.
http://ift.tt/2p1kFI1
Selective glucocorticoid receptor modulators (SGRMs) delay castrate-resistant prostate cancer growth
Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here we report that two novel non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect AR signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective non-steroidal SGRMs potently inhibit GR activity and PC growth despite AR pathway inhibition demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC.
http://ift.tt/2o9Rxzj
Mechanisms of Pinometostat (EPZ-5676) Treatment Emergent Resistance in MLL Rearranged Leukemia
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well characterized leukemic genes. Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment emergent resistance (TER) in cell lines confirmed to have MLL-r. TER was achieved in five MLL-r cell lines, KOPN-8, MOLM-13, MV4-11, NOMO-1, and SEM. Two of the cell lines, KOPN-8 and NOMO-1 were thoroughly characterized to understand the mechanisms involved in pinometostat resistance. Unlike many other targeted therapies, resistance does not appear to be achieved through drug-induced selection of mutations of the target itself. Instead, we identified both drug efflux transporter dependent and independent mechanisms of resistance to pinometostat. In KOPN-8 TER cells, increased expression of the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the primary mechanism of drug resistance. In contrast, resistance in NOMO-1 cells occurs through a mechanism other than upregulation of a specific efflux pump. RNA-seq analysis performed on both parental and resistant KOPN-8 and NOMO-1 cell lines supported two unique candidate pathway mechanisms that may explain the pinometostat resistance observed in these cell lines. These results are the first demonstration of TER models of the DOT1L inhibitor pinometostat and may provide useful tools for investigating clinical resistance.
http://ift.tt/2orVEmi
Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.
http://ift.tt/2oa1cWv
Primary Ewing Sarcoma / Primitive Neuroectodermal Tumor of the Kidney: A Clinicopathologic Study of 23 Cases
Abstract
Primary Ewing sarcoma / primitive neuroectodermal tumor (ES) of the kidney is a rare neoplasm with limited clinicopathologic data. We report 23 such cases with no history of ES elsewhere in the body. The patients included 13 male and 10 female, aged 8–70 years (mean, 31 years). The average tumor size was 11.7 cm (range, 5–20 cm). Microscopic analysis showed predominantly lobular growth (n = 14), with focal papillary (n = 3), alveolar (n = 1), and hemangiopericytoma-like (n = 1) patterns. Several tumors (n = 11) exhibited robust mitotic activity (>10 mitoses/10 high-power fields). Necrosis (n = 13) and lymphovascular invasion (n = 14) were common. Homer Wright rosettes (n = 6) and perivascular pseudorosettes (n = 1) were also identified. The tumors invaded the renal sinus or perinephric fat (n = 11), renal vein (n = 13), and adrenal gland (n = 2). Molecular and fluorescence in situ hybridization analysis showed rearrangement of EWSR1 gene (10/10), associated with EWSR1-FLI1 gene fusion (7/10). All patients with follow-up information (n = 18) had metastasis, commonly in the lungs (n = 12) and bone (n = 6). Twelve patients died of disease in a mean of 21 months; 6 patients were alive at a mean of 49 months after diagnosis. Primary kidney ES usually present at an advanced stage with extrarenal spread and metastasis. Although renal ES share histologic, immunohistochemical, and molecular features with their bone and soft tissue counterparts, they appear to be more aggressive tumors with poorer clinical outcome.
http://ift.tt/2ouAGTb
Prognostic value of dynamic hypoxia PET in head and neck cancer: Results from a planned interim analysis of a randomized phase II hypoxia-image guided dose escalation trial
To prospectively assess the prognostic value of tumour hypoxia determined by dynamic [18F]Fluoromisonidazole (dynFMISO) PET/CT, and to evaluate both feasibility and toxicity in patients with locally advanced squamous cell carcinomas of the head and neck (LASCCHN) treated with dynFMISO image-guided dose escalation (DE) using dose-painting by contours.
http://ift.tt/2orAEfy
Improved outcomes with dose escalation in localized prostate cancer treated with precision image-guided radiotherapy
Dose-escalated radiotherapy (DE) improves outcomes in localized prostate cancer (PCa). The impact of DE in the context of image-guided radiotherapy (IGRT) remains unknown. Herein, we determined outcomes of three sequential cohorts treated with progressive DE-IGRT.
http://ift.tt/2o9pHTz
Quantitative imaging: Correlating image features with the segmentation accuracy of PET based tumor contours in the lung
The purpose of this study was to investigate the correlation between image features extracted from PET images and the accuracy of manually drawn lesion contours in the lung. Such correlations are interesting in that they could potentially be used in predictive models to help guide physician contouring. In this work, 26 synthetic PET datasets were created using an anthropomorphic phantom and Monte Carlo simulation. Manual contours of simulated lesions were provided by 10 physicians. Contour accuracy was quantified using five commonly used similarity metrics which were then correlated with several features extracted from the images.
http://ift.tt/2orKqOx
Patterns of care survey: Radiotherapy for women with locally advanced cervical cancer
Regarding latest developments, the need of a radiotherapy 'Patterns of Care' survey was expressed by the Dutch National Platform Radiotherapy for Gynaecological Cancer (LPRGT). Therefore, this study investigated current practice for cervical cancer in all 16 radiation oncology centres in the Netherlands specialised in gynaecological oncology.
http://ift.tt/2o9AMUZ
MuPeXI: prediction of neo-epitopes from tumor sequencing data
Abstract
Personalization of immunotherapies such as cancer vaccines and adoptive T cell therapy depends on identification of patient-specific neo-epitopes that can be specifically targeted. MuPeXI, the mutant peptide extractor and informer, is a program to identify tumor-specific peptides and assess their potential to be neo-epitopes. The program input is a file with somatic mutation calls, a list of HLA types, and optionally a gene expression profile. The output is a table with all tumor-specific peptides derived from nucleotide substitutions, insertions, and deletions, along with comprehensive annotation, including HLA binding and similarity to normal peptides. The peptides are sorted according to a priority score which is intended to roughly predict immunogenicity. We applied MuPeXI to three tumors for which predicted MHC-binding peptides had been screened for T cell reactivity, and found that MuPeXI was able to prioritize immunogenic peptides with an area under the curve of 0.63. Compared to other available tools, MuPeXI provides more information and is easier to use. MuPeXI is available as stand-alone software and as a web server at http://ift.tt/2pIfAoY.
from Cancer via ola Kala on Inoreader http://ift.tt/2ovCGut
via IFTTT
MuPeXI: prediction of neo-epitopes from tumor sequencing data
Abstract
Personalization of immunotherapies such as cancer vaccines and adoptive T cell therapy depends on identification of patient-specific neo-epitopes that can be specifically targeted. MuPeXI, the mutant peptide extractor and informer, is a program to identify tumor-specific peptides and assess their potential to be neo-epitopes. The program input is a file with somatic mutation calls, a list of HLA types, and optionally a gene expression profile. The output is a table with all tumor-specific peptides derived from nucleotide substitutions, insertions, and deletions, along with comprehensive annotation, including HLA binding and similarity to normal peptides. The peptides are sorted according to a priority score which is intended to roughly predict immunogenicity. We applied MuPeXI to three tumors for which predicted MHC-binding peptides had been screened for T cell reactivity, and found that MuPeXI was able to prioritize immunogenic peptides with an area under the curve of 0.63. Compared to other available tools, MuPeXI provides more information and is easier to use. MuPeXI is available as stand-alone software and as a web server at http://ift.tt/2pIfAoY.
http://ift.tt/2ovCGut
MuPeXI: prediction of neo-epitopes from tumor sequencing data
Abstract
Personalization of immunotherapies such as cancer vaccines and adoptive T cell therapy depends on identification of patient-specific neo-epitopes that can be specifically targeted. MuPeXI, the mutant peptide extractor and informer, is a program to identify tumor-specific peptides and assess their potential to be neo-epitopes. The program input is a file with somatic mutation calls, a list of HLA types, and optionally a gene expression profile. The output is a table with all tumor-specific peptides derived from nucleotide substitutions, insertions, and deletions, along with comprehensive annotation, including HLA binding and similarity to normal peptides. The peptides are sorted according to a priority score which is intended to roughly predict immunogenicity. We applied MuPeXI to three tumors for which predicted MHC-binding peptides had been screened for T cell reactivity, and found that MuPeXI was able to prioritize immunogenic peptides with an area under the curve of 0.63. Compared to other available tools, MuPeXI provides more information and is easier to use. MuPeXI is available as stand-alone software and as a web server at http://ift.tt/2pIfAoY.
from Cancer via ola Kala on Inoreader http://ift.tt/2ovCGut
via IFTTT
18F-Fluorodeoxyglucose uptake on positron emission tomography/computed tomography is associated with metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma
Abstract
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality worldwide. Several studies have investigated the relationship between 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography and the prognosis of patients with HCC, although the relationship between 18F-FDG uptake and expression of EMT-related proteins in these patients remains unclear. We retrospectively enrolled 116 patients with HCC treated by curative surgical resection and who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) for preoperative staging. The relationship between the tumor-to-liver standardized uptake value ratio (TLR) and the presence of metastasis was determined. By using HCC cell lines with different 18F-FDG uptake, we assessed the effect of 18F-FDG uptake on in vitro cell proliferation and migration on the inhibition of glucose uptake. Ten (29.4%) of 34 patients with high TLRs had extrahepatic metastases, whereas six (7.3%) of 82 patients with low TLRs had extrahepatic metastases (p = 0.002). Hepatocellular carcinomas with high TLRs showed higher expression of glucose transporter isoform 1 and EMT markers than did HCCs with low TLRs. After treatment with a glucose uptake inhibitor, HCC cells with high 18F-FDG uptake showed decreased cell proliferation and migration and a reversal in the expression of EMT markers. High 18F-FDG uptake on PET/CT is associated with frequent extrahepatic metastasis and EMT in patients with HCC. Inhibition of glucose uptake reduced cell proliferation, reversed EMT-related protein expression, and decreased cellular migration. Glycolytic regulation could be a new therapeutic target to reduce tumor growth and metastatic potential in HCCs with a high glycolytic phenotype.
from Cancer via ola Kala on Inoreader http://ift.tt/2pIAqEP
via IFTTT
Feasibility and Acceptability of “Healthy Directions” a Lifestyle Intervention for Adults with Lung Cancer
Abstract
Objective
The aims of this feasibility study of an adapted lifestyle intervention for adults with lung cancer were to: 1) determine rates of enrollment, attrition and completion of five nurse-patient contacts, 2) examine demographic characteristics of those more likely to enroll into the program, 3) determine acceptability of the intervention, and 4) identify patient preferences for the format of supplemental educational intervention materials.
Methods
This study used a single arm, pre-and post-test design. Feasibility was defined as > 20% enrollment and a completion rate of 70% for five nurse-patient contact sessions. Acceptability was defined as 80% of patients recommending the program to others. Data was collected through electronic data-bases and phone interviews. Descriptive statistics, Fisher's exact test and Wilcoxon rank sum test were used for analyses.
Results
Of 147 eligible patients, 42 (28.6%) enrolled and of these, 32 (76.2%) started the intervention and 27 (N = 27/32; 84.4%; 95% CI: 67.2-94.7%) completed the intervention. Patients who were younger were more likely to enroll in the study (p = 0.04) whereas there were no significant differences by gender (p = 0.35). Twenty-three of the 24 (95.8%) participants' contacted post-test recommended the intervention for others. Nearly equal numbers of participants chose the website, (n = 16, 50%) vs. print (n = 14, 44%).
Conclusion
The intervention was feasible and acceptable in patients with lung cancer. Recruitment rates were higher and completion rates were similar as compared to previous home-based lifestyle interventions for patients with other types of cancer. Strategies to enhance recruitment of older adults are important for future research.
from Cancer via ola Kala on Inoreader http://ift.tt/2pIuPhr
via IFTTT
18F-Fluorodeoxyglucose uptake on positron emission tomography/computed tomography is associated with metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma
Abstract
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality worldwide. Several studies have investigated the relationship between 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography and the prognosis of patients with HCC, although the relationship between 18F-FDG uptake and expression of EMT-related proteins in these patients remains unclear. We retrospectively enrolled 116 patients with HCC treated by curative surgical resection and who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) for preoperative staging. The relationship between the tumor-to-liver standardized uptake value ratio (TLR) and the presence of metastasis was determined. By using HCC cell lines with different 18F-FDG uptake, we assessed the effect of 18F-FDG uptake on in vitro cell proliferation and migration on the inhibition of glucose uptake. Ten (29.4%) of 34 patients with high TLRs had extrahepatic metastases, whereas six (7.3%) of 82 patients with low TLRs had extrahepatic metastases (p = 0.002). Hepatocellular carcinomas with high TLRs showed higher expression of glucose transporter isoform 1 and EMT markers than did HCCs with low TLRs. After treatment with a glucose uptake inhibitor, HCC cells with high 18F-FDG uptake showed decreased cell proliferation and migration and a reversal in the expression of EMT markers. High 18F-FDG uptake on PET/CT is associated with frequent extrahepatic metastasis and EMT in patients with HCC. Inhibition of glucose uptake reduced cell proliferation, reversed EMT-related protein expression, and decreased cellular migration. Glycolytic regulation could be a new therapeutic target to reduce tumor growth and metastatic potential in HCCs with a high glycolytic phenotype.
http://ift.tt/2pIAqEP
Feasibility and Acceptability of “Healthy Directions” a Lifestyle Intervention for Adults with Lung Cancer
Abstract
Objective
The aims of this feasibility study of an adapted lifestyle intervention for adults with lung cancer were to: 1) determine rates of enrollment, attrition and completion of five nurse-patient contacts, 2) examine demographic characteristics of those more likely to enroll into the program, 3) determine acceptability of the intervention, and 4) identify patient preferences for the format of supplemental educational intervention materials.
Methods
This study used a single arm, pre-and post-test design. Feasibility was defined as > 20% enrollment and a completion rate of 70% for five nurse-patient contact sessions. Acceptability was defined as 80% of patients recommending the program to others. Data was collected through electronic data-bases and phone interviews. Descriptive statistics, Fisher's exact test and Wilcoxon rank sum test were used for analyses.
Results
Of 147 eligible patients, 42 (28.6%) enrolled and of these, 32 (76.2%) started the intervention and 27 (N = 27/32; 84.4%; 95% CI: 67.2-94.7%) completed the intervention. Patients who were younger were more likely to enroll in the study (p = 0.04) whereas there were no significant differences by gender (p = 0.35). Twenty-three of the 24 (95.8%) participants' contacted post-test recommended the intervention for others. Nearly equal numbers of participants chose the website, (n = 16, 50%) vs. print (n = 14, 44%).
Conclusion
The intervention was feasible and acceptable in patients with lung cancer. Recruitment rates were higher and completion rates were similar as compared to previous home-based lifestyle interventions for patients with other types of cancer. Strategies to enhance recruitment of older adults are important for future research.
http://ift.tt/2pIuPhr
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