Capillary refill time, bleeding time, clotting time, erythrocyte sedimentation rate and prothrombin time in natural cases of canine Trypanosoma congolense infection

Abstract

Trypanosomiasis of man and his domestic animals continues to pose enormous public health and economic problems in many parts of Africa and South America. Thirty-one dogs were used for this study. 23 of the dogs were apparently healthy while eight were confirmed to be suffering from Trypanosoma congolense. Confirmation of trypanosomiasis was done by wet mount and by the use of Dip Quick™ stain. Capillary refill time, bleeding time, clotting time, erythrocyte sedimentation rate and prothrombin time were determined. The mean values for the apparently healthy dogs were 1.32 s (seconds), 3.34 min (minutes), 4.71 min, 3.85 mm/h (millimetres/hours) and 24.1 s, respectively for capillary refill time, bleeding time, clotting time, erythrocyte sedimentation rate and prothrombin time, respectively, while in cases of T.congolense, 2.75 s, 5.49 min, 8.17 min, 9.63 mm/h and 45 s, respectively. There was significant (P < 0.05) increase in capillary refill time, bleeding time, clotting time, erythrocyte sedimentation rate and prothrombin time in dogs naturally infected by T.congolense. The tests or parameters evaluated in this work, though not of diagnostic value, can help in the screening and monitoring of canine trypanosomiasis.

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Cupressus sempervirens extract inhibited human basal cell carcinoma tumorigenesis, local invasion, and angiogenic property

Abstract

Basal cell carcinoma, a noninvasive and rarely metastatic tumor, correlates with clinical and histological involvement of basal epithelial cells. It occurs due to dysregulation of hedgehog-patched1 signaling pathway. The current study was conducted to evaluate the in vitro cytotoxic effects of Cupressus sempervirens methanolic extract against primary basal cell carcinoma cells, over a period of 48 h. We measured protein level of Annexin-V and the leakage rate of lactate dehydrogenase in cells being exposed to 420 μM extract. In addition to transcript levels of PTCH-1, a receptor of  of hedgehog signaling pathway, angiogenic activity of tumor cells were determined in terms of the amount of vascular endothelial growth factor and angiopoietin-2, and metastatic levels of matrix metalloproteinase 2 and 9.

The cytotoxicity test results showed that BCC cells survival decreased dose-dependently over 48 h after exposure to plant extract. The expression of Annexin-V was induced (p < 0.05) in treated cells which coincided with raised levels of lactate dehydrogenase in supernatant media (p < 0.05). Noticeably, the expression of PTCH-1, vascular endothelial growth factor, angiopoietin-2, and matrix metalloproteinase 2 and 9 were robustly decreased. Interestingly, 6-month clinical trial follow-up of C. sempervirens extract 5% ointment showed antitumor activity against cutaneous basal cell carcinoma by the reduction of tumor and inflammatory cells replaced with fibrotic stroma. The data of present experiment may suggest that the methanolic extracts of C. sempervirens possess oncostatic and cytotoxic properties, and therefore, can be prescribed as natural protective and therapeutic ingredients for basal cell associate cutaneous tumor.

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The prevalence and control of bovine mastitis in Leptospira outbreak

Abstract

Leptospirosis is considered as one of the most widespread zoonotic disease among many species of wild and domesticated animals, including dairy cows worldwide. Due to its presence and proliferation capacity in the lactating mammary gland, leptospires-related mastitis and milk drop syndrome occur in lactating dairy cows. The aims of this study were to evaluate 1) the occurrence of mastitis due to leptospirosis and 2) the differences of Leptospira mastitis occurrence between primiparous and multiparous cows. Leptospirosis occurred in a large industrial dairy cattle herd complex in the northwest of Iran for 2 years including 760 Holstein dairy cows. The microscopic agglutination test (MAT) was used for diagnosis. Sera were screened against 22 life antigens. A MAT titer of ≥1:100 were considered positive. MAT titer was among 1:100 to 1:3200. The MAT showed that cows were infected by Leptospira interrogans (L. I.) hardjo, pomona, grippotyphosa, icterohaemorrhagiae, and canicola serovars. All of the tested cows had reaction against L. I. hardjo. In total, 406 (53%) out of 760 cows showed clinical mastitis. It was also observed that 255 (63%) dairy cows with ≥3rd lactation number had the highest mastitis. In primiparous cows, the prevalence of leptospiral clinical mastitis was significantly lower than multiparous dairy cows (P < 0.05) (19 vs 63%). During this 2 years leptospirosis outbreak, the control and treatment strategies limited the occurrence. They included the following: antibiotic therapy as treatment and prophylaxis, vaccination, control rodents population, and implementation of tight hygiene management.

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Double germline mutations in APC and BRCA2 in an individual with a pancreatic tumor

Abstract

We report on three brothers affected by pancreatic tumors, all due to different causes, including mutations associated with two different cancer predisposition syndromes in the same individual. In the index patient a germline mutation both in the APC and BRCA2 gene was identified while one affected brother showed the BRCA2 mutation only and another brother is supposed to have developed pancreatic cancer due to multiple non-genetic risk factors. We outline the impact of a double germline mutation in two tumor predisposition genes in one individual and proven heterogeneity of multiple cases of pancreatic tumors in one family. With the growing implementation of next generation sequence based panel testing for multiple genes involved in tumor predisposition syndromes, relevant variants in two (or more) genes will be found more frequently. This family illustrates the importance of family studies, especially when using gene panel tests.

http://ift.tt/2fMZcOT

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

Abstract

In recent years, familial pheochromocytoma (PHEO) with germline mutations in the MAX (MYC associated factor X) gene has been reported in a few cases. Here, we investigated a 25–year-old patient with multiple PHEOs associated with a non-sense germline MAX mutation. Preoperative ¹⁸F-FDOPA PET/CT revealed bilateral adrenal involvement with multiple tumors. In addition, both adrenal glands were found to have diffuse or nodular adrenal medullary hyperplasia (AMH), a histopathological feature previously described as a precursor of MEN2- and SDHB-related PHEOs but not MAX. After bilateral adrenalectomy, different paraffin-embedded and frozen samples were analyzed for allelic imbalances of the MAX gene using allelic quantification by pyrosequencing. The expression of the protein MAX was studied by immunohistochemistry. All PHEOs but also nodular AMH exhibited a loss of the normal allele. By contrast, the diffuse AMH did not show loss-of-heterozygosity. Nevertheless, immunohistochemistry demonstrated loss of protein MAX expression in all samples including diffuse hyperplasia, suggesting a causative role of MAX mutation for both PHEOs and AMH. The present case shows that both nodular and diffuse AMH belongs to the spectrum of MAX-related disease. These data support the possible continuum between nodular AMH and PHEO, expanding the qualification of micro-PHEO to nodular AMH.

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Cancer-derived extracellular vesicles: the ‘soil conditioner’ in breast cancer metastasis?

Abstract

It has been recognized that cancer-associated mortality is more often a result of the disrupted physiological functions in multiple organs following metastatic dissemination of cancer cells, rather than the presence and growth of the primary tumor. Despite advances in our understanding of the events leading to cancer initiation, growth, and acquisition of invasive properties, we are still unable to effectively treat metastatic disease. It is now being accepted that the secretion of extracellular vesicles, such as exosomes from cancer cells, has a profound impact on the initiation and propagation of metastatic breast cancer. These cancer-secreted vesicles differ from other means of cellular communication due to their capability of bulk delivery and organotropism. Here, we provide an overview of the role of extracellular vesicles in breast cancer metastasis and discuss key areas that may facilitate our understanding of metastatic breast cancer to guide our efforts towards providing better therapies.

http://ift.tt/2fO3V0K

Cancer-derived extracellular vesicles: the ‘soil conditioner’ in breast cancer metastasis?

Abstract

It has been recognized that cancer-associated mortality is more often a result of the disrupted physiological functions in multiple organs following metastatic dissemination of cancer cells, rather than the presence and growth of the primary tumor. Despite advances in our understanding of the events leading to cancer initiation, growth, and acquisition of invasive properties, we are still unable to effectively treat metastatic disease. It is now being accepted that the secretion of extracellular vesicles, such as exosomes from cancer cells, has a profound impact on the initiation and propagation of metastatic breast cancer. These cancer-secreted vesicles differ from other means of cellular communication due to their capability of bulk delivery and organotropism. Here, we provide an overview of the role of extracellular vesicles in breast cancer metastasis and discuss key areas that may facilitate our understanding of metastatic breast cancer to guide our efforts towards providing better therapies.

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Long-Term Survival with Chemoradiation Alone in Locally Advanced Unresectable Gallbladder Cancer: First Case Report of a New Paradigm

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Long-Term Survival with Chemoradiation Alone in Locally Advanced Unresectable Gallbladder Cancer: First Case Report of a New Paradigm

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Acknowledgment to reviewers

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Acknowledgment to reviewers

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Amino acids essential for the interaction between cellular heat shock protein 90 and a Kaposi’s sarcoma-associated herpesvirus-encoded protein kinase ORF36

Abstract

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Amino acids essential for the interaction between cellular heat shock protein 90 and a Kaposi’s sarcoma-associated herpesvirus-encoded protein kinase ORF36

Abstract

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Evaluation of reproducibility of tumor repositioning during multiple breathing cycles for liver stereotactic body radiotherapy treatment

Publication date: Available online 12 November 2016
Source:Reports of Practical Oncology & Radiotherapy
Author(s): Ludovic Bedos, Olivier Riou, Norbert Aillères, Antoine Braccini, Jessica Molinier, Carmen Llacer Moscardo, David Azria, Pascal Fenoglietto
AimTo evaluate the tumor repositioning during gated volumetric modulated arc therapy (VMAT) for liver stereotactic body radiotherapy(SBRT) treatment using implanted fiducial markers and intrafraction kilovoltage (kV) images acquired during dose delivery.Materials and methodsSince 2012, 47 liver cancer patients with implanted fiducial markers were treated using the gated VMAT technique with a Varian Truebeam STx linear accelerator. The fiducial markers were implanted inside or close to the tumor target before treatment simulation. They were defined at the maximum inhalation and exhalation phases on a 4-dimensionnal computed tomography (4DCT) acquisition. During the treatment, kV images were acquired just before the beam-on at each breathing cycle at maximum exhalation and inhalation phases to verify the fiducial markers positions. For the five first fractions of treatment in the first ten consecutive patients, a total of 2705 intrafraction kV images were retrospectively analyzed to assess the differences between expected and actual positions of the fiducial markers along the cranio-caudal (CC) direction during the exhalation phase.ResultsThe mean absolute intrafractional fiducial marker deviation along the CC direction was 1.0mm at the maximum exhalation phase. In 99%, 95% and 90% cases, the fiducial marker deviations were ≤4.5mm, 2.8mm and 2.2mm, respectively.ConclusionIntrafraction kV images allowed us to ensure the consistency of tumor repositioning during treatment. In 99% cases, the fiducial marker deviations were ≤4.5mm corresponding to our 5mm treatment margin. This margin seems to be well-adapted to the gated VMAT SBRT treatment in liver disease.



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Biodistribution of diphenhydramine in reproductive organs in an overdose case

Abstract

Motion sickness medications such as Travelmin^® prescribed in Japan include diphenhydramine (DPH), dyphylline, diphenidol, and/or caffeine. Herein, we report a patient who died due to rhabdomyolysis after ingesting a DPH containing motion sickness medication. A Japanese male in his 30 s reported missing after going out for a drive early in the morning was found dead in his car in the evening of the same day. An autopsy showed moderate edema, congestion, and several petechiae in both lungs. The brain was congested and edematous with no atherosclerosis of cerebral arteries. The prostate and both testes were slightly edematous. Gastric contents included approximately 15 mL of dark-brown fluid without tablets or food residue. Toxicological examination showed that blood DPH levels in all tissues were between 4.90 and 7.27 μg/mL, which represented toxic to lethal levels. DPH (μg/mL) levels were approximately 3–9 times higher in the prostate (73.42) and testes (left, 28.23; right, 30.09) than those in all regions of the brain (range 7.75–12.33). Blood dyphylline, diphenidol and caffeine levels in reproductive organs reached high, but not toxic levels. In conclusion, DPH, dyphylline, diphenidol, and caffeine levels were higher in reproductive organs such as the prostate and testes than in the central nervous system and heart. As we determined in this case, motion sickness medications might accumulate in reproductive organs. Thus, further examination of tissue biodistribution of DPH, dyphylline, diphenidol, and caffeine is necessary to assess their potential long-term effects in these sites.

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Studies on non-synonymous polymorphisms altering human DNA Topoisomerase II-alpha interaction with Amsacrine and Mitoxantrone: An in silico approach.

Related Articles

Studies on non-synonymous polymorphisms altering human DNA Topoisomerase II-alpha interaction with Amsacrine and Mitoxantrone: An in silico approach.

Curr Cancer Drug Targets. 2016 Nov 09;

Authors: Farsani FM, Ganjalikhany MR, Vallian S

Abstract
DNA topoisomerase II-α (Top2-α), an essential enzyme for the management of DNA during replication, transcription, recombination, and chromatin remodeling, is one of the most important anticancer targets. Numerous molecules have been designed as Top2-α inhibitors. However, several studies have shown that polymorphisms and mutations in Top2 have conferred resistance to most of these anticancer drugs. The aim of this study was to computationally examine the mechanisms by which genomic variations in Top2-α could affect its resistance to Amsacrine and Mitoxantrone as important inhibitors of the enzyme. The results showed that variants K529E, R568H, R568G and T530M could affect Top2-α inhibition by Amsacrine causing possible drug-resistant. Moreover, R487K and Y481C variants could change the response of the enzyme to Mitoxantrone. These results could facilitate the prediction and development of more effective drugs for Top2-α variants, making the cancer chemotherapy more effective.

PMID: 27834128 [PubMed - as supplied by publisher]

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Biodistribution of diphenhydramine in reproductive organs in an overdose case

Abstract

Motion sickness medications such as Travelmin^® prescribed in Japan include diphenhydramine (DPH), dyphylline, diphenidol, and/or caffeine. Herein, we report a patient who died due to rhabdomyolysis after ingesting a DPH containing motion sickness medication. A Japanese male in his 30 s reported missing after going out for a drive early in the morning was found dead in his car in the evening of the same day. An autopsy showed moderate edema, congestion, and several petechiae in both lungs. The brain was congested and edematous with no atherosclerosis of cerebral arteries. The prostate and both testes were slightly edematous. Gastric contents included approximately 15 mL of dark-brown fluid without tablets or food residue. Toxicological examination showed that blood DPH levels in all tissues were between 4.90 and 7.27 μg/mL, which represented toxic to lethal levels. DPH (μg/mL) levels were approximately 3–9 times higher in the prostate (73.42) and testes (left, 28.23; right, 30.09) than those in all regions of the brain (range 7.75–12.33). Blood dyphylline, diphenidol and caffeine levels in reproductive organs reached high, but not toxic levels. In conclusion, DPH, dyphylline, diphenidol, and caffeine levels were higher in reproductive organs such as the prostate and testes than in the central nervous system and heart. As we determined in this case, motion sickness medications might accumulate in reproductive organs. Thus, further examination of tissue biodistribution of DPH, dyphylline, diphenidol, and caffeine is necessary to assess their potential long-term effects in these sites.

http://ift.tt/2fMDUkk

NKG2D ligand expression in pediatric brain tumors.

Related Articles

NKG2D ligand expression in pediatric brain tumors.

Cancer Biol Ther. 2016 Nov 11;:0

Authors: Haberthur K, Brennan K, Hoglund V, Balcaitis S, Chinn H, Davis A, Kreuser S, Winter C, Leary SE, Deutsch GH, Ellenbogen RG, Crane CA

Abstract
Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the eight known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

PMID: 27834580 [PubMed - as supplied by publisher]

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NKG2D ligand expression in pediatric brain tumors.

Related Articles

NKG2D ligand expression in pediatric brain tumors.

Cancer Biol Ther. 2016 Nov 11;:0

Authors: Haberthur K, Brennan K, Hoglund V, Balcaitis S, Chinn H, Davis A, Kreuser S, Winter C, Leary SE, Deutsch GH, Ellenbogen RG, Crane CA

Abstract
Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the eight known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

PMID: 27834580 [PubMed - as supplied by publisher]

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Predictors of fatigue and poor sleep in adult survivors of childhood Hodgkin’s lymphoma: a report from the Childhood Cancer Survivor Study

Abstract

Purpose

Survivors of pediatric Hodgkin's lymphoma (HL) are at risk for a number of debilitating late effects. Excessive fatigue and poor sleep quality are primary complaints of HL survivors. Understanding the emotional and physical factors that influence fatigue and sleep quality may provide opportunities for intervention to improve health-related quality of life for HL survivors.

Methods

Data from 751 adult survivors of childhood HL who participated in the Childhood Cancer Survivor Study (CCSS) from 2000–2002 were analyzed. Multivariable logistic regression analyses investigated the demographic, psychological, and physical variables that predicted clinically significant levels of poor sleep quality, fatigue, and excessive daytime sleepiness.

Results

Survivors' self-reported level of emotional distress, pain, and physical functioning limitations did not differ from population norms. Clinically elevated levels of emotional distress (OR 8.38, 95% CI 4.28–16.42) and pain (OR 3.73, 95% CI 2.09–6.67) increased the risk for endorsing elevated levels of fatigue. Survivors with elevated levels of emotional distress (OR 6.83, 95% CI 2.71–15.90) and pain (OR 5.27, 95% CI 1.78–15.61) were more likely to report poor sleep quality. Pain (OR 2.11, 95% CI 1.39–3.34) was related to excessive daytime sleepiness.

Conclusions

Emotional and physical factors are associated with elevated levels of fatigue, excessive daytime sleepiness, and poor sleep quality in survivors of pediatric HL. This is consistent with findings from research conducted with non-cancer survivors.

Implications for cancer survivors

These results suggest that interventions designed to target sleep and fatigue difficulties in the general population may be well suited for pediatric HL survivors as well.

http://ift.tt/2fmNcDm

Return to work among self-employed cancer survivors

Abstract

Purpose

The aim of this study is to investigate whether salaried and self-employed workers differ regarding factors relevant for return to work after being diagnosed with cancer. The possible mediators of an effect of self-employment on work ability were also investigated.

Methods

A total of 1115 cancer survivors (1027 salaried and 88 self-employed) of common invasive cancer types who were in work at the time of diagnosis completed a mailed questionnaire 15–39 months after diagnosis.

Results

Twenty-four percent of self-employed cancer survivors reported that they had not returned to work at the time of the survey, and 18 % of those who were salaried had not. While 9 % of the self-employed had received disability or early retirement pension, only 5 % had received such a pension among salaried employees. Compared with the salaried workers, the self-employed people reported significantly more often reduced work hours (P < 0.001), negative cancer-related financial (P < 0.001), and occupational changes (P = 0.005) and low overall health (P = 0.02), quality of life (P = 0.04), and total work ability (P = 0.02). The negative effect of self-employment on total work ability seems to be mediated by reduced work hours and a negative cancer-related financial change.

Conclusions

Compared with salaried, self-employed workers in Norway, they seem to struggle with work after cancer. This may be because the two groups have different work tasks and because self-employed people have lower social support at work and less legal support from the Working Environment Act and public health insurance.

Implications for cancer survivors

Self-employed people with cancer should be informed about the work-related challenges they may encounter and be advised to seek practical help from social workers who know about the legal rights of self-employed people.

http://ift.tt/2fNuzXG

Predictors of fatigue and poor sleep in adult survivors of childhood Hodgkin’s lymphoma: a report from the Childhood Cancer Survivor Study

Abstract

Purpose

Survivors of pediatric Hodgkin's lymphoma (HL) are at risk for a number of debilitating late effects. Excessive fatigue and poor sleep quality are primary complaints of HL survivors. Understanding the emotional and physical factors that influence fatigue and sleep quality may provide opportunities for intervention to improve health-related quality of life for HL survivors.

Methods

Data from 751 adult survivors of childhood HL who participated in the Childhood Cancer Survivor Study (CCSS) from 2000–2002 were analyzed. Multivariable logistic regression analyses investigated the demographic, psychological, and physical variables that predicted clinically significant levels of poor sleep quality, fatigue, and excessive daytime sleepiness.

Results

Survivors' self-reported level of emotional distress, pain, and physical functioning limitations did not differ from population norms. Clinically elevated levels of emotional distress (OR 8.38, 95% CI 4.28–16.42) and pain (OR 3.73, 95% CI 2.09–6.67) increased the risk for endorsing elevated levels of fatigue. Survivors with elevated levels of emotional distress (OR 6.83, 95% CI 2.71–15.90) and pain (OR 5.27, 95% CI 1.78–15.61) were more likely to report poor sleep quality. Pain (OR 2.11, 95% CI 1.39–3.34) was related to excessive daytime sleepiness.

Conclusions

Emotional and physical factors are associated with elevated levels of fatigue, excessive daytime sleepiness, and poor sleep quality in survivors of pediatric HL. This is consistent with findings from research conducted with non-cancer survivors.

Implications for cancer survivors

These results suggest that interventions designed to target sleep and fatigue difficulties in the general population may be well suited for pediatric HL survivors as well.

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Return to work among self-employed cancer survivors

Abstract

Purpose

The aim of this study is to investigate whether salaried and self-employed workers differ regarding factors relevant for return to work after being diagnosed with cancer. The possible mediators of an effect of self-employment on work ability were also investigated.

Methods

A total of 1115 cancer survivors (1027 salaried and 88 self-employed) of common invasive cancer types who were in work at the time of diagnosis completed a mailed questionnaire 15–39 months after diagnosis.

Results

Twenty-four percent of self-employed cancer survivors reported that they had not returned to work at the time of the survey, and 18 % of those who were salaried had not. While 9 % of the self-employed had received disability or early retirement pension, only 5 % had received such a pension among salaried employees. Compared with the salaried workers, the self-employed people reported significantly more often reduced work hours (P < 0.001), negative cancer-related financial (P < 0.001), and occupational changes (P = 0.005) and low overall health (P = 0.02), quality of life (P = 0.04), and total work ability (P = 0.02). The negative effect of self-employment on total work ability seems to be mediated by reduced work hours and a negative cancer-related financial change.

Conclusions

Compared with salaried, self-employed workers in Norway, they seem to struggle with work after cancer. This may be because the two groups have different work tasks and because self-employed people have lower social support at work and less legal support from the Working Environment Act and public health insurance.

Implications for cancer survivors

Self-employed people with cancer should be informed about the work-related challenges they may encounter and be advised to seek practical help from social workers who know about the legal rights of self-employed people.

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NKG2D ligand expression in pediatric brain tumors.

Related Articles

NKG2D ligand expression in pediatric brain tumors.

Cancer Biol Ther. 2016 Nov 11;:0

Authors: Haberthur K, Brennan K, Hoglund V, Balcaitis S, Chinn H, Davis A, Kreuser S, Winter C, Leary SE, Deutsch GH, Ellenbogen RG, Crane CA

Abstract
Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the eight known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

PMID: 27834580 [PubMed - as supplied by publisher]

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NKG2D ligand expression in pediatric brain tumors.

Related Articles

NKG2D ligand expression in pediatric brain tumors.

Cancer Biol Ther. 2016 Nov 11;:0

Authors: Haberthur K, Brennan K, Hoglund V, Balcaitis S, Chinn H, Davis A, Kreuser S, Winter C, Leary SE, Deutsch GH, Ellenbogen RG, Crane CA

Abstract
Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the eight known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

PMID: 27834580 [PubMed - as supplied by publisher]

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Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma

Abstract

Purpose

Because of the observed success of phase I/II trials, the novel anti-CD30 agent brentuximab vedotin is now being evaluated as a frontline agent in the high-risk pediatric Hodgkin lymphoma trial HLHR13. The objectives of this study were to evaluate the pharmacokinetic variability during weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data, and evaluate toxicity of brentuximab vedotin in the pediatric population.

Methods

Brentuximab vedotin, MMAE and anti-therapeutic antibody levels were measured in the serum samples of 16 pediatric patients with Hodgkin lymphoma. A compartmental pharmacokinetic model was fit to the data by using nonlinear mixed-effects modeling.

Results

Clearance and volume of brentuximab vedotin were significantly correlated with weight (p < .001), which was responsible for over 60% of the parameters inter-individual variability. Clearance and volume were higher in boys compared to girls (p = 0.08 and p = 0.03, respectively). Brentuximab vedotin's AUC and C _max were lower in our pediatric study than those reported in adult studies (25 and 11%, respectively). Toxicity was comparable to that of the standard-of-care backbone using vincristine instead of brentuximab vedotin. The sera of all 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy.

Conclusions

As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin's pharmacokinetic variability in pediatric patients. Exposure to weekly dosing appears to be safe and tolerable in pediatric patients.

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Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Abstract

Purpose

Tumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.

Methods

In vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.

Results

The combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.

Conclusion

These studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.

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Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma

Abstract

Purpose

Because of the observed success of phase I/II trials, the novel anti-CD30 agent brentuximab vedotin is now being evaluated as a frontline agent in the high-risk pediatric Hodgkin lymphoma trial HLHR13. The objectives of this study were to evaluate the pharmacokinetic variability during weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data, and evaluate toxicity of brentuximab vedotin in the pediatric population.

Methods

Brentuximab vedotin, MMAE and anti-therapeutic antibody levels were measured in the serum samples of 16 pediatric patients with Hodgkin lymphoma. A compartmental pharmacokinetic model was fit to the data by using nonlinear mixed-effects modeling.

Results

Clearance and volume of brentuximab vedotin were significantly correlated with weight (p < .001), which was responsible for over 60% of the parameters inter-individual variability. Clearance and volume were higher in boys compared to girls (p = 0.08 and p = 0.03, respectively). Brentuximab vedotin's AUC and C _max were lower in our pediatric study than those reported in adult studies (25 and 11%, respectively). Toxicity was comparable to that of the standard-of-care backbone using vincristine instead of brentuximab vedotin. The sera of all 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy.

Conclusions

As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin's pharmacokinetic variability in pediatric patients. Exposure to weekly dosing appears to be safe and tolerable in pediatric patients.

http://ift.tt/2fkBZCZ

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Abstract

Purpose

Tumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.

Methods

In vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.

Results

The combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.

Conclusion

These studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.

http://ift.tt/2fKTScV

Evaluation of the sonographic visibility and sonographic appearance of the breast biopsy marker (UltraClip ® ) placed in phantoms and patients

Abstract

Purpose

To evaluate the usefulness of the UltraClip^® dual trigger breast tissue marker (UltraClip) for sonographic localization, we investigate the sonographic visibility and sonographic appearance of the UltraClip placed in phantoms and patients.

Materials and methods

Ten UltraClips were placed in the target lesions in the phantoms. After the ultrasound examination of the UltraClip, the ultrasound images were compared to the real appearance of the UltraClip obtained by cutting the phantoms. In the patient, the UltraClip markers were placed after biopsy of a suspicious breast lesion or before or during neoadjuvant chemotherapy. The patients consented to return 1–3 weeks after the procedure for ultrasound imaging of the UltraClip.

Results

The UltraClip placed in the phantom appeared as a hyperechoic structure with a mean maximum diameter of 5.5 mm, which was found to correspond to the metallic clip in 90% (9/10) of the cases, and as a hyperechoic tubular structure with a maximum diameter of 9.0 mm corresponded to the expanded polyvinyl alcohol polymer in the remaining 10% (1/10) of cases. On the other hand, the UltraClip was detected as a hyperechoic structure measuring 3.5 mm in size only in 9 of the 15 (60%) patients. The sonographic visibility of the UltraClip was not affected depending on whether the target lesion or post-biopsy scar was sonographically detectable or not [60% (6/10) vs. 60% (3/5)].

Conclusions

While sonographic localization by targeting the UltraClip may be useful in 60% of the patients, another localization technique will be needed in the remaining patients.

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Non-calcified ductal carcinoma in situ of the breast: comparison of diagnostic accuracy of digital breast tomosynthesis, digital mammography, and ultrasonography

Abstract

Background

To retrospectively compare the diagnostic accuracy of digital breast tomosynthesis (DBT), digital mammography (DM), and ultrasonography (US) in non-calcified ductal carcinoma in situ (DCIS, include DCIS with micro-invasion).

Patients and methods

Ninety-eight patients with non-calcified DCIS (include DCIS with micro-invasion) were enrolled in our study. Breast carcinoma in situ was confirmed by surgical pathologic evaluation. Our Institutional Review Board granted approval and the participating women provided written informed consent. The imaging findings were evaluated according to the Breast Imaging Reporting and Data System (BI-RADS) of the American College of Radiology (ACR) by comparing the differences in the detection rate and diagnostic accuracy among the three techniques in all cases, in dense breasts, and in non-dense breasts.

Results

The detection rates of DBT, DM, and US for non-calcified DCIS in all cases were 83.7, 68.4, and 94.9%, respectively, and in patients with dense breasts were 81.2, 63.8, and 95.0%. The detection rate of US was higher than DBT, which, in turn, was higher than DM both in all cases and in dense breasts. Pairwise comparisons among the three techniques showed that the differences were statistically significant (P = 0.000 and P = 0.000, respectively). The experts identified a case as abnormal for all criteria (BI-RADS score of 4B-5) in 68.4% of ratings using DBT, 43.9% of ratings using DM, and 66.3% of ratings using US; for dense breasts, the positive identification rates were 62.5% of ratings using DBT, 41.2% of ratings using DM, and 61.2% of ratings using US. The diagnostic accuracy of DBT and US was significantly higher than that of DM in all cases (P = 0.001 and P = 0.006, respectively) and in dense breasts (P = 0.007 and P = 0.011, respectively). The diagnostic accuracy of DBT was slightly higher than US in all cases and in dense breasts, but the difference was not statistically significant (P = 0.761 and P = 0.871, respectively). By DBT, most non-calcified cases of DCIS presented as a mass lesion (54.9%) with an irregular shape (46.7%), indistinct margin (53.3%), and isodense composition (71.1%). Using US, 72 of 93 patients (77.4%) were shown to have a mass. Most mass lesions had an irregular shape (83.3%), indistinct margin (55.5%), and parallel the skin (82.8%).

Conclusion

DBT and US gave better detection rates and diagnostic accuracy for non-calcified DCIS compared with DM in all cases and in dense breasts. The detection rate of DBT was lower than that of US in all cases and in dense breasts. The diagnostic accuracy of DBT was slightly higher than that of US in all cases and in dense breasts, but the difference was not statistically significant. Imaging findings for non-calcified DCIS were relatively non-specific.

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Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series

Abstract

Background

The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.

Methods

We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.

Results

Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.

Conclusions

Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach.

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Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series

Abstract

Background

The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.

Methods

We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.

Results

Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.

Conclusions

Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach.

http://ift.tt/2fmdtSc

Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series

Abstract

Background

The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.

Methods

We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.

Results

Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.

Conclusions

Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach.

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Safety of raltegravir-based antiretroviral therapy in HIV-infected patients receiving multi-kinase inhibitors

Summary

Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm³, and 860 cells/mm³ after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm³) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.

http://ift.tt/2fHih2B

Safety of raltegravir-based antiretroviral therapy in HIV-infected patients receiving multi-kinase inhibitors

Summary

Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm³, and 860 cells/mm³ after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm³) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.

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Withaferin A and its potential role in glioblastoma (GBM)

Abstract

Within the Ayurvedic medical tradition of India, Ashwagandha (Withania somnifera) is a well-known herb. A large number of withanolides have been isolated from both its roots and its leaves and many have been assessed for their pharmacological activities. Amongst them, Withaferin A is one of its most bioactive phytoconstituents. Due to the lactonal steroid's potential to modulate multiple oncogenic pathways, Withaferin A has gained much attention as a possible anti-neoplastic agent. This review focuses on the use of Withaferin A alone, or in combination with other treatments, as a newer option for therapy against the most aggressive variant of brain tumors, Glioblastoma. We survey the various studies that delineate Withaferin A's anticancer mechanisms, its toxicity profiles, its pharmacokinetics and pharmacodynamics and its immuno-modulating properties.

http://ift.tt/2erK7Tf

Exosomal miR-221 targets DNM3 to induce tumor progression and temozolomide resistance in glioma

Abstract

MicroRNA is an important regulator of glioblastoma. This study aims at validating microRNA-221 (miR-221) as a biomarker for glioblastoma, and understanding how miR-221 regulates glioblastoma progression. Using clinical samples, miR-221 expression was analyzed by quantitative reverse-transcriptase PCR (qPCR). SHG-44 cells were treated with anti-miR-221 or U87MG-derived exosomes followed by monitoring changes in cell viability, migration and temozolomide (TMZ) resistance. Bioinformatics approach was used to identify targets of miR-221. The interaction between miR-221 and its target, DNM3 gene, was studied with dual-luciferase reporter assay, Spearman's correlation analysis, and western blotting. To verify that RELA regulates miR-221 expression, RELA-expressing vector or shRNA was introduced into SHG-44 cells and its effect on miR-221 expression was monitored. Both tissue-level and exosomal miR-221 expression increased with glioma grades. In SHG-44 cells, downregulating miR-221 expression inhibited cell proliferation, migration, and TMZ resistance, whereas incubation with U87MG-derived exosomes exerted tumor-promoting effects. DNM3 gene is a target of miR-221. RELA induced miR-221 expression. In glioma, elevated miR-221 expression is a biomarker for glioma. DNM3 is a target of miR-221 and RELA regulates miR-221 expression. The RELA/miR-221 axis is a target for glioma diagnosis and therapy.

http://ift.tt/2f394Rc

Intra-rater variability in low-grade glioma segmentation

Abstract

Assessment of size and growth are key radiological factors in low-grade gliomas (LGGs), both for prognostication and treatment evaluation, but the reliability of LGG-segmentation is scarcely studied. With a diffuse and invasive growth pattern, usually without contrast enhancement, these tumors can be difficult to delineate. The aim of this study was to investigate the intra-observer variability in LGG-segmentation for a radiologist without prior segmentation experience. Pre-operative 3D FLAIR images of 23 LGGs were segmented three times in the software 3D Slicer. Tumor volumes were calculated, together with the absolute and relative difference between the segmentations. To quantify the intra-rater variability, we used the Jaccard coefficient comparing both two (J2) and three (J3) segmentations as well as the Hausdorff Distance (HD). The variability measured with J2 improved significantly between the two last segmentations compared to the two first, going from 0.87 to 0.90 (p = 0.04). Between the last two segmentations, larger tumors showed a tendency towards smaller relative volume difference (p = 0.07), while tumors with well-defined borders had significantly less variability measured with both J2 (p = 0.04) and HD (p < 0.01). We found no significant relationship between variability and histological sub-types or Apparent Diffusion Coefficients (ADC). We found that the intra-rater variability can be considerable in serial LGG-segmentation, but the variability seems to decrease with experience and higher grade of border conspicuity. Our findings highlight that some criteria defining tumor borders and progression in 3D volumetric segmentation is needed, if moving from 2D to 3D assessment of size and growth of LGGs.

http://ift.tt/2erHII2

Withaferin A and its potential role in glioblastoma (GBM)

Abstract

Within the Ayurvedic medical tradition of India, Ashwagandha (Withania somnifera) is a well-known herb. A large number of withanolides have been isolated from both its roots and its leaves and many have been assessed for their pharmacological activities. Amongst them, Withaferin A is one of its most bioactive phytoconstituents. Due to the lactonal steroid's potential to modulate multiple oncogenic pathways, Withaferin A has gained much attention as a possible anti-neoplastic agent. This review focuses on the use of Withaferin A alone, or in combination with other treatments, as a newer option for therapy against the most aggressive variant of brain tumors, Glioblastoma. We survey the various studies that delineate Withaferin A's anticancer mechanisms, its toxicity profiles, its pharmacokinetics and pharmacodynamics and its immuno-modulating properties.

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via IFTTT

Exosomal miR-221 targets DNM3 to induce tumor progression and temozolomide resistance in glioma

Abstract

MicroRNA is an important regulator of glioblastoma. This study aims at validating microRNA-221 (miR-221) as a biomarker for glioblastoma, and understanding how miR-221 regulates glioblastoma progression. Using clinical samples, miR-221 expression was analyzed by quantitative reverse-transcriptase PCR (qPCR). SHG-44 cells were treated with anti-miR-221 or U87MG-derived exosomes followed by monitoring changes in cell viability, migration and temozolomide (TMZ) resistance. Bioinformatics approach was used to identify targets of miR-221. The interaction between miR-221 and its target, DNM3 gene, was studied with dual-luciferase reporter assay, Spearman's correlation analysis, and western blotting. To verify that RELA regulates miR-221 expression, RELA-expressing vector or shRNA was introduced into SHG-44 cells and its effect on miR-221 expression was monitored. Both tissue-level and exosomal miR-221 expression increased with glioma grades. In SHG-44 cells, downregulating miR-221 expression inhibited cell proliferation, migration, and TMZ resistance, whereas incubation with U87MG-derived exosomes exerted tumor-promoting effects. DNM3 gene is a target of miR-221. RELA induced miR-221 expression. In glioma, elevated miR-221 expression is a biomarker for glioma. DNM3 is a target of miR-221 and RELA regulates miR-221 expression. The RELA/miR-221 axis is a target for glioma diagnosis and therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2f394Rc
via IFTTT

Intra-rater variability in low-grade glioma segmentation

Abstract

Assessment of size and growth are key radiological factors in low-grade gliomas (LGGs), both for prognostication and treatment evaluation, but the reliability of LGG-segmentation is scarcely studied. With a diffuse and invasive growth pattern, usually without contrast enhancement, these tumors can be difficult to delineate. The aim of this study was to investigate the intra-observer variability in LGG-segmentation for a radiologist without prior segmentation experience. Pre-operative 3D FLAIR images of 23 LGGs were segmented three times in the software 3D Slicer. Tumor volumes were calculated, together with the absolute and relative difference between the segmentations. To quantify the intra-rater variability, we used the Jaccard coefficient comparing both two (J2) and three (J3) segmentations as well as the Hausdorff Distance (HD). The variability measured with J2 improved significantly between the two last segmentations compared to the two first, going from 0.87 to 0.90 (p = 0.04). Between the last two segmentations, larger tumors showed a tendency towards smaller relative volume difference (p = 0.07), while tumors with well-defined borders had significantly less variability measured with both J2 (p = 0.04) and HD (p < 0.01). We found no significant relationship between variability and histological sub-types or Apparent Diffusion Coefficients (ADC). We found that the intra-rater variability can be considerable in serial LGG-segmentation, but the variability seems to decrease with experience and higher grade of border conspicuity. Our findings highlight that some criteria defining tumor borders and progression in 3D volumetric segmentation is needed, if moving from 2D to 3D assessment of size and growth of LGGs.

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via IFTTT

Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series

Abstract

Background

The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.

Methods

We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.

Results

Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.

Conclusions

Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach.

from Cancer via ola Kala on Inoreader http://ift.tt/2fmdtSc
via IFTTT

Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series

Abstract

Background

The efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.

Methods

We present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.

Results

Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.

Conclusions

Retreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach.

http://ift.tt/2fmdtSc

Adenocarcinoma mimicking appendicular lump: a diagnostic dilemma—a case report

Abstract

Background

Primary appendiceal adenocarcinoma is a rare tumor, mucinous variety being common. This case is reported to highlight the unusual presentation and diagnostic difficulty of appendiceal adenocarcinoma.

Case presentation

Patient presented with acute appendicitis with ill-defined tender lump which responded to conservative management.

Conclusions

High index of suspicion should be kept in mind for elderly patients presenting with appendicular lump. Every effort should be made during elective appendectomy to remove stump in case of sloughed out appendix.

http://ift.tt/2f32iuL

Adenocarcinoma mimicking appendicular lump: a diagnostic dilemma—a case report

Abstract

Background

Primary appendiceal adenocarcinoma is a rare tumor, mucinous variety being common. This case is reported to highlight the unusual presentation and diagnostic difficulty of appendiceal adenocarcinoma.

Case presentation

Patient presented with acute appendicitis with ill-defined tender lump which responded to conservative management.

Conclusions

High index of suspicion should be kept in mind for elderly patients presenting with appendicular lump. Every effort should be made during elective appendectomy to remove stump in case of sloughed out appendix.

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There is no point in cervical cancer screening below 25 years of age

Publication date: Available online 11 November 2016
Source:Cancer Epidemiology
Author(s): Wiebren A.A. Tjalma




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There is no point in cervical cancer screening below 25 years of age

Publication date: Available online 11 November 2016
Source:Cancer Epidemiology
Author(s): Wiebren A.A. Tjalma




http://ift.tt/2fZE7C5

Table of Content Volume 56, Number 1, January 2017

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Table of Content Volume 56, Number 1, January 2017

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