Cancer by Sfakianakis Alexandros: 02/12/18

Δευτέρα 12 Φεβρουαρίου 2018

Practical Transfusion Medicine, 5th ed

No abstract available

http://ift.tt/2nWl1hR

Intensive Care Unit Enhanced Recovery Pathway for Patients Undergoing Orthotopic Liver Transplants Recipients: A Prospective, Observational Study

BACKGROUND: Liver transplant recipients continue to have high perioperative resource utilization and prolonged length of stay despite improvements in perioperative care. Enhanced recovery pathways have been shown in other surgical populations to produce reductions in hospital resource utilization. METHODS: A prospective, observational study was performed to examine the effect of an enhanced recovery pathway for postoperative care after liver transplantation. Outcomes from patients undergoing liver transplantation from November 1, 2013, to October 31, 2014, managed by the pathway were compared to transplant recipients from the year before pathway implementation. Multivariable regression analysis was used to assess the association of the clinical pathway on clinical outcomes. RESULTS: The intervention and control groups included 141 and 106 patients, respectively. There were no demographic differences between the control and intervention group including no differences between the length of surgery and cold ischemic time. Median intensive care unit length of stay was reduced from 4.4 to 2.6 days (P

http://ift.tt/2o2CDb2

How to Implement Evidence-Based Healthcare

No abstract available

http://ift.tt/2nXXtJm

Surveying the Literature: Synopsis of Recent Key Publications

No abstract available

http://ift.tt/2o313kP

Significance, Errors, Power, and Sample Size: The Blocking and Tackling of Statistics Erratum

No abstract available

http://ift.tt/2nXNBPS

Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients

Abstract

Purpose

To report outcomes of a population of anal cancer patients treated with modern intensity-modulated radiotherapy and daily image-guided radiotherapy techniques.

Methods

We analyzed data of 155 patients consecutively treated with intensity-modulated radiotherapy +/− chemotherapy in three radiotherapy departments. One hundred twenty-two patients presented a stage II–IIIA disease. Chemotherapy was administered in 138 patients, mainly using mitomycin C and 5-fluorouracil (n = 81). All patients received 36 Gy (1.8 Gy/fraction) on the pelvic and inguinal nodes, on the rectum, on the mesorectum and on the anal canal, and a sequential boost up to a total dose of 59.4 Gy (1.8 Gy/fraction) on the anal canal and on the nodal gross tumor volumes.

Results

Median follow-up was 38 months (interquartile range 12–51). Toxicity data were available for 143 patients: 22% of them presented a G3+ acute toxicity, mainly as moist desquamation (n = 25 patients) or diarrhea (n = 10). Three patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Patients treated with fixed-gantry IMRT delivered with a sliding window technique presented a significantly higher risk of acute grade 3 (or more) toxicity compared to those treated with VMAT or helical tomotherapy (38.5 vs 15.3%, p = 0.049). Actuarial 4-year local control rate was 82% (95% CI 76–91%).

Conclusions

Modern intensity-modulated radiotherapy with daily image-guided radiotherapy is effective and safe in treating anal cancer patients and should be considered the standard of care in this clinical setting.

from Cancer via ola Kala on Inoreader http://ift.tt/2G7OfB8
via IFTTT

Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients

Abstract

Purpose

To report outcomes of a population of anal cancer patients treated with modern intensity-modulated radiotherapy and daily image-guided radiotherapy techniques.

Methods

Results

Conclusions

http://ift.tt/2G7OfB8

Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review

Abstract

Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3–7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III–IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP–5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.

from Cancer via ola Kala on Inoreader http://ift.tt/2EYpDv5
via IFTTT

Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review

Abstract

http://ift.tt/2EYpDv5

Hypertonicity primes malignant melanoma cells for apoptosis

Abstract

The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na⁺ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.

http://ift.tt/2o3qwdR

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab

Abstract

Background

There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab.

Methods

We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed.

Results

The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of ≥ 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.0 months (p = 0.00515).

Conclusion

The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.

http://ift.tt/2nVCRSj

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab

Abstract

Background

Methods

Results

Conclusion

The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.

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

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

Abstract

Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.

http://ift.tt/2sqNMbd

The clinical impact of molecular breast imaging in women with proven invasive breast cancer scheduled for breast-conserving surgery

Abstract

Purpose

To investigate the clinical utility of molecular breast imaging (MBI) in patients with proven invasive breast cancer scheduled for breast-conserving surgery (BCS).

Methods

Following approval by the institutional review board and written informed consent, records of patients with newly diagnosed breast cancer scheduled for BCS who had undergone MBI for local staging in the period from March 2012 till December 2014 were retrospectively reviewed.

Results

A total of 287 women (aged 30–88 years) were evaluated. MBI showed T stage migration in 26 patients (9%), with frequent detection of in situ carcinoma around the tumor. Surgical management was adjusted in 14 of these patients (54%). In 17 of 287 patients (6%), MBI revealed 21 proven additional lesions in the ipsilateral, contralateral breast or both. In 18 of these additional foci (86%), detected in 15 patients, malignancy was found. Thirteen of these 15 patients had ipsilateral cancer and 2 patients bilateral malignancy. In total, MBI revealed a larger tumor extent, additional tumor foci or both in 40 patients (14%), leading to treatment adjustment in 25 patients (9%).

Conclusion

MBI seems to be a useful imaging modality with a high predictive value in revealing ipsilateral and bilateral disease not visualized by mammography and ultrasound. It may play an important role in delineating the extent of the index lesion during preoperative planning. Incorporation of MBI in the clinical work-up as an adjunct modality to mammography and ultrasound may lead to better selection of patients who could benefit from BCS.

http://ift.tt/2BrFeDZ

Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma

Summary

Diagnosis of endometrial cancer is primarily based on symptoms and imaging, with early-stage disease being difficult to diagnose. Therefore, development of potential diagnostic biomarkers is required. Metabolomics, a quantitative measurement of the dynamic metabolism in living systems, can be applied to determine metabolite profiles in different disease states. Here, serum metabolomics was performed in forty-six early stage endometrial cancer patients and forty-six healthy volunteers. In addition, the effect of identified metabolites on tumour cell behavior (invasion, migration, proliferation, apoptosis, autophagy), was examined in endometrial cancer cell lines. Compared with controls, phenylalanine, indoleacrylic acid (IAA), phosphocholine and lyso-platelet activating factor-16 (lyso-PAF), were differentially detected in patients. Functional analyses demonstrated that IAA, PAF and phenylalanine all dose-dependently inhibited tumour cell invasion and migration, and suppressed cell proliferation. PAF also induced tumour cell apoptosis and autophagy, while phenylalanine had no effect on apoptosis or autophagy. IAA triggered apoptosis and had a biphasic effect on autophagy: inhibiting autophagy with doses less than 1mM but inducing at 1mM. Interestingly, the alterations in proliferation, apoptosis and autophagy caused by 1mM IAA, were all reversed by the concomitant treatment of tryptophan (100μM). Phosphocholine inhibited tumour cell invasion and migration, and promoted cell proliferation and autophagy all in a dose-dependent manner. Phosphocholine also protected cells from TNF-α-induced apoptosis. In conclusion, four serum metabolites were identified by serum metabolomics in endometrial cancer patients and functional analyses suggested that they may play roles in modulation of tumour cell behavior, although their exact mode of action still needs to be determined.

from Cancer via ola Kala on Inoreader http://ift.tt/2BU8xjv
via IFTTT

Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma

Summary

http://ift.tt/2BU8xjv

Cellular Pliancy and the Multistep Process of Tumorigenesis

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Alain Puisieux, Roxane M. Pommier, Anne-Pierre Morel, Fabrice Lavial
Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.

Teaser

Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.

from Cancer via ola Kala on Inoreader http://ift.tt/2H9lt4x
via IFTTT

Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Chia-Wei Li, Seung-Oe Lim, Ezra M. Chung, Yong-Soo Kim, Andrew H. Park, Jun Yao, Jong-Ho Cha, Weiya Xia, Li-Chuan Chan, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Chao-Kai Chou, Yen-Liang Liu, Hsin-Chih Yeh, Evan P. Perillo, Andrew K. Dunn, Chu-Wei Kuo, Kay-Hooi Khoo, Jennifer L. Hsu, Yun Wu, Jung-Mao Hsu, Hirohito Yamaguchi, Tzu-Hsuan Huang, Aysegul A. Sahin, Gabriel N. Hortobagyi, Stephen S. Yoo, Mien-Chie Hung
Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.

Teaser

Li et al. show that glycosylation of PD-L1 is essential for PD-L1/PD-1 interaction and immunosuppression in triple-negative breast cancer (TNBC). They generate a glycosylation-specific antibody that induces PD-L1 internalization and an antibody-drug conjugate with potent anti-tumor activities in TNBC models.

from Cancer via ola Kala on Inoreader http://ift.tt/2G7IeUY
via IFTTT

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Christopher A.G. Booth, Nikolaos Barkas, Wen Hao Neo, Hanane Boukarabila, Elizabeth J. Soilleux, George Giotopoulos, Noushin Farnoud, Alice Giustacchini, Neil Ashley, Joana Carrelha, Lauren Jamieson, Deborah Atkinson, Tiphaine Bouriez-Jones, Rab K. Prinjha, Thomas A. Milne, David T. Teachey, Elli Papaemmanuil, Brian J.P. Huntly, Sten Eirik W. Jacobsen, Adam J. Mead
Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.

Graphical abstract

Teaser

Booth et al. show that inactivation of Ezh2 and Runx1 in early thymic progenitors (ETPs) causes cell expansion and gene expression changes similar to those seen in human ETP leukemia. Addition of Flt3-ITD to the Ezh2^−/−;Runx1^−/− ETP cells leads to aggressive leukemia, which is sensitive to BET inhibition.

from Cancer via ola Kala on Inoreader http://ift.tt/2G7Iaoc
via IFTTT

Glycans Pave the Way for Immunotherapy in Triple-Negative Breast Cancer

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Mariana Salatino, María Romina Girotti, Gabriel A. Rabinovich
The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.

Teaser

The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/2H9lxBj
via IFTTT

c-Raf in KRas Mutant Cancers: A Moving Target

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Frank McCormick
Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRas^G12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.

Teaser

Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRas^G12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.

from Cancer via ola Kala on Inoreader http://ift.tt/2G7IvY0
via IFTTT

HIPPO Stampede in Nerve Sheath Tumors

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): M. Laura Feltri, Yannick Poitelon
Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.

Teaser

Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.

from Cancer via ola Kala on Inoreader http://ift.tt/2H97j38
via IFTTT

An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back)

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Verena Wagner, Jesús Gil
Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.

Teaser

Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.

from Cancer via ola Kala on Inoreader http://ift.tt/2G8KGuk
via IFTTT

Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Donald P. McDonnell, John D. Norris, Ching-yi Chang
In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.

Teaser

In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.

from Cancer via ola Kala on Inoreader http://ift.tt/2G7Yy87
via IFTTT

Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Rinath Jeselsohn, Johann S. Bergholz, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Agostina Nardone, Tengfei Xiao, Wei Li, Xintao Qiu, Gilles Buchwalter, Ariel Feiglin, Kayley Abell-Hart, Teng Fei, Prakash Rao, Henry Long, Nicholas Kwiatkowski, Tinghu Zhang, Nathanael Gray, Diane Melchers, Rene Houtman, X. Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P. Winer, Jean Zhao, Myles Brown
Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER⁺) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.

Graphical abstract

Teaser

Jeselsohn et al. show that estrogen receptor α (ER) mutations found in endocrine treatment-resistant metastatic breast cancers confer not only ligand-independent ER functions, but also allele-specific neomorphic properties. Importantly, the authors identify potential approaches for treating these breast cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/2H9lqWp
via IFTTT

The Integrated Genomic Landscape of Thymic Epithelial Tumors

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Milan Radovich, Curtis R. Pickering, Ina Felau, Gavin Ha, Hailei Zhang, Heejoon Jo, Katherine A. Hoadley, Pavana Anur, Jiexin Zhang, Mike McLellan, Reanne Bowlby, Thomas Matthew, Ludmila Danilova, Apurva M. Hegde, Jaegil Kim, Mark D.M. Leiserson, Geetika Sethi, Charles Lu, Michael Ryan, Xiaoping Su, Andrew D. Cherniack, Gordon Robertson, Rehan Akbani, Paul Spellman, John N. Weinstein, D. Neil Hayes, Ben Raphael, Tara Lichtenberg, Kristen Leraas, Jean Claude Zenklusen, Junya Fujimoto, Cristovam Scapulatempo-Neto, Andre L. Moreira, David Hwang, James Huang, Mirella Marino, Robert Korst, Giuseppe Giaccone, Yesim Gokmen-Polar, Sunil Badve, Arun Rajan, Philipp Ströbel, Nicolas Girard, Ming S. Tsao, Alexander Marx, Anne S. Tsao, Patrick J. Loehrer
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.

Graphical abstract

Teaser

Radovich et al. perform multi-platform analyses of thymic epithelial tumors. They identify high prevalence of GTF2I mutations and enrichment of mutations in HRAS, NRAS, and TP53 and link overexpression of muscle autoantigens and increased aneuploidy in thymoma and patients' risk of having myasthenia gravis.

from Cancer via ola Kala on Inoreader http://ift.tt/2HcH2Rx
via IFTTT

Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Lai Man Natalie Wu, Yaqi Deng, Jincheng Wang, Chuntao Zhao, Jiajia Wang, Rohit Rao, Lingli Xu, Wenhao Zhou, Kwangmin Choi, Tilat A. Rizvi, Marc Remke, Joshua B. Rubin, Randy L. Johnson, Thomas J. Carroll, Anat O. Stemmer-Rachamimov, Jianqiang Wu, Yi Zheng, Mei Xin, Nancy Ratner, Q. Richard Lu
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.

Graphical abstract

Teaser

Wu et al. find that HIPPO-TAZ/YAP expression is elevated in malignant peripheral nerve sheath tumors (MPNST). Lats1/2 deficiency in Schwann cells induces hyperactivation of TAZ/YAP and increased PDGFR signaling, leading to the development of MPNST in mice. Inhibition of TAZ/YAP and PDGFR reduces MPNST growth.

from Cancer via ola Kala on Inoreader http://ift.tt/2H9lmpD
via IFTTT

DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W. Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L.F. Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A. Zahnow, Nita Ahuja, Stephen B. Baylin, Hariharan Easwaran
Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention.

Graphical abstract

Teaser

Xie et al. show that transformation-associated methylation changes arise stochastically and evolve independently of senescence. A subset of transformation-associated hypermethylated genes favoring cell self-renewal and survival exhibits highest methylation gains during aging and early tumorigenesis.

from Cancer via ola Kala on Inoreader http://ift.tt/2G7I4gk
via IFTTT

Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Yong Yu, Kolja Schleich, Bin Yue, Sujuan Ji, Philipp Lohneis, Kristel Kemper, Mark S. Silvis, Nouar Qutob, Ellen van Rooijen, Melanie Werner-Klein, Lianjie Li, Dhriti Dhawan, Svenja Meierjohann, Maurice Reimann, Abdel Elkahloun, Steffi Treitschke, Bernd Dörken, Christian Speck, Frédérick A. Mallette, Leonard I. Zon, Sheri L. Holmen, Daniel S. Peeper, Yardena Samuels, Clemens A. Schmitt, Soyoung Lee
Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases—the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)—disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo.

Graphical abstract

Teaser

Yu et al. show that two different types of histone H3 lysine 9 (H3K9) demethylases, LSD1 and JMJD2C, disable oncogenic Ras- or Braf-induced senescence by enabling the expression of E2F target genes, which permits transformation. Inhibition of the H3K9 demethylases restores senescence and controls tumor growth.

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

Glycans Pave the Way for Immunotherapy in Triple-Negative Breast Cancer

Teaser

c-Raf in KRas Mutant Cancers: A Moving Target

Teaser

HIPPO Stampede in Nerve Sheath Tumors

Teaser

An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back)

Teaser

Cellular Pliancy and the Multistep Process of Tumorigenesis

Teaser

Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery

Teaser

Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

Graphical abstract

Teaser

Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1

Teaser

The Integrated Genomic Landscape of Thymic Epithelial Tumors

Graphical abstract

Teaser

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Graphical abstract

Teaser

Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis

Graphical abstract

Teaser

DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk

Graphical abstract

Teaser

Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Graphical abstract

Teaser

Treatment of glioblastoma with herbal medicines

Abstract

Background

In the latest years, a lot of research studies regarding the usage of active agents from plants in the treatment of tumors have been published, but there is no data about successful usage of herbal remedies in the treatment of glioblastoma in humans.

Methods

The phytotherapy involved five types of herbal medicine which the subjects took in the form of tea, each type once a day at regular intervals. Three patients took herbal medicine along with standard oncological treatment, while two patients applied for phytotherapy after completing medical treatment. The composition of herbal medicine was modified when necessary, which depended on the results of the control scans using the nuclear magnetic resonance technique and/or computed tomography.

Results

Forty-eight months after the introduction of phytotherapy, there were no clinical or radiological signs of the disease, in three patients; in one patient, the tumor was reduced and his condition was stable, and one patient lived for 48 months in spite of a large primary tumor and a massive recurrence, which developed after the treatment had been completed.

Conclusions

The results achieved in patients in whom tumor regression occurred exclusively through the use of phytotherapy deserve special attention.

In order to treat glioblastoma more effectively, it is necessary to develop innovative therapeutic strategies and medicines that should not be limited only to the field of conventional medicine. The results presented in this research paper are encouraging and serve as a good basis for further research on the possibilities of phytotherapy in the treatment of glioblastoma.

http://ift.tt/2ChrNmx

Impact of the anti-cancer drug NT157 on tyrosine kinase signalling networks

The small molecule drug NT157 has demonstrated promising efficacy in pre-clinical models of a number of different cancer types, reflecting activity against both cancer cells and the tumour microenvironment. Two known mechanisms of action are degradation of insulin-receptor substrates (IRS)-1/2, and reduced Stat3 activation, although it is possible that others exist. In order to interrogate the effects of this drug on cell signalling pathways in an unbiased manner, we have undertaken mass spectrometry-based global tyrosine phosphorylation profiling of NT157-treated A375 melanoma cells. Bioinformatic analysis of the resulting dataset resolved 5 different clusters of tyrosine-phosphorylated peptides that differed in the directionality and timing of response to drug treatment over time. The receptor tyrosine kinase AXL exhibited a rapid decrease in phosphorylation in response to drug treatment, followed by proteasome-dependent degradation, identifying an additional potential target for NT157 action. However, NT157 treatment also resulted in increased activation of p38 MAPKα and , as well as the JNKs and specific Src family kinases. Importantly, co-treatment with the p38 MAPK inhibitor SB203580 attenuated the anti-proliferative effect of NT157, while synergistic inhibition of cell proliferation was observed when NT157 was combined with a Src inhibitor. These findings provide novel insights into NT157 action on cancer cells, and highlight how globally profiling the impact of a specific drug on cellular signalling networks can identify effective combination treatments.

http://ift.tt/2EmEulZ

Treatment of glioblastoma with herbal medicines

Abstract

Background

Methods

Results

Conclusions

The results achieved in patients in whom tumor regression occurred exclusively through the use of phytotherapy deserve special attention.

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

Impact of the anti-cancer drug NT157 on tyrosine kinase signalling networks

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

A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiological stemness of the resulting cell populations. Here we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn-cells intracytoplasmically. Release of Gn-cells occurred by ejection through crevices in P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1-cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1-cells were competent to horizontally transmit offspring Gn-cells into other specific proximal cells, injecting them to receptor R1-cells via cell-cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1-cells with low expression of stem cell markers despite their physiological stemness, the first offspring generations of daughter G1-cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1- and Gn-cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1-cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell-biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/2o2J2Dh
via IFTTT

Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts non-oncogenic PKM2 to a tumor promoter and induces cancer stem-like cells

The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed non-tumorigenic tetramers in non-transformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phospho-mimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing YAP protein nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.

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

Crosstalk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer

Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase (RTK) profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the monoclonal antibody CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that crosstalk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that co-targeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors

from Cancer via ola Kala on Inoreader http://ift.tt/2o2gSZ7
via IFTTT

RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma

Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis. Inhibition of RSK reduced PFKFB2 activity and glycolytic flux in melanoma cells, suggesting an important role for RSK in BRAF-mediated metabolic rewiring. Consistent with this, expression of a phosphorylation-deficient mutant of PFKFB2 decreased aerobic glycolysis and reduced the growth of melanoma in mice. Together these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF-mutated melanomas.

from Cancer via ola Kala on Inoreader http://ift.tt/2nV2PW0
via IFTTT

FOXO transcription factors both suppress and support breast cancer progression.

FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K-signaling, all of which must be carefully balanced for tumor cells to thrive.

from Cancer via ola Kala on Inoreader http://ift.tt/2o5LQj8
via IFTTT

Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints.

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

A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age-dependence and predilection of RMC towards the right kidney.

from Cancer via ola Kala on Inoreader http://ift.tt/2F1KeyU
via IFTTT

A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity

Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts non-oncogenic PKM2 to a tumor promoter and induces cancer stem-like cells

Crosstalk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer

RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma

FOXO transcription factors both suppress and support breast cancer progression.

Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

http://ift.tt/2EoExcU

A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma

http://ift.tt/2F1KeyU

SMURF1 facilitates estrogen receptor ɑ signaling in breast cancer cells

Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulato...

from Cancer via ola Kala on Inoreader http://ift.tt/2o5VGBB
via IFTTT

Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists

The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.

http://ift.tt/2nV0gmM

Respiratory symptoms of an abdominal origin

Description

A 75-year-old, fully dependent woman was sent to the emergency department due to a sudden onset of fever (38°C), polypnoea and dyspnoea. The patient had a history of Parkinson's disease and vascular dementia, making it impossible to cooperate in the medical interview. She was feverish, breathing rapidly, although haemodynamically stable and with peripheral oxygen saturation of over 95%. Blood tests showed increase in C-reactive protein (8.51 mg/dL), leucocytosis (13x10⁹/L, 67% neutrophils and 23.1% lymphocytes) and slight hypokalaemia (3 mmol/L), without respiratory insufficiency in the arterial blood. Chest X-ray showed no clear infectious consolidation.

Acute tracheobronchitis was assumed, so she was given an antibiotic and potassium chloride and was discharged. The patient returned the next day without fever but with all of the other symptoms, adding to them prostration. She was still breathing rapidly but her abdomen was larger and tympanic, with noticeable pain while it was being palpated, adding therefore...

http://ift.tt/2o0TLhB

Basilar artery fenestration: an unusual possible cause of ischaemic stroke?

Basilar artery fenestration is an uncommon congenital dysplasia and may be associated with ischaemic stroke. We present a case of a previously healthy 36-year-old man who presented with vertigo and vomiting. MRI showed posterior circulation territory infarction. High-resolution magnetic resonance angiography revealed a slit-like fenestration in the basilar artery. This patient had no traditional vascular risk factors or aetiology of cryptogenic stroke. The patient recovered from his neurological deficit after antiplatelet therapy and was given prophylactic aspirin therapy. There was no recurrence of symptoms after 12 months of follow-up.

http://ift.tt/2nVJwMm

Propionibacterium acnes and Staphylococcus epidermidis olecranon bursitis/osteomyelitis: a case involving surgical and antibiotic treatment

This report describes a 63-year-old generally healthy male with septic olecranon bursitis caused by Propionibacterium acnes. The patient sustained a small laceration after striking the posterior aspect of his left elbow on a metal railing when he was at a public swimming pool. We concluded that P. acnes was not initially detected because cultures were only kept for 5 days. Consequently, initial antibiotic treatment failed. P. acnes and Staphylococcus epidermidis grew in a subsequent tissue culture. The infection did not respond to intravenous vancomycin although soft-tissue debridements were done. This likely reflected the presence of olecranon osteomyelitis (seen on MRI scans) in addition to inadequate treatment with this antibiotic in the setting of a polymicrobial infection. Eventually, the infection was eradicated with multiple soft-tissue debridements in addition to the continuation of vancomycin with daily intravenous piperacillin/tazobactam that was added for the final 4 weeks of antibiotic treatment.

http://ift.tt/2o0TGKP

Rhabdomyolysis: a rare complication of Hashimotos thyroiditis precipitated by statin therapy

Hashimoto's thyroiditis (HT) or chronic lymphocytic thyroiditis is the most common form of primary hypothyroidism. Muscular manifestations like weakness, pain, stiffness and elevated muscle enzymes have been noticed in hypothyroidism. Statins are also known to cause myositis and rhabdomyolysis. This is a case of a middle-aged man, on statin therapy, who presented with severe muscle aches and pain and was found to have rhabdomyolysis. Further evaluation revealed an underlying HT as the culprit for his condition. He was managed with intravenous fluids and levothyroxine along with cessation of statins, following which he improved.

http://ift.tt/2nWN1C5

Withdrawn: Cutaneous larva migrans with pulmonaryinvolvement

Maslin D, Wallace M. Cutaneous larva migrans with pulmonary involvement. BMJ Case Rep. Published Online: 12 Jan 2018. doi: 10.1136/bcr-2017-223508.

With no admission of liability, BMJ has removed this article voluntarily at the request of the patient concerned.

http://ift.tt/2o2mORN

Oncologic outcomes for open and laparoscopic radical nephroureterectomy in patients with upper tract urothelial carcinoma

Abstract

Background

Oncologic benefits of laparoscopic radical nephroureterectomy (LNU) are unclear. We aimed to evaluate the impact of surgical approach for radical nephroureterectomy on oncologic outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC).

Methods

Of 426 patients who underwent radical nephroureterectomy at five medical centers between February 1995 and February 2017, we retrospectively investigated oncological outcomes in 229 with locally advanced UTUC (stages cT3-4 and/or cN+). The surgical approach was classified as open nephroureterectomy (ONU) or LNU, and oncologic outcomes, including intravesical recurrence-free survival (RFS), visceral RFS, cancer-specific survival (CSS), and overall survival (OS), were compared between the groups. The inverse probability of treatment weighting (IPTW)-adjusted Cox-regression analyses was performed to evaluate the impact of LNU on the prognosis.

Results

Of the 229 patients, 48 (21%) underwent LNU. There were significant differences in patient backgrounds, including preoperative renal function, lymph-node involvement, lymphovascular invasion, and surgical margins, between the groups. Before the background adjustment, intravesical RFS, visceral RFS, CSS, and OS were significantly inferior in the ONU group than in the LNU group. However, in the IPTW-adjusted Cox-regression analysis, no significant differences were observed in intravesical RFS (hazard ratio [HR], 0.65; P = 0.476), visceral RFS (HR, 0.46; P = 0.109), CSS (HR, 0.48; P = 0.233), and OS (HR, 0.40; P = 0.147).

Conclusion

Surgical approaches were not independently associated with prognosis in patients with locally advanced UTUC.

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

Comparison of clinical utility between neutrophil count and neutrophil–lymphocyte ratio in patients with ovarian cancer: a single institutional experience and a literature review

Abstract

Objective

We retrospectively investigated the prognostic significance and clinical utility of pretreatment neutrophilia and elevated neutrophil–lymphocyte ratio (NLR) in patients with epithelial ovarian cancer.

Methods

Clinical data were collected from 344 surgically staged ovarian cancer patients between April 2007 and March 2016 and retrospectively reviewed. Neutrophilia and elevated NLR were defined as a neutrophil count ≥ 8,000/μl and an NLR ≥ 4.0, respectively. Univariate or multivariate analysis was conducted to evaluate the association between pretreatment neutrophilia or elevated NLR and clinicopathological characteristics, optimal surgery rate, progression-free survival (PFS) and disease-specific survival (DSS). Finally, we compared the clinical utility between neutrophil count and NLR by receiver operating characteristic (ROC) analysis.

Results

Pretreatment neutrophilia and elevated NLR were observed in 24 (7.0%) and 142 (41.3%) patients, respectively. In univariate analysis, both neutrophilia and elevated NLR were found to be associated with short PFS and DSS (p < 0.005). Multivariate analysis showed that neutrophilia and elevated NLR were predictors for shorter survival. In ROC analysis, the NLR tended to have a greater area under the ROC curve (AUC) value than the neutrophil count in predicting recurrence (0.7011 vs 0.6516, p = 0.0546) and had a significantly greater AUC value in predicting DSS (0.7249 vs 0.6379, p = 0.0182). Finally, based on the neutrophil count and NLR, we divided the patients into 3 prognostic groups—high-risk group (elevated NLR with neutrophilia), intermediate-risk group (elevated NLR without neutrophilia), and low-risk group (normal NLR), which allows for individualized and accurate survival estimates.

Conclusions

Pretreatment neutrophilia and elevated NLR are independent poor prognostic factors in epithelial ovarian cancer patients. The NLR was superior to neutrophil count in predicting the survival of epithelial ovarian cancer patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2BWLLr2
via IFTTT

The 5-year outcomes of moderately hypofractionated radiotherapy (66 Gy in 22 fractions, 3 fractions per week) for localized prostate cancer: a retrospective study

Abstract

Background

Hypofractionated radiotherapy using fewer and larger fractional doses may be more beneficial than conventional external-beam radiotherapy for localized prostate cancer. We evaluated the 5-year outcomes of moderately hypofractionated radiotherapy for localized prostate cancer.

Methods

We retrospectively evaluated 195 patients with localized prostate cancer (T1–3N0M0) who underwent intensity-modulated radiotherapy (IMRT) (66 Gy delivered in fractions of 3 Gy every other weekday) between May 2005 and December 2011. Patients received androgen deprivation therapy depending on the perceived intermediate or high risk of their disease. A prostate-specific antigen nadir +2.0 ng/ml indicated biochemical failure. We assessed toxicity using the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria, and patient-reported outcomes using the Expanded Prostate Cancer Index Composite (EPIC).

Results

The risk classifications (proportion) were low risk (13.8%), intermediate risk (35.9%), and high risk (50.3%). The median follow-up was 69 months. Thirteen (6.66%) patients experienced biochemical failure within a median of 40 months (interquartile range, 25–72 months). The 5-year overall survival rate and no biological evidence of disease rate were 97.7% and 92.4%, respectively. Based on the RTOG/EORTC criteria, no patient experienced acute or late toxicity of grade 3 or higher. The EPIC scores revealed significant differences in the average value of all domains (p < 0.01). At 1 month postradiotherapy completion, the general urinary and bowel domain scores had decreased, but these scores returned to baseline level by 3 months post radiotherapy.

Conclusions

The moderately hypofractionated radiotherapy protocol yielded short-term satisfactory clinical outcomes with acceptable toxicity.

from Cancer via ola Kala on Inoreader http://ift.tt/2Bp5K0x
via IFTTT

Oncologic outcomes for open and laparoscopic radical nephroureterectomy in patients with upper tract urothelial carcinoma

Abstract

Background

Methods

Results

Conclusion

Surgical approaches were not independently associated with prognosis in patients with locally advanced UTUC.

http://ift.tt/2BqOurZ