Intensity-Modulated Radiation Therapy Improves the Target Coverage Over 3-D Planning While Meeting Lung Tolerance Doses for All Patients With Malignant Pleural Mesothelioma

Purpose:

To investigate high conformality on target coverage and the ability on creating strict lung dose limitation of intensity-modulated radiation therapy in malignant pleural mesothelioma.

Patients and Methods:

Twenty-four radiation therapy plannings were evaluated and compared with dosimetric outcomes of conformal radiation therapy and intensity-modulated radiation therapy. Hemithoracal radiation therapy was performed on 12 patients with a fraction of 1.8 Gy to a total dose of 50.4 Gy. All organs at risk were contoured. Radiotherapy plannings were differed according to the technique; conformal radiation therapy was planned with conventionally combined photon–electron fields, and intensity-modulated radiation therapy was planned with 7 to 9 radiation beam angles optimized in inverse planning. Strict dose–volume constraints were applied.

Results:

Intensity-modulated radiation therapy was statistically superior in target coverage and dose homogeneity (intensity-modulated radiation therapy-planning target volume 95 mean 100%; 3-dimensional conformal radiation therapy-planning target volume 95 mean 71.29%, P = .0001; intensity-modulated radiation therapy-planning target volume 105 mean 11.14%; 3-dimensional conformal radiation therapy-planning target volume 105 mean 35.69%, P = .001). The dosimetric results of the remaining lung was below the limitations on intensity-modulated radiation therapy planning data (intensity-modulated radiation therapy-lung mean dose mean 7.5 [range: 5.6%-8.5%]; intensity-modulated radiation therapy-lung V5 mean 55.55% [range: 47%-59.9%]; intensity-modulated radiation therapy-lung V20 mean 4.5% [range: 0.5%-9.5%]; intensity-modulated radiation therapy-lung V13 mean 13.43% [range: 4.2%-22.9%]).

Conclusion:

With a complex and large target volume of malignant pleural mesothelioma, intensity-modulated radiation therapy has the ability to deliver efficient tumoricidal radiation dose within the safe dose limits of the remaining lung tissue.

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Alveolar echinococcosis of the right adrenal gland: a case report and review of the literature

Extrahepatic manifestations of Echinococcus multilocularis are very rare, especially in the adrenal glands. To the best of our knowledge, only seven cases of adrenal alveolar echinococcosis have been reported, al...

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Hysteroscopic management of a heterotopic pregnancy following uterine artery embolization: a case report

Intra-uterine pregnancy coexisting with cervical pregnancy (heterotopic pregnancy) is a rare condition and its management is challenging because of the massive bleeding associated with cervical pregnancy. Uter...

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Purtscher’s retinopathy and renal cortical necrosis: two rare vaso-occlusive complications in a patient with acute pancreatitis: a case report

Purtscher's retinopathy and renal cortical necrosis are two rare vaso-occlusive complications of acute pancreatitis. Purtscher's retinopathy causes sudden impairment of vision, which was first reported in a pa...

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Nanomedicine in Management of Hepatocellular Carcinoma: Challenges and Opportunities

Abstract

Hepatocellular carcinoma is the second leading cause of cancer deaths worldwide. It is characterized by unique features that can be utilized for selective and targeted therapy, which aids in preserving healthy tissues from deteriorating effects of traditional chemotherapeutics. In this minireview, a brief overview of recent drug delivery attempts for the management of hepatocellular carcinoma with the aid of nanomedical structures is presented. The beneficial impact of nanomaterials in terms of prolonged retention in blood and target sites, controlled biodistribution and improved stability of the encapsulated payloads, will be described, together with the possibility of incorporating more than one cargo into the same nanostructure. Incorporation of stimuli-responsive components, decoration with targeting moieties, and the use of molecularly-targeted drugs for treatment of hepatocellular carcinoma are also highlighted. This article is protected by copyright. All rights reserved.

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Periodontal disease and risk of non-Hodgkin lymphoma in the Health Professionals Follow-up Study

Abstract

Periodontal disease is a chronic inflammatory condition that has been associated with chronic diseases, including cancer. In an earlier prospective cohort analysis within the Health Professionals Follow-Up Study (HPFS), we observed a 31% higher risk of non-Hodgkin lymphoma (NHL) among participants with severe periodontal disease at baseline. Here, we extend the study with an additional 8 years of follow-up, and conduct analyses with updated periodontal disease status and NHL subtypes. The HPFS is an ongoing prospective cohort study of 51,529 men in the U.S. Between baseline in 1986 and 2012, 875 cases of NHL were diagnosed, including 290 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 85 diffuse large B-cell lymphomas, and 91 follicular lymphomas. We performed multivariable Cox proportional hazards regression to evaluate associations of interest. History of periodontal disease at baseline was positively associated with risk of NHL overall (hazard ratio (HR) = 1.26, 95% confidence interval (CI): 1.06-1.49) and CLL/SLL (HR = 1.41, 95% CI: 1.04-1.90). With updated periodontal status, HRs were 1.30, (95% CI: 1.11-1.51) for NHL overall and 1.41 (95% CI: 1.08-1.84) for CLL/SLL. In contrast, after adjusting for periodontal disease, tooth loss was inversely associated with NHL, suggesting that other causes or consequences of tooth loss may have different implications for NHL etiology. Our findings suggest that periodontal disease is a risk factor for NHL. Whether periodontal disease is a direct or indirect cause of NHL, or is a marker of underlying systemic inflammation and/or immune dysregulation, warrants further investigation. This article is protected by copyright. All rights reserved.

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Dietary trace element intake and liver cancer risk: results from two population-based cohorts in China

Abstract

Dietary factors have been hypothesized to affect the risk of liver cancer via various mechanisms, but the influence has been not well studied and the evidence is conflicting. We investigated associations of dietary trace element intake, assessed through a validated food frequency questionnaire, with risk of liver cancer in 2 prospective cohort studies of 132,765 women (1997-2013) and men (2002-2013) in Shanghai, China. The associations were first evaluated in cohort studies and further assessed in a case-control study nested within these cohorts adjusting for hepatitis B virus infection. For cohort analyses, Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals. For nested case-control analyses, conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. After a median follow-up time of 15.2 years for the Shanghai Women's Health Study and 9.3 years for the Shanghai Men's Health Study, 192 women and 344 men developed liver cancer. Dietary intake of manganese was inversely associated with liver cancer risk (highest vs. lowest quintile, HR = 0.51, 95% CI: 0.35-0.73; p _trend = 0.001). Further adjustment for hepatitis B virus infection in the nested case-control study yielded a similar result (highest vs. lowest quintile, OR = 0.38, 95% CI: 0.21-0.69; p _trend < 0.001). No significant association was found between dietary intake of selenium, iron, zinc, copper and liver cancer risk. The results suggest that higher intake of manganese may be associated with a lower risk of liver cancer in China. This article is protected by copyright. All rights reserved.

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Impact of sustained viral response post curative therapy of hepatitis C-related hepatocellular carcinoma: A systematic review and meta-analysis

Abstract

Antiviral therapy with interferon based therapies (IBT) has shown potential in improving survival in patients who have undergone resection or locoregional therapy for hepatitis C-associated hepatocellular carcinoma (HCV-HCC). However, this benefit has not been definitively ascribed to sustained viral response (SVR). Since IBT has been replaced with new directly acting agents (DAA) which are more efficacious in the treatment of HCV, we sought to better determine the prognostic impact of SVR in HCV-HCC. A systematic search of MEDLINE and Embase from inception through October 2015 was performed to identify studies that described the impact of presence of SVR in patients who underwent curative treatment of HCV-HCC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated for recurrence-free survival (RFS) and Overall Survival (OS) utilizing a random-effects model. After reviewing 858 abstracts, ten studies which included a total of 1794 patients were selected and data was extracted. Of these ten studies, the impact of SVR on RFS and OS was reported in eight and seven studies respectively. In a meta-analysis which included 1519 patients, SVR was associated with improved OS (HR 0.18; 95% CI 0.11- 0.29, I²= 2%). We also found that SVR was associated with better RFS in a meta-analysis (1241 patients; HR 0.50; 95% CI 0.40-0.63, I²= 0). In conclusion, SVR is associated with improved OS and RFS in patients with HCV who have undergone resection or locoregional therapy for HCC. Newer DAA therapies which offer increased tolerability and viral eradication should be considered as adjunctive therapy. This article is protected by copyright. All rights reserved.

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Cardiac glycosides and breast cancer risk: A systematic review and meta-analysis of observational studies

Abstract

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, 9 studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR=1.34; 95% CI 1.25, 1.44; p<0.001) with little variation in the association between studies (I²=16%, p for heterogeneity =0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables. This article is protected by copyright. All rights reserved.

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Overexpression of UNC5B in bladder cancer cells inhibits proliferation and reduces the volume of transplantation tumors in nude mice

Abstract

Background

The netrin-1 receptor UNC5B plays vital roles in angiogenesis, inflammation, embryonic development and carcinogenesis. However, the functional significance of UNC5B overexpression in bladder cancer remains unclear. In this study, we investigated the role of UNC5B in bladder cancer in vitro and in vivo.

Methods

Stable transfection of the human bladder cancer cell line 5637 with UNC5B (5637-U) was confirmed by real-time RT-PCR, western blot and immunofluorescence assays. UNC5B expression in 5637 and 5637-U cells and mice tumor specimens derived from these cell lines was analyzed by immunohistochemistryand western blotting. Changes in the levels of cell cycle proteins were evaluated by western blotting. Flow cytometry, CCK-8 and scratch tests were used to examine cell cycle distribution, proliferation and migration, respectively.

Results

UNC5B overexpression in 5637 cells inhibited cell multiplication and migration and induced cell cycle arrest at the G2/M phase, meanwhile exhibited changes in the expression of cell cycle-associated proteins, showing that UNC5B may inhibit metastatic behaviors in bladder cancer cells. In addition, tumors generated from 5637-U cells were smaller than tumors generated from control 5637 cells.

Conclusions

Our findings suggest that UNC5B is a potential anti-neoplastic target in bladder cancer progression.

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Adolescent and Young Adult Cancer Survivors' Perspectives on Their Internet Use for Seeking Information on Healthy Eating and Exercise

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


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On-Site Fertility Preservation Services for Adolescents and Young Adults in a Comprehensive Cancer Center

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


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A rare case with synchronous gastric gastrointestinal stromal tumor, pancreatic neuroendocrine tumor, and uterine leiomyoma

Abstract

Background

Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, they comprise less than 1% of all gastrointestinal tumors. Neuroendocrine tumors (NET) of the gastro-enteropancreatic system are also rare, representing about 2% of all gastrointestinal neoplasms. Pancreatic localization of NET is extremely uncommon—these tumors are only 1–5% of all pancreatic cancers.

Case presentation

We describe an unusual case with triple tumor localization—a gastric tumor, a formation in the pancreas, which involves the retroperitoneal space, and a uterine leiomyoma. The exact diagnosis was confirmed with immunohistochemical study after surgical treatment of the patient. Distal pancreatic resection, splenectomy, partial gastrectomy, omentectomy, and hysterectomy were performed. The histological examination proved an epithelioid type of gastric GIST. Immunostaining showed focal positive expression of c-kit and no mitotic figures per 50 HPF. Histology of the pancreatic and retroperitoneal formation proved a well-differentiated NET with origin from the islets of Langerhans. The immunohistochemical study demonstrated co-expression of chromogranin A and synaptophysin.

Conclusions

This is the fourth case published so far of a patient with synchronous pancreatic NET and gastric GIST. The main objective of the study is to present a unique case because we have not found any reports for coexistence of the described three types of neoplasm, as in our patient, and we hope that it will be valuable in the future investigations about the genesis, diagnosis, and treatment of these types of tumors.

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\Communication about Melanoma and Risk Reduction after Melanoma Diagnosis

Abstract

Objective

Melanoma patients are advised to perform regular risk reduction practices including sun protection as well as skin self-examinations (SSE) and physician-led examinations. Melanoma-specific communication regarding family risk and screening may promote such behaviors. To this end, associations between patients' melanoma-specific communication and risk reduction were examined.

Methods

Melanoma patients (N = 169) drawn from a population-based cancer registry reported their current risk reduction practices, perceived risk of future melanoma, and communication with physicians and relatives about melanoma risk and screening.

Results

Patients were, on average, 56 years-old and 6.7 years' post-diagnosis; 51% were male, 93% reported "fair/very fair" skin color, 75% completed at least some college, and 22% reported a family history of melanoma. Patients reported varying levels of regular (always/nearly always) sun protection: sunscreen use (79%), shade-seeking (60%), hat use (54%), and long-sleeve shirts use (30%). Only 28% performed thorough SSE regularly, whereas 92% reported undergoing physician-led skin examinations within the past year. Participants who were female, younger, and had a higher perceived risk of future melanoma were more likely to report past communication. In adjusted analyses, communication remained uniquely associated with increased sunscreen use and SSE.

Conclusions: Encouraging melanoma patients to have a more active role in discussions concerning melanoma risk and screening with relatives and physicians alike may be a useful strategy to promote two key risk-reduction practices post melanoma diagnosis and treatment. Future research is needed to identify additional strategies to improve comprehensive risk reduction in long-term melanoma patients.

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Multidetector computer tomography in the pancreatic adenocarcinoma assessment: an update

Abstract

Ductal adenocarcinoma of the pancreas is one of the most aggressive forms of cancer, with only a minority of cases being resectable at the moment of their diagnosis. The accurate detection and characterization of pancreatic carcinoma is very important for patient management. Multidetector-row computed tomography (MDCT) has become the cross-sectional modality of choice in the diagnosis, staging, treatment planning, and follow-up of patients with pancreatic tumors. However, approximately 11% of ductal adenocarcinomas still remain undetected at MDCT because of the lack of attenuation gradient between the lesion and the adjacent pancreatic parenchyma. In this systematic literature review we investigate the current evolution of the CT technique, limitations, and perspectives in the evaluation of pancreatic carcinoma.

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Intrafractional dose variation and beam configuration in carbon ion radiotherapy for esophageal cancer

In carbon ion radiotherapy (CIR) for esophageal cancer, organ and target motion is a major challenge for treatment planning due to potential range deviations. This study intends to analyze the impact of intraf...

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Pro- and anti-inflammatory cytokine associations with major depression in cancer patients

Abstract

Objective

Cytokines may be linked to depression, although it has been challenging to demonstrate this association in cancer because of the overlap between depressive symptoms and other sickness behaviours. This study investigates the relationship between cytokines and depression in cancer patients, accounting for confounding clinical and methodological factors.

Methods

The GRID Hamilton Rating Scale for Depression (Ham-D) and Neurotoxicity Rating Scale (NRS) for cytokine-induced sickness behaviours were administered to 61 cancer patients, and 38 healthy controls. The cancer group were of mixed type and largely late stage, with a recruitment rate of 35% and completion rate of 47%. Major depression was diagnosed in 19/61 (31%) of cancer patients. Multiplexed cytokine assays for inflammatory and anti-inflammatory cytokines were conducted in plasma samples using electrochemiluminescence.

Results

All cancer patients had high NRS scores and elevated levels of most cytokines. Cancer patients with major depression had higher NRS scores than those without major depression. IL-1r was positively associated with Ham-D scores of depressive symptoms (regression coefficient: 3.52 ± 1.18, p = 0.004), but not major depression. Major depression was negatively associated with the anti-inflammatory cytokine IL-4 (regression coefficient: - 0.65 ± 0.26, p = 0.013), but not IL-1r.

Conclusions

Depressive symptoms in cancer patients may represent sickness behaviours, which may have distinct cytokine associations from major depression. Sickness behaviours may be associated with an increase in inflammatory cytokines, whereas major depression may be induced by a failure to adequately resolve inflammation. Our findings suggest that cytokine-mediated interventions may be of value to treat depression in this population.

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Sexual distress and associated factors among cervical cancer survivors: A cross-sectional multicenter observational study

Abstract

Objectives

To assess whether sexual distress among cervical cancer (CC) survivors is associated with frequently reported vaginal sexual symptoms, other proposed biopsychosocial factors, and whether worries about painful intercourse mediates the relation between vaginal sexual symptoms and sexual distress.

Methods

A cross-sectional study was conducted among 194 sexually active partnered CC survivors aged 25-69 years. Sexual distress, vaginal sexual symptoms, sexual pain worry, anxiety, depression, body image concerns, and relationship dissatisfaction, and the socio-demographic variables age, time since treatment, and relationship duration, were assessed using validated self-administrated questionnaires.

Results

In total, 33% (n = 64) of the survivors scored above the cut-off score for sexual distress. Higher levels of sexual distress were shown to be associated with higher levels of vaginal sexual symptoms, sexual pain worry, relationship dissatisfaction, and body image concerns. Furthermore, the results showed that sexual pain worry partly mediated the association between vaginal sexual symptoms and sexual distress, when controlling for relationship dissatisfaction and body image concerns.

Conclusions

Appropriate rehabilitation programs should be developed for CC survivors, to prevent and reduce not only vaginal sexual symptoms, but also sexual pain worry, relationship dissatisfaction and body image concerns, in order to reduce sexual distress.

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Psychosocial Effects of a Skin Camouflage Program in the Female Survivors with Head and Neck Cancer: A Randomized Controlled Trial

Abstract

Objective

The purpose of this study was to evaluate the effects of a skin camouflage program on disfigurement, self-esteem, social interaction, and body image in female head and neck cancer (HNC) survivors.

Methods

A prospective, repeated measures, randomized controlled therapeutic intervention design was employed. A total 66 participants were randomly assigned to each group, with 32 in the experimental group and 34 in the control group. The experimental group received a four-session skin camouflage program, and the control group received routine care. Patients were assessed at three time points: baseline assessment (T0), and then at 1, 2, and 3-months (T1, T2, and T3) after participating in the skin camouflage program.

Results

Patients in the experimental group had significantly less facial disfigurement, depression, fear of social interaction, and anxiety regarding social interaction compared to those in the control group. Participants in both groups had significantly lower levels of facial disfigurement, depression, fear of social interaction, anxiety of social interaction, and body image at the final post-test assessment than at the pretest assessment. There were no differences between the groups and within groups with respect to self-esteem.

Conclusions

The 3-month skin camouflage program effectively improved facial disfigurement, fear of social interaction, anxiety of social interaction, and body image of female HNC survivors. A survival care plan should include a skin camouflage program to improve body image perception and decrease anxiety after treatment of HNC.

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UK guidelines for the management of soft tissue sarcomas

Abstract

Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues, and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location means that developing evidence-based guidelines is complicated by the limitations of the data available. However, this makes it more important that STS are managed by teams, expert in such cases, to ensure consistent and optimal treatment, as well as recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous version published in 2010 (Grimer et al. in Sarcoma 2010:506182, 2010). The original guidelines were drawn up following a consensus meeting of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This current version has been updated and amended with reference to other European and US guidance. There are specific recommendations for the management of selected subtypes of disease including retroperitoneal and uterine sarcomas, as well as aggressive fibromatosis (desmoid tumours) and other borderline tumours commonly managed by sarcoma services. An important aim in sarcoma management is early diagnosis and prompt referral. In the UK, any patient with a suspected soft tissue sarcoma should be referred to one of the specialist regional soft tissues sarcoma services, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging, plus a biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon. In tumours at higher risk of recurrence or metastasis pre- or post-operative radiotherapy should be considered. Systemic anti-cancer therapy (SACT) may be utilized in some cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late-effects of treatment. For local recurrence, and more rarely in selected cases of metastatic disease, surgical resection would be considered. Treatment for metastases may include radiotherapy, or systemic therapy guided by the sarcoma subtype. In some cases, symptom control and palliative care support alone will be appropriate.

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Correlates and trends of IMRT use in locally advanced rectal cancer

Abstract

Objectives

Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) are both utilized in rectal cancer treatment. We investigated the impact of demographic and clinical factors for the selection of each modality utilizing the National Cancer Database.

Methods

Adult patients with stage II and stage III adenocarcinoma of the rectum diagnosed from 2004 to 2013 were included. Chi-squared analysis was used to compare demographic and clinical variables in the 3DCRT and IMRT treatment groups. Univariate and multivariate logistic regression modeling was used to identify factors predictive of receipt of each radiation therapy (RT) modality.

Results

A total of 9027 patients were identified: 8141 in the neoadjuvant RT group and 886 in the adjuvant RT group. In both cohorts, the utilization of IMRT increased over the study period (p < 0.01). Factors predictive of receiving IMRT on multivariate analysis include non-white race (OR 1.28, 95 % CI 1.12–1.48 for neoadjuvant RT, OR 1.72, 95 % CI 1.08–2.72 for adjuvant RT) and West, Northeast, and South geographic regions. Other factors predictive of receiving IMRT in the neoadjuvant setting include treatment at an academic institution (OR 1.15, 95 % CI 1.03–1.28) and radiation dose >5400 centigray (cGy) (OR 2.07, 95 % CI 1.69–2.53).

Conclusions

The use of IMRT for locally advanced rectal cancer is increasing and surpassed 3DCRT as the most common radiation modality at the beginning of 2010. Intensity-modulated radiotherapy was given more commonly for adjuvant treatment than for neoadjuvant treatment and was associated with higher RT doses and treatment at an academic institution in the neoadjuvant setting.

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Autophagy is associated with chemoresistance in neuroblastoma

Abstract

Background

Neuroblastoma (NB) is a frequent pediatric tumor characterized by a poor prognosis where a majority of tumors progress despite intensive multimodality treatments. Autophagy, a self-degradative process in cells, could be induced by chemotherapy and be associated with chemoresistance. The aim of this study was to determine whether: 1) autophagy is present in NB, 2) chemotherapy modified its levels, and 3) its inhibition decreased chemoresistance.

Methods

Immunohistochemical stainings were performed on samples from 184 NB patients in order to verify the expression of LC3B, a specific marker for autophagy, and Beclin 1, a positive regulator of autophagy. In addition, we performed an in vitro study with six NB cell lines and six drugs (vincristine, doxorubicin, cisplatin temozolomide, LY294002 and syrolimus). Inhibition of autophagy was performed using ATG5 knockdown cells or hydroxychloroquine (HCQ). Cell survival was measured using the MTT cell proliferation assay. Autophagy was detected by monodansylcadaverine, confocal microscopy and Western blot. In vivo study with tumor xenografts in NSG mice was performed.

Results

Our results have indicated that autophagy was present at low levels in NB and was not a prognostic factor, while Beclin 1 was highly expressed in children with poor NB prognosis. However, autophagy levels increased after chemotherapy in vitro and in vivo. Tumor progression was significantly decreased in mice treated with a combination of HCQ and vincristine.

Conclusions

Taken together, autophagy is present in NB, induced by chemotherapy and associated with chemoresistance, which is significantly reduced by its inhibition. Therefore, targeting autophagy represents a very attractive approach to develop new therapeutic strategies in NB.

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Is alcohol consumption a risk factor for prostate cancer? A systematic review and meta–analysis

Abstract

Background

Research on a possible causal association between alcohol consumption and risk of prostate cancer is inconclusive. Recent studies on associations between alcohol consumption and other health outcomes suggest these are influenced by drinker misclassification errors and other study quality characteristics. The influence of these factors on estimates of the relationship between alcohol consumption and prostate cancer has not been previously investigated.

Methods

PubMed and Web of Science searches were made for case–control and cohort studies of alcohol consumption and prostate cancer morbidity and mortality (ICD–10: C61) up to December 2014. Studies were coded for drinker misclassification errors, quality of alcohol measures, extent of control for confounding and other study characteristics. Mixed models were used to estimate relative risk (RR) of morbidity or mortality from prostate cancer due to alcohol consumption with study level controls for selection bias and confounding.

Results

A total of 340 studies were identified of which 27 satisfied inclusion criteria providing 126 estimates for different alcohol exposures. Adjusted RR estimates indicated a significantly increased risk of prostate cancer among low (RR = 1.08, P < 0.001), medium (RR = 1.07, P < 0.01), high (RR = 1.14, P < 0.001) and higher (RR = 1.18, P < 0.001) volume drinkers compared to abstainers. There was a significant dose–response relationship for current drinkers (P_trend < 0.01). Studies free from misclassification errors produced the highest risk estimates for drinkers versus abstainers in adjusted models (RR = 1.22, P < 0.05).

Conclusion

Our study finds, for the first time, a significant dose–response relationship between level of alcohol intake and risk of prostate cancer starting with low volume consumption (>1.3, <24 g per day). This relationship is stronger in the relatively few studies free of former drinker misclassification error. Given the high prevalence of prostate cancer in the developed world, the public health implications of these findings are significant. Prostate cancer may need to be incorporated into future estimates of the burden of disease alongside other cancers (e.g. breast, oesophagus, colon, liver) and be integrated into public health strategies for reducing alcohol related disease.

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miR-124-3p functions as a tumor suppressor in breast cancer by targeting CBL

Abstract

Background

The origin and development of breast cancer remain complex and obscure. Recently, microRNA (miRNA) has been identified as an important regulator of the initiation and progression of breast cancer, and some studies have shown the essential role of miR-124-3p as a tumor suppressor in breast tumorigenesis. However, the detailed role of miR-124-3p in breast cancer remains poorly understood.

Methods

Quantitative RT-PCR and western blotting assays were used to measure miR-124-3p and CBL expression levels in breast cancer tissues, respectively. Luciferase reporter assay was employed to validate the direct targeting of CBL by miR-124-3p. Cell proliferation and invasion assays were performed to analyze the biological functions of miR-124-3p and CBL in breast cancer cells.

Results

In the present study, we found that miR-124-3p was consistently downregulated in breast cancer tissues. Moreover, we showed that miR-124-3p significantly suppressed the proliferation and invasion of breast cancer cells. In addition, we investigated the molecular mechanism through which miR-124-3p contributes to breast cancer tumorigenesis and identified CBL (Cbl proto-oncogene, E3 ubiquitin protein ligase) as a direct target gene of miR-124-3p. Moreover, we found that ectopic expression of CBL can attenuate the inhibitory effect of miR-124-3p on cell proliferation and invasion in breast cancer cells.

Conclusions

This study identified a new regulatory axis in which miR-124-3p and CBL regulate the proliferation and invasion of breast cancer cells.

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Cancers, Vol. 8, Pages 105: Caregiving and Its Resulting Effects—The Care Study to Evaluate the Effects of Caregiving on Caregivers of Patients with Advanced Cancer in Singapore

Informal caregivers (IC) are key to enabling home deaths, where preferred, at the end-of-life. Significant morbidity from advanced cancer can make caregiving burdensome. However, knowledge about the nature of the caregiving burden for caregivers in Singapore is limited. Hence, the key objective in this study was to examine the impact of the caregiving burden on quality of life (QOL), mental health and work capacity among local ICs. Eligible English-speaking ICs of hospitalized advanced cancer patients were recruited through non-random sampling. The Zarit Burden Interview (ZBI), Caregiver Quality of Life Index—Cancer (CQOLC), Center for Epidemiologic Studies Depression Scale—Revised (CESD-R), and Work Productivity and Activity Impairment Questionnaire (WPAI) were interviewer-administered to eligible ICs. Altogether, 16 ICs were surveyed. The mean age of ICs was 43.8 years. Most were children of patients (43.8%), and eight ICs had high burden (ZBI > 17). Those with ZBI > 17 had lower QOL, higher depression scores as well as greater work and activity impairment. In conclusion, high caregiver burden has adverse effects on QOL, mental health and work productivity. Non-physical elements of caregiving (particularly financial and decision-making) and increased number of care roles undertaken by a single IC contribute to high burden. Future interventions for caregiving burden in Singapore should also address the financial and decision-making aspects of caregiving. Outsourcing selected aspects of the caregiving role to community services may reduce the number of caregiving aspects undertaken by a single IC and caregiver burden.

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Intrafractional dose variation and beam configuration in carbon ion radiotherapy for esophageal cancer

Abstract

Background

In carbon ion radiotherapy (CIR) for esophageal cancer, organ and target motion is a major challenge for treatment planning due to potential range deviations. This study intends to analyze the impact of intrafractional variations on dosimetric parameters and to identify favourable settings for robust treatment plans.

Methods

We contoured esophageal boost volumes in different organ localizations for four patients and calculated CIR-plans with 13 different beam geometries on a free-breathing CT. Forward calculation of these plans was performed on 4D-CT datasets representing seven different phases of the breathing cycle. Plan quality was assessed for each patient and beam configuration.

Results

Target volume coverage was adequate for all settings in the baseline CIR-plans (V₉₅ > 98% for two-beam geometries, > 94% for one-beam geometries), but reduced on 4D-CT plans (V₉₅ range 50–95%). Sparing of the organs at risk (OAR) was adequate, but range deviations during the breathing cycle partly caused critical, maximum doses to spinal cord up to 3.5x higher than expected. There was at least one beam configuration for each patient with appropriate plan quality.

Conclusions

Despite intrafractional motion, CIR for esophageal cancer is possible with robust treatment plans when an individually optimized beam setup is selected depending on tumor size and localization.

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Active Surveillance for Favourable-Risk Prostate Cancer: Is there a Greater Psychological Impact than Previously Thought? A Systematic, Mixed Studies Literature Review.

Abstract

Objective

Active Surveillance (AS) allows men with favourable-risk prostate cancer (PCa) to avoid or postpone active treatment and hence spares potential adverse side effects for a significant proportion of these patients. Active surveillance may create an additional emotional burden for these patients.

The aim of the review was to determine the psychological impact of AS to inform future study in this area and to provide recommendations for clinical practice.

Methods

Studies were identified through database searching from inception to September 2015. Quantitative or qualitative non-interventional studies published in English that assessed the psychological impact of AS were included. The Mixed Methods Appraisal Tool was used to assess methodological quality.

Results

Twenty-three papers were included (20 quantitative, 3 qualitative). Quantitatively, the majority of patients do not report psychological difficulties, however when appropriateness of study design is considered, the conclusion that AS has minimal impact on wellbeing, may not be accurate. This is due to small sample sizes, inappropriately timed baseline, and inappropriate/lack of comparison groups. In addition, a mismatch in outcome was noted between the outcome of quantitative and qualitative studies in uncertainty, with qualitative studies indicating a greater psychological impact.

Conclusions

Due to methodological concerns, many quantitative studies may not provide a true account of the burden of AS. Further mixed-methods studies are necessary to address the limitations highlighted and to provide clarity on the impact of AS. Practitioners should be aware that despite findings of previous reviews, patients may require additional emotional support.

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The perceived influence of childhood cancer on the parents’ relationship

Abstract

Objective

When a child is diagnosed with cancer, parents are faced with many practical and emotional challenges that can significantly affect their relationship. This study explores how having a child with cancer affects the quality of the parents' relationship; categorizes time points and events during the child's treatment when the relationship becomes most stressed and/or strengthened; identifies factors that help couples remain emotionally engaged throughout their child's cancer treatment; and assesses parental interest in a counseling intervention.

Methods

This is a cross sectional, multi-center study conducted via a semi-structured self-administered questionnaire that included The Revised Dyadic Adjustment Scale.

Results

192 parents of children diagnosed between the ages of 1-21 participated. Forty percent felt their relationship moved in a negative direction. Diagnosis and relapse of disease were cited as the most individually stressful time points in the disease trajectory, with hospitalizations and relapse being most stressful on the relationship. Participants felt most emotionally connected at diagnosis, and least emotionally connected at the start and end of treatment. The majority of couples indicated interest in counseling to address ways to support their relationship. Soon after diagnosis and during treatment was reported as the preferred time to offer these interventions.

Conclusion

This study identified specific events and parent behaviors that strain the couples' relationship during the childhood cancer trajectory. This information can inform the development of a couple's intervention. Prospective research is needed to better understand how childhood cancer affects caregivers' partnerships through survivorship and beyond.

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Survival prediction of anxious emotion in advanced cancer patients receiving palliative care

Abstract

Objective

This study was to investigate the prognostic value of baseline and dynamic changes in anxious emotion in advanced cancer patients undergoing palliative care.

Methods

The association between anxious emotion and survival was investigated in a retrospective sample of 377 consecutive advanced cancer patients receiving palliative care from August 2013 to October 2015 and in an extended follow-up study of 106 of those patients.

Results

The prevalence of anxious emotion was 24.93% (94/377) overall, 22.48% (47/209) in males and 27.97% (47/168) in females. Significant associations between baseline anxious emotion and overall survival (OS) were not found in the whole sample or in females. However, univariate and multivariate analyses showed that anxious emotion was an independent prognostic indicator of OS in males (HR:1.811, P = 0.003). Moreover, findings showed that newly developed anxious emotion was significantly associated with poor OS in all readmitted patients (HR:5.568, P < 0.001), in males (HR:5.104, P = 0.006) and females (HR:5.820, P = 0.004).

Conclusions

Our study suggests that anxious emotion, especially dynamic changes in anxious emotion, needs to be monitored in advanced cancer patients, whether targeted interventions would prolong survival requires further studies. This article is protected by copyright. All rights reserved.

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Patient experiences of acute myeloid leukemia (AML): A qualitative study about diagnosis, illness understanding, and treatment decision-making

Abstract

Purpose

Patients with acute myeloid leukemia (AML) face a unique, difficult situation characterized by sudden changes in health, complex information, and pressure to make quick treatment decisions amid sizeable tradeoffs. Yet, little is known about patients' experiences with AML. We used qualitative methods to learn about their experiences with diagnosis and treatment decision-making, to identify areas for improvement.

Methods

We recruited hospitalized patients with AML to participate in semi-structured qualitative interviews about their experiences being diagnosed with AML, receiving information, and making a treatment decision. Interviews were conducted during their hospitalization for induction chemotherapy. We analyzed data using a constant comparison approach.

Results

Thirty-two patients completed an interview. Four main themes emerged: (1) shock and suddenness, (2) difficulty processing information, (3) poor communication, and (4) uncertainty. Patients frequently described their diagnosis as shocking. They also felt the amount of information was too great and too difficult to process, which negatively impacted their understanding. Patients frequently described a lack of emotional support from clinicians and described uncertainty about their prognosis, the number and nature of available treatments, and what to expect from treatment.

Conclusions

AML poses a sudden, emotionally challenging, information-laden situation, where little time is available to make important decisions. This results in difficulty processing information and is sometimes complicated by a lack of emotive communication from clinicians. Results indicate a need for targeted interventions to improve AML patients' understanding of illness and treatment options, and to address their traumatic experiences around diagnosis. This article is protected by copyright. All rights reserved.

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UNRelenting Translation UNRestrains Melanoma Migration

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Ashani T. Weeraratna, Myriam Gorospe
The cytoplasmic RNA-binding protein UNR influences key developmental processes by controlling mRNA turnover and translation initiation. In this issue of Cancer Cell, Wurth et al. report that UNR is highly expressed in melanoma and enhances invasion and metastasis at least partly by inducing translation elongation of VIM and RAC1 mRNAs.

Teaser

The cytoplasmic RNA-binding protein UNR influences key developmental processes by controlling mRNA turnover and translation initiation. In this issue of Cancer Cell, Wurth et al. report that UNR is highly expressed in melanoma and enhances invasion and metastasis at least partly by inducing translation elongation of VIM and RAC1 mRNAs.


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One Step Forward in the Challenging Arena of MLL-AF4 Leukemia

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Nancy J. Zeleznik-Le
MLL-AF4 leukemia is the predominant infant acute leukemia and has a poor prognosis. No current experimental models accurately reflect the human disease. Lin et al., in this issue of Cancer Cell, describe their model that recapitulates multiple key aspects of this aggressive disease, facilitating future mechanistic and preclinical studies.

Teaser

MLL-AF4 leukemia is the predominant infant acute leukemia and has a poor prognosis. No current experimental models accurately reflect the human disease. Lin et al., in this issue of Cancer Cell, describe their model that recapitulates multiple key aspects of this aggressive disease, facilitating future mechanistic and preclinical studies.


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An Unexpected Chink in the Transcriptional Armor of Plasmacytoid Dendritic Neoplasms

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Maria Kleppe, Ross L. Levine
In this issue of Cancer Cell, Ceribelli et al. use functional genomic and chemical screening to reveal the existence of a TCF4/BRD4-dependent oncogenic regulatory network in blastic plasmacytoid dendritic cell neoplasm (BPDCN) and demonstrate that BPDCN cells are highly sensitive to therapeutic targeting of this novel dependency.

Teaser

In this issue of Cancer Cell, Ceribelli et al. use functional genomic and chemical screening to reveal the existence of a TCF4/BRD4-dependent oncogenic regulatory network in blastic plasmacytoid dendritic cell neoplasm (BPDCN) and demonstrate that BPDCN cells are highly sensitive to therapeutic targeting of this novel dependency.


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An Alternative Sugar Fuels AML

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Rob A. Cairns, Tak W. Mak
Although altered glucose metabolism is a well-studied feature of malignant cells, little is known about the direct metabolism of fructose. In this issue of Cancer Cell, Chen et al. report that AML cells consume fructose and use it to maintain viability, especially when glucose is scarce.

Teaser

Although altered glucose metabolism is a well-studied feature of malignant cells, little is known about the direct metabolism of fructose. In this issue of Cancer Cell, Chen et al. report that AML cells consume fructose and use it to maintain viability, especially when glucose is scarce.


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Sticking It to the Niche: CD98 Mediates Critical Adhesive Signals in AML

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Andreas Reinisch, Ravindra Majeti
In this issue of Cancer Cell, Bajaj and colleagues report that CD98, a heterodimeric protein highly expressed in acute myeloid leukemia (AML) and largely dispensable for basal hematopoiesis, plays an important role in facilitating leukemia stem cell adhesion to bone marrow vasculature and is a potential therapeutic target in AML.

Teaser

In this issue of Cancer Cell, Bajaj and colleagues report that CD98, a heterodimeric protein highly expressed in acute myeloid leukemia (AML) and largely dispensable for basal hematopoiesis, plays an important role in facilitating leukemia stem cell adhesion to bone marrow vasculature and is a potential therapeutic target in AML.


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Cholesterol: An Achilles’ Heel for Glioblastoma?

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Zhenyi An, William A. Weiss
In this issue of Cancer Cell, Villa et al. report that survival of glioblastoma cells is dependent on uptake of cholesterol. A synthetic agonist of the Liver X receptor depleted cholesterol in GBM cells, slowing growth of GBM xenografts.

Teaser

In this issue of Cancer Cell, Villa et al. report that survival of glioblastoma cells is dependent on uptake of cholesterol. A synthetic agonist of the Liver X receptor depleted cholesterol in GBM cells, slowing growth of GBM xenografts.


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Unraveling the DNA Methylome in Mantle Cell Lymphoma: New Insights into the Cellular Origin

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Larry Mansouri, Richard Rosenquist
Our understanding of the DNA methylome and its impact on cancer evolution and disease progression is rapidly evolving. In this issue of Cancer Cell, Queirós et al. provide a detailed characterization of the DNA methylome in mantle cell lymphoma and reveal novel molecular subtypes, potentially with different cellular origins.

Teaser

Our understanding of the DNA methylome and its impact on cancer evolution and disease progression is rapidly evolving. In this issue of Cancer Cell, Queirós et al. provide a detailed characterization of the DNA methylome in mantle cell lymphoma and reveal novel molecular subtypes, potentially with different cellular origins.


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Characteristics and Significance of the Pre-metastatic Niche

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Yang Liu, Xuetao Cao
Primary tumors create a favorable microenvironment, namely, pre-metastatic niche, in secondary organs and tissue sites for subsequent metastases. The pre-metastatic niche can be primed and established through a complex interplay among primary tumor-derived factors, tumor-mobilized bone marrow-derived cells, and local stromal components. We review here our current understanding of the key components and underlying mechanisms for pre-metastatic niche formation. We propose six characteristics that define the pre-metastatic niche, which enable tumor cell colonization and promote metastasis, including immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, and reprogramming. We highlight the significance of the pre-metastatic niche, and discuss potential implications and future research directions.

Teaser

Primary tumors create a favorable microenvironment, namely, pre-metastatic niche, in secondary organs and tissue sites for subsequent metastases. The pre-metastatic niche can be primed and established through a complex interplay among primary tumor-derived factors, tumor-mobilized bone marrow-derived cells, and local stromal components. Liu and Cao review the current understanding of key components and the underlying mechanisms for pre-metastatic niche formation. Six characteristics are proposed that define the pre-metastatic niche which enable tumor cell colonization and promote metastasis, including immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, and reprogramming. The significance of the pre-metastatic niche is highlighted, and potential implications and future research directions are discussed.


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ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Hui-Lung Sun, Ri Cui, JianKang Zhou, Kun-yu Teng, Yung-Hsuan Hsiao, Kotaro Nakanishi, Matteo Fassan, Zhenghua Luo, Guqin Shi, Esmerina Tili, Huban Kutay, Francesca Lovat, Caterina Vicentini, Han-Li Huang, Shih-Wei Wang, Taewan Kim, Nicola Zanesi, Young-Jun Jeon, Tae Jin Lee, Jih-Hwa Guh, Mien-Chie Hung, Kalpana Ghoshal, Che-Ming Teng, Yong Peng, Carlo M. Croce
MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.

Teaser

Sun et al. find that ERK phosphorylates XPO5, which induces a Pin1-mediated conformational change that inhibits the ability of XPO5 to load and export pre-miRNA from the nucleus. Phosphorylation of XPO5 is associated with global miRNA downregulation and correlates with poor survival in hepatocellular carcinoma.


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Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Shan Lin, Roger T. Luo, Anetta Ptasinska, Jon Kerry, Salam A. Assi, Mark Wunderlich, Toshihiko Imamura, Joseph J. Kaberlein, Ahmad Rayes, Mark J. Althoff, John Anastasi, Maureen M. O'Brien, Amom Ruhikanta Meetei, Thomas A. Milne, Constanze Bonifer, James C. Mulloy, Michael J. Thirman
The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34⁺ cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. Such incongruity was also observed in t(4;11) patients in whom leukemia evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

Graphical abstract

Teaser

Lin et al. design a human MLL-mouse Af4 (MLL-Af4) fusion that can transform human CD34⁺ cells to generate pro-B acute lymphoblastic leukemia (ALL) with the characteristic features of t(4;11) ALL. MLL-Af4 DNA binding drives differential gene expression distinct from MLL-AF9 and confers cells with a lymphoid preference.


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A Druggable TCF4- and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Michele Ceribelli, Zhiying Esther Hou, Priscilla N. Kelly, Da Wei Huang, George Wright, Karthik Ganapathi, Moses O. Evbuomwan, Stefania Pittaluga, Arthur L. Shaffer, Guido Marcucci, Stephen J. Forman, Wenming Xiao, Rajarshi Guha, Xiaohu Zhang, Marc Ferrer, Laurence Chaperot, Joel Plumas, Elaine S. Jaffe, Craig J. Thomas, Boris Reizis, Louis M. Staudt
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.

Teaser

Ceribelli et al. use a combination of RNAi and small-molecule screening to identify TCF4 as a crucial transcriptional regulator required for maintenance of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and show that bromodomain inhibitors are potential therapeutics for BPDCN, through targeting of TCF4.


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Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Ana C. Queirós, Renée Beekman, Roser Vilarrasa-Blasi, Martí Duran-Ferrer, Guillem Clot, Angelika Merkel, Emanuele Raineri, Nuria Russiñol, Giancarlo Castellano, Sílvia Beà, Alba Navarro, Marta Kulis, Núria Verdaguer-Dot, Pedro Jares, Anna Enjuanes, María José Calasanz, Anke Bergmann, Inga Vater, Itziar Salaverría, Harmen J.G. van de Werken, Wyndham H. Wilson, Avik Datta, Paul Flicek, Romina Royo, Joost Martens, Eva Giné, Armando Lopez-Guillermo, Hendrik G. Stunnenberg, Wolfram Klapper, Christiane Pott, Simon Heath, Ivo G. Gut, Reiner Siebert, Elías Campo, José I. Martín-Subero
We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.

Graphical abstract

Teaser

As part of the IHEC consortium, Queirós et al. perform an epigenomic analysis of mantle cell lymphoma, which reveals two major subtypes with distinct clinicobiological features and identifies distant enhancers as potential epigenetic drivers. Explore the Cell Press IHEC web portal http://ift.tt/2gczkgR.


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Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Min Lu, Hilde Breyssens, Victoria Salter, Shan Zhong, Ying Hu, Caroline Baer, Indrika Ratnayaka, Alex Sullivan, Nicholas R. Brown, Jane Endicott, Stefan Knapp, Benedikt M. Kessler, Mark R. Middleton, Christian Siebold, E. Yvonne Jones, Elena V. Sviderskaya, Jonathan Cebon, Thomas John, Otavia L. Caballero, Colin R. Goding, Xin Lu




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Pulmonary Artery Dissection: A Fatal Complication of Pulmonary Hypertension

Pulmonary artery dissection is extremely rare but it is a really life-threatening condition when it happens. Most patients die suddenly from major bleeding or tamponade caused by direct rupture into mediastinum or retrograde into the pericardial sac. What we are reporting is a rare case of a 46-year-old female patient whose pulmonary artery dissection involves both the pulmonary valve and right pulmonary artery. The patient had acute chest pain and severe dyspnea, and the diagnosis of pulmonary artery dissection was confirmed by ultrasonography and CT angiography. Moreover, its etiology, clinical manifestations, and management are also discussed in this article.

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Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action

Abstract

Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumour cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI. In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.

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PD1/PD-L1 inhibition as a potential radiosensitizer in head and neck squamous cell carcinoma: a case report

Abstract

Background

Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated.

Case presentation

We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy.

Conclusion

T cell activation induced by checkpoint inhibition may dramatically improve tumor response to radiation. More data are needed to identify the toxicity and efficacy of sequential or concurrent checkpoint inhibitors and radiotherapy.

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Targeted therapy and elderly people: A review

Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Amaury Daste, Camille Chakiba, Charlotte Domblides, Marine Gross-goupil, Amandine Quivy, Alain Ravaud, Pierre Soubeyran
The use of targeted therapy (TT) has radically changed the outcome of various cancers and introduces the era of personalised medicine. Elderly patients (≥65 years) represent the majority of cancer diagnoses and deaths by age group with an increase expected over the next decade. This group of patients is heterogeneous with three categories of patients: fit, vulnerable and frail, with specific treatment for each subgroup. In this review, we assess safety and efficacy of TT in elderly patients, principally from data of pivotal clinical trials with subgroup analysis, but elderly people represented a small percentage of the total number of patients. Few specific trials have been carried out for TT in elderly people with most patients considered to be fit. However, tolerance and efficacy of TT in elderly patients seems similar to that for younger patients, with an increase in incidence of specific adverse events in elderly patients for selected TTs. An adapted geriatric selection and strict monitoring could help to decrease toxicity, and specific clinical trials for elderly cancer patients would be useful.



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Combined BRAF V600E and MEK blockade for BRAF V600E -mutant gliomas

Abstract

BRAF^V600E is a common finding in glioma (about 10–60% depending on histopathologic subclassification). BRAF^V600E monotherapy shows modest preclinical efficacy against BRAF^V600E gliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAF^V600E inhibition in glioma. Furthermore, we investigate BRAF^V600E/MEK combination therapy that overcomes intrinsic resistance to BRAF^V600E inhibitor and also prevents BRAF^V600E inhibitor induced secondary malignancies. Immunoblotting and Human Phospho-Receptor Tyrosine Kinase Array assays were used to interrogate MAPK pathway activation. The cellular effect of BRAF^V600E and MEK inhibition was determined by WST-1 viability assay and cell cycle analysis. Flanked and orthotopic GBM mouse models were used to investigate the in vivo efficacy of BRAF^V600E/MEK combination therapy and the effect on secondary malignancies. BRAF^V600E inhibition leads to recovery of ERK phosphorylation. Combined BRAF^V600E and MEK inhibition prevents reactivation of the MAPK signaling, which correlates with decreased cell viability and augmented cell cycle arrest. Similarly, mice bearing BRAF^V600E glioma showed reduced tumor growth when treated with a combination of BRAF^V600E and MEK inhibitor compared to BRAF^V600E inhibition alone. Additional benefit of BRAF^V600E/MEK inhibition was reflected by reduced cutaneous squamous-cell carcinoma (cSCC) growth (a surrogate for RAS-driven secondary maligancies). In glioma, recovery of MAPK signaling upon BRAF inhibition accounts for intrinsic resistance to BRAF^V600E inhibitor. Combined BRAF^V600E and MEK inhibition prevents rebound of MAPK activation, resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development.

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The effect of IDH1 mutation on the structural connectome in malignant astrocytoma

Abstract

Mutation of the IDH1 gene is associated with differences in malignant astrocytoma growth characteristics that impact phenotypic severity, including cognitive impairment. We previously demonstrated greater cognitive impairment in patients with IDH1 wild type tumor compared to those with IDH1 mutant, and therefore we hypothesized that brain network organization would be lower in patients with wild type tumors. Volumetric, T1-weighted MRI scans were obtained retrospectively from 35 patients with IDH1 mutant and 32 patients with wild type malignant astrocytoma (mean age = 45 ± 14 years) and used to extract individual level, gray matter connectomes. Graph theoretical analysis was then applied to measure efficiency and other connectome properties for each patient. Cognitive performance was categorized as impaired or not and random forest classification was used to explore factors associated with cognitive impairment. Patients with wild type tumor demonstrated significantly lower network efficiency in several medial frontal, posterior parietal and subcortical regions (p < 0.05, corrected for multiple comparisons). Patients with wild type tumor also demonstrated significantly higher incidence of cognitive impairment (p = 0.03). Random forest analysis indicated that network efficiency was inversely, though nonlinearly associated with cognitive impairment in both groups (p < 0.0001). Cognitive reserve appeared to mediate this relationship in patients with mutant tumor suggesting greater neuroplasticity and/or benefit from neuroprotective factors. Tumor volume was the greatest contributor to cognitive impairment in patients with wild type tumor, supporting our hypothesis that greater lesion momentum between grades may cause more disconnection of core neurocircuitry and consequently lower efficiency of information processing.

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Phase II study of MEDI-575, an anti-platelet-derived growth factor-α antibody, in patients with recurrent glioblastoma

Abstract

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23–79), 66 % were male, and 66 % were aged ≥65 years. PFS-6 was 15.4 % [90 % confidence interval (CI) 8.1–24.9]. No complete or partial responses were observed; 23 (41.1 %) patients had stable disease as best response. Median PFS was 1.4 months (90 % CI 1.4, 1.8); median OS was 9.7 months (90 % CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16 %), nausea (13 %), and fatigue (13 %). Twelve (21 %) patients reported grade ≥3 AEs, with hydrocephalus (n = 3), dysphagia (n = 2), and convulsion (n = 2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n = 1 each). Seven patients (13 %) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.

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