Paradoxical Effects of MLL Paralogs in MLL-Rearranged Leukemia

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Michael J. Thirman
Conflicting data exist on the requirement for wild-type MLL1 in MLL-rearranged leukemia. In this issue of Cancer Cell, Chen et al. describe complementary approaches demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis. They also observe an unexpected role for MLL2 in MLL-rearranged leukemia cells and identify potential therapeutic targets.

Teaser

Conflicting data exist on the requirement for wild-type MLL1 in MLL-rearranged leukemia. In this issue of Cancer Cell, Chen et al. describe complementary approaches demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis. They also observe an unexpected role for MLL2 in MLL-rearranged leukemia cells and identify potential therapeutic targets.


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Aberrant Glycosylation in Cancer: A Novel Molecular Mechanism Controlling Metastasis

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Ana Magalhães, Henrique O. Duarte, Celso A. Reis
Glycosylation alterations are involved in several steps of human cancer pathogenesis. In this issue of Cancer Cell, Agrawal et al. identified the glycosyltransferase FUT8 as a previously unrecognized mediator of melanoma metastasis, establishing core fucosylation as a potential therapeutic target for prevention and treatment of metastatic tumors.

Teaser

Glycosylation alterations are involved in several steps of human cancer pathogenesis. In this issue of Cancer Cell, Agrawal et al. identified the glycosyltransferase FUT8 as a previously unrecognized mediator of melanoma metastasis, establishing core fucosylation as a potential therapeutic target for prevention and treatment of metastatic tumors.


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Intertumoral Heterogeneity within Medulloblastoma Subgroups

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Florence M.G. Cavalli, Marc Remke, Ladislav Rampasek, John Peacock, David J.H. Shih, Betty Luu, Livia Garzia, Jonathon Torchia, Carolina Nor, A. Sorana Morrissy, Sameer Agnihotri, Yuan Yao Thompson, Claudia M. Kuzan-Fischer, Hamza Farooq, Keren Isaev, Craig Daniels, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa A. Grajkowska, Marta Perek-Polnik, Alexandre Vasiljevic, Cecile Faure-Conter, Anne Jouvet, Caterina Giannini, Amulya A. Nageswara Rao, Kay Ka Wai Li, Ho-Keung Ng, Charles G. Eberhart, Ian F. Pollack, Ronald L. Hamilton, G. Yancey Gillespie, James M. Olson, Sarah Leary, William A. Weiss, Boleslaw Lach, Lola B. Chambless, Reid C. Thompson, Michael K. Cooper, Rajeev Vibhakar, Peter Hauser, Marie-Lise C. van Veelen, Johan M. Kros, Pim J. French, Young Shin Ra, Toshihiro Kumabe, Enrique López-Aguilar, Karel Zitterbart, Jaroslav Sterba, Gaetano Finocchiaro, Maura Massimino, Erwin G. Van Meir, Satoru Osuka, Tomoko Shofuda, Almos Klekner, Massimo Zollo, Jeffrey R. Leonard, Joshua B. Rubin, Nada Jabado, Steffen Albrecht, Jaume Mora, Timothy E. Van Meter, Shin Jung, Andrew S. Moore, Andrew R. Hallahan, Jennifer A. Chan, Daniela P.C. Tirapelli, Carlos G. Carlotti, Maryam Fouladi, José Pimentel, Claudia C. Faria, Ali G. Saad, Luca Massimi, Linda M. Liau, Helen Wheeler, Hideo Nakamura, Samer K. Elbabaa, Mario Perezpeña-Diazconti, Fernando Chico Ponce de León, Shenandoah Robinson, Michal Zapotocky, Alvaro Lassaletta, Annie Huang, Cynthia E. Hawkins, Uri Tabori, Eric Bouffet, Ute Bartels, Peter B. Dirks, James T. Rutka, Gary D. Bader, Jüri Reimand, Anna Goldenberg, Vijay Ramaswamy, Michael D. Taylor
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Graphical abstract

Teaser

Cavalli et al. analyze 763 primary medulloblastoma samples using the similarity network fusion approach. They identify subtypes that have distinct somatic copy-number aberrations, activated pathways, and clinical outcomes within each of the four known subgroups and further delineate group 3 from group 4 MB.


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MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Yufei Chen, Konstantinos Anastassiadis, Andrea Kranz, A. Francis Stewart, Kathrin Arndt, Claudia Waskow, Akihiko Yokoyama, Kenneth Jones, Tobias Neff, Yoo Lee, Patricia Ernst
The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy, but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML.

Graphical abstract

Teaser

Chen et al. report that wild-type MLL1 is dispensable for MLL fusion leukemia, but instead loss of MLL2 reduces the survival of leukemia cells from human cell lines and in a mouse model of MLL-AF9 AML. Combined loss of MLL1 and MLL2 further reduces leukemia cell viability.


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From One to Many: Further Refinement of Medulloblastoma Subtypes Offers Promise for Personalized Therapy

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Abhishek Bavle, D. Williams Parsons
There is significant intertumoral heterogeneity within the four molecular subgroups of medulloblastoma. In this issue of Cancer Cell, Cavalli et al. apply similarity network fusion to gene expression and DNA methylation data to identify 12 medulloblastoma subtypes with distinct molecular and clinical profiles, making an important step toward molecularly tailored therapy.

Teaser

There is significant intertumoral heterogeneity within the four molecular subgroups of medulloblastoma. In this issue of Cancer Cell, Cavalli et al. apply similarity network fusion to gene expression and DNA methylation data to identify 12 medulloblastoma subtypes with distinct molecular and clinical profiles, making an important step toward molecularly tailored therapy.


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Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Detian Yuan, Shan Huang, Emanuel Berger, Lei Liu, Nina Gross, Florian Heinzmann, Marc Ringelhan, Tracy O. Connor, Mira Stadler, Michael Meister, Julia Weber, Rupert Öllinger, Nicole Simonavicius, Florian Reisinger, Daniel Hartmann, Rüdiger Meyer, Maria Reich, Marco Seehawer, Valentina Leone, Bastian Höchst, Dirk Wohlleber, Simone Jörs, Marco Prinz, Duncan Spalding, Ulrike Protzer, Tom Luedde, Luigi Terracciano, Matthias Matter, Thomas Longerich, Percy Knolle, Thomas Ried, Verena Keitel, Fabian Geisler, Kristian Unger, Einat Cinnamon, Eli Pikarsky, Norbert Hüser, Roger J. Davis, Darjus F. Tschaharganeh, Roland Rad, Achim Weber, Lars Zender, Dirk Haller, Mathias Heikenwalder
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Graphical abstract

Teaser

Yuan et al. show that mitochondrial dysfunction and oxidative stress in the liver increase tumor necrosis factor (TNF) expression by Kupffer cells to cause JNK-mediated cholangiocellular proliferation and transformation. The ROS/TNF/JNK axis may be an effective target for intrahepatic cholangiocarcinoma therapy.


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ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Kiran Mahajan, Pavani Malla, Harshani R. Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J. Lawrence, Nupam P. Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.

Graphical abstract

Teaser

Mahajan et al. report that ACK1 phosphorylates histone H4 at Y88 upstream of the AR transcription start site, leading to the WDR5/MLL2 complex-mediated increase of AR transcription. Inhibition of ACK1 reverses the pY88-H4 marks and reduces AR and AR-V7 levels to mitigate castration-resistant prostate tumor growth.


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A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Praveen Agrawal, Barbara Fontanals-Cirera, Elena Sokolova, Samson Jacob, Christopher A. Vaiana, Diana Argibay, Veronica Davalos, Meagan McDermott, Shruti Nayak, Farbod Darvishian, Mireia Castillo, Beatrix Ueberheide, Iman Osman, David Fenyö, Lara K. Mahal, Eva Hernando
Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of α-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.

Graphical abstract

Teaser

Using a systems-based approach to assess glycosylation in matched primary and metastatic melanoma samples, Agrawal et al. find increased core fucosylation mediated by FUT8 in metastatic melanoma. FUT8 facilitates invasion and tumor dissemination, in part due to reduced cleavage of core-fucosylated L1CAM.


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Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Xiaoju Wang, Yuanyuan Qiao, Irfan A. Asangani, Bushra Ateeq, Anton Poliakov, Marcin Cieślik, Sethuramasundaram Pitchiaya, Balabhadrapatruni V.S.K. Chakravarthi, Xuhong Cao, Xiaojun Jing, Cynthia X. Wang, Ingrid J. Apel, Rui Wang, Jean Ching-Yi Tien, Kristin M. Juckette, Wei Yan, Hui Jiang, Shaomeng Wang, Sooryanarayana Varambally, Arul M. Chinnaiyan




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SnapShot: Immune Checkpoint Inhibitors

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Gabriel Abril-Rodriguez, Antoni Ribas
Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses. However, a significant number of patients do not respond (innate resistance), and a subset progress after responding (acquired resistance). A better understanding of the molecular mechanisms underlying checkpoint blockade therapies will facilitate the design of novel strategies to treat and prevent resistance. To view this SnapShot, open or download the PDF.

Teaser

Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses. However, a significant number of patients do not respond (innate resistance), and a subset progress after responding (acquired resistance). A better understanding of the molecular mechanisms underlying checkpoint blockade therapies will facilitate the design of novel strategies to treat and prevent resistance. To view this SnapShot, open or download the PDF.


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Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast?

Background and Objectives

Adenoid cystic carcinoma (ACC) is a rare, typically triple-negative, breast cancer reported to have a favorable prognosis and low rate of nodal metastasis. No consensus guidelines exist for axillary staging and treatment.

Methods

We identified all patients with ACC evaluated at our institution from January 1994 to August 2016. Patient, tumor, and treatment variables were abstracted and analyzed.

Results

We identified 20 pure ACCs (0.13% of all invasive breast cancers) with size range 0.2-4.8 cm, in 19 women, median age 59 years. Preoperative axillary ultrasound was normal in 10/13 women and suspicious in 3/13 who had a subsequent negative lymph node fine needle aspiration (FNA). Fifteen patients (75%) had sentinel lymph node surgery and were pathologically node-negative, while the remaining five had no axillary surgery. With 3.6 years median follow-up (range 0.2-38.6 years), three patients experienced an in-breast recurrence at 2, 16, and 17 years, respectively, while none recurred in regional nodes.

Conclusions

We observed no cases of nodal metastasis in 20 consecutive cases of ACC of the breast. Preoperative axillary ultrasound with FNA of suspicious nodes accurately predicted pathologic nodal stage. These data suggest axillary surgery might be omitted safely in patients with pure ACC and a clinically negative axilla.

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A review of CD19-targeted immunotherapies for relapsed or refractory acute lymphoblastic leukemia

Journal of Oncology Pharmacy Practice, Ahead of Print.


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BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Why overall survival and not progression free survival improves in era of program death inhibitors

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Interdisciplinary implementation of tacrolimus intravenous standard concentration in hematopoietic stem cell transplantation recipients

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Impact of a specialty pharmacy case management service on adherence in patients receiving oral antineoplastic agents

Journal of Oncology Pharmacy Practice, Ahead of Print.


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The impact of pharmacist telephone calls after discharge on satisfaction of oncology patients: A randomized controlled study

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Assessment of adherence and relative dose intensity with oral chemotherapy in oncology clinical trials at an academic medical center

Journal of Oncology Pharmacy Practice, Ahead of Print.


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How can we ensure value for money from expenditure on injectable cancer drugs?

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Carry-over of antineoplastic drug contamination in Dutch hospital pharmacies

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Prediction of cardiovascular risk in cancer patients of South India using WHO/ISH risk prediction charts and Framingham score – A prospective study

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Cost-effectiveness and safety of ramucirumab plus paclitaxel chemotherapy in the treatment of advanced and recurrent gastric cancer

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Feasibility of extended dosing intervals of denosumab

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Assessing the need for improved strategies and medication-related education to increase adherence for oral anticancer medications in the young adult oncology population

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Impact of an integrated oral chemotherapy program on patient adherence

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Chemotherapy preparation processes: Methodological issues on reliability and validity

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Recommendation or refusal but why not quality of surgery?

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Clinical impact and management of fluconazole discontinuation on sirolimus levels in bone marrow transplant patients

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Supporting Adolescents and Young Adults with Cancer: Oncology Provider Perceptions of Adolescent and Young Adult Unmet Needs

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


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Predictors of surgical quality for retroperitoneal sarcoma: Volume matters

Background and Objectives

The volume-outcome relationship is well recognized. We sought to investigate this relationship in retroperitoneal sarcoma (RPS) surgery.

Methods

Non-metastatic RPS cases from 2004 to 2014 in the National Cancer Database were analyzed. Hospitals in the top 10th percentile for volume were defined as high-volume. Outcomes were selected a priori based on their known prognostic significance, including surgery use, R0/R1 resection, and R0 resection. Volume-outcome associations were assessed by univariate and multivariable analyses.

Results

Of 3141 RPS cases identified, 70.0% were managed surgically. Of these, 93.0% were R0/R1 resections, and 67.6% were R0 resections. Surgical management, R0/R1 resection, and R0 resection were each associated with improved overall survival (P < 0.001). Hospital volume was an independent predictor of surgical management, R0 resection, and R0/R1 resection. Patients treated at high-volume centers had 1.9-fold higher odds of undergoing surgical management (P < 0.001), 2.5-fold higher odds of receiving a R0/R1 resection (P = 0.026), and 1.8-fold higher odds of an R0 resection (P < 0.001). Academic setting predicted use of surgical management (P < 0.001) and R0/R1 resection (P = 0.015) but not R0 resection (P = 0.882).

Conclusions

High-volume hospitals are significantly associated with surgery use and improved surgical outcomes. Consideration should be given to further centralization of RPS care.

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Xeno-pericardial patch repair of the inferior vena cava for radical resection of renal cell carcinoma with tumor thrombus

Background and Objectives

For tumor thrombus in the inferior vena cava (IVC) complicated with kidney cancer, we built a surgical team to achieve (1) en bloc tumor resection; (2) xeno-pericardial patch IVC repair; and (3) minimum organ damages. We reviewed outcome of the case series to verify rationale of this approach.

Methods

A consecutive series of 12 patients having the IVC tumor thrombus by renal cell carcinoma in the last 3 years was enrolled. Minimum kidney ischemia was induced in five cases (Procedure I), whereas liver and kidney ischemia was induced in five cases (Procedure II). Mild hypothermic extracorporeal circulation was used in two cases (Procedure III).

Results

There was no mortality or severe morbidities related to the surgery. Postoperative recovery was most prompt by the Procedure I. Liver and kidney ischemic time was longer in the Procedure III than the Procedure II, whereas organ function was not substantially impaired in either series. The resected IVC margin was free from the cancer in all cases, while local recurrence was not seen in any cases.

Conclusions

En bloc resection with xeno-pericardial patch repair of the IVC was successfully performed in the tumor thrombus complicated with kidney cancer with minimum organ damage.

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The impact of the use of intraoperative radiotherapy on costs, travel time and distance for women with breast cancer in the Mexico City Metropolitan Area

Background and Objectives

The low availability and poor access to external beam radiotherapy (EBRT) in developing countries makes it hard for women with breast cancer to receive breast conservation. We studied the effect of providing intraoperative radiotherapy (IORT) on the travel time, distance, and costs of in the Mexico City Metropolitan Area (MCMA).

Methods

Sixty-nine patients treated between January 2013 and September 2014 were analyzed. Travel distance and transit time was calculated using Google Maps. The time and distance patients living in the MCMA treated with IORT would have spent if they had received EBRT was calculated. Cost analysis for each modality was performed.

Results

71% (n = 49) lived in the MCMA. Sixteen (33%) received additional EBRT and 33 (66%) received IORT only. Mean driving distance and transit time of those 33 women was 132.6 km (SD 25.7) and 66 min (SD 32.9). Patients from the MCMA receiving IORT alone avoided 990 visits, 43 700 km and 65 400 min in transit. IORT led to a 12% reduction in costs per patient.

Conclusions

By reducing costs and time needed for patients to receive radiotherapy, IORT could potentially enhance access to breast conservation in resource-limited developing countries.

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Evaluation of the 8th edition American Joint Commission on Cancer (AJCC) staging system for patients with intrahepatic cholangiocarcinoma: A surveillance, epidemiology, and end results (SEER) analysis

Background

The objective of this study was to assess the prognostic performance of American Joint Committee on Cancer (AJCC) 8th edition in patients with intrahepatic cholangiocarcinoma (ICC) using a cancer registry.

Methods

The Surveillance, Epidemiology, and End Results (SEER) cancer registry was queried to identify 1008 patients who underwent surgical resection of ICC during 1998-2013. Kaplan-Meier method and Cox proportional hazards regression models were used to analyze long-term survival. The relative discriminative abilities were assessed using the Harrell's concordance index.

Results

Median patient age was 62 years and 47.6% of the patients were male. Most tumors were T1 or T2 (n = 413, 41.0% and n = 329, 32.6%, respectively) and 22.1% of patients had lymph node (LN) metastasis. Median tumor size was 5.5 cm. With a median follow-up of 18 months, median survival was 27 months and 5-year OS was 30.6%. The OS c-index for the AJCC 8th staging system was 0.669, which was comparable with the c-index for the 7th edition AJCC staging system (c-index: 0.667); the AJCC 8th-edition did provide more discrete stratification of patients.

Conclusions

The new AJCC 8th-edition staging system for ICC was largely comparable to the 7th-edition version and did not provide a marked improvement in overall prognostic discrimination.

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Novel nomogram combining depth of invasion and size can accurately predict the risk for regional nodal metastases for appendiceal neuroendocrine tumors (A-NET)

Introduction

The need for regional lymphadenectomy for treating appendiceal neuroendocrine tumors (A-NET) is determined by the risk of nodal metastasis. Current guidelines for A-NET are solely based on tumor size.

Methods Patients with A-NET from 1988 to 2012 were identified from the SEER registry. The depth of invasion was defined as limited to the lamina propria (LP), invading the muscularis propria (MP), and through the serosa (TS).

Results

A total of 418 patients were included; the majority were female, white, and node-negative. On univariate and multivariable, the risk of nodal metastasis was associated with age, size, depth of invasion, and extent of surgery. The model predicted the likelihood of nodal metastasis, with an area under the curve of 0.89. On survival analysis, age and tumor size predicted the survival in A-NET. In a Cox regression model, they continued to predict survival. These data were utilized to create a nomogram to predict the risk of nodal metastases.

Conclusion

This nomogram, accurately predicts the risk of regional nodal metastases in A-NET. In addition to providing valuable information on risk for regional nodal metastases, the depth of invasion is also predictive of survival for A-NET.

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Interval between cytoreductions as a marker of tumor biology in selecting patients for repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

Background and Objectives

Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for recurrence of peritoneal surface malignancies is safe and effective. Patient selection and factors associated with a favorable outcome are still evolving.

Methods

A prospectively maintained institutional database consisting of 1314 CRS/HIPEC procedures performed between February 1993 and December 2015 was reviewed. Clinicopathologic data from 103 patients and 112 (8.5%) repeat CRS/HIPEC procedures were retrospectively analyzed.

Results

Primary tumors were appendiceal for 60 patients (58.3%), mesothelioma for 14 (13.6%), colorectal for 9 (8.7%), ovarian for 8 (7.8%). R0/R1 resection was achieved in 46 (46.5%) patients. The time interval between the initial and the repeat CRS/HIPEC was <1 year for 21 (20.4%), 1-2 years for 40 (38.8%), and >2 years for 42 patients (40.8%). Overall median survival was 4.3 years and correlated with the time interval (1.3 years for <1 years, 3.7 years for 1-2 years, and 7 years for >2 years; P < 0.001). In multivariate analysis, the R status (P = 0.005) and a time interval of more than 2 years (P = 0.0002) were strongly associated with survival with each additional month between the surgeries conferring a 2.6% reduction in the risk of death.

Conclusions

The current series validates time interval between cytoreductions as a major surrogate of tumor biology in selection of patients with recurrent peritoneal surface malignancies for repeat CRS/HIPEC. Complete repeat cytoreduction more than 2 years from the initial surgery is associated with a favorable outcome.

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Neoadjuvant chemoradiotherapy of pancreatic cancer induces a favorable immunogenic tumor microenvironment associated with increased major histocompatibility complex class I-related chain A/B expression

Background

Damage-associated molecular patterns (DAMPs) are related to immune responses in malignant tumors including tumor-infiltrating lymphocytes (TILs). The aim of the present study was to determine the relationship between expression of components of DAMPs and TILs in pancreatic cancer patients who underwent neoadjuvant chemoradiotherapy (NACRT) versus those who did not.

Methods

NACRT was administered to 51 patients with borderline-resectable pancreatic cancer and not to 33 patients with resectable pancreatic cancer. Resected specimens were analyzed for the presence of DAMPs, major histocompatibility complex class I-related chain A/B (MICA/B), and CD8⁺ TILs, CD4⁺ TILs, and forkhead box P3 positive (Foxp3⁺) TILs. The Treg/TIL ratio was obtained by dividing the number of Foxp3⁺ TILs, a surrogate for regulatory T cells, by the sum of CD8⁺ and CD4⁺ TILs.

Results

Overexpression of calreticulin, Hsp70, and MICA/B were all significantly correlated with NACRT administration. In the NACRT group, high MICA/B expression was associated with a low Treg/TIL ratio, indicating a favorable immunogenic tumor microenvironment. Patients with a lower Treg/TIL ratio had longer survival.

Conclusions

Overexpression of MICA/B, a component of DAMPs induced by NACRT, may play an important role in acquiring a favorable immune response for pancreatic cancer which contributes to longer survival, suggesting the potential of immunotherapy of this recalcitrant disease, especially for patients with overexpression of DAMPs.

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Extranodal extension of lymph node metastasis as a prognostic indicator of recurrence and survival in papillary thyroid carcinoma

Background and Objectives

Stratification of extranodal extension (ENE) extent has the potential to improve the accuracy of risk estimations in papillary thyroid carcinoma (PTC). This study examined the prognostic importance of nodal factors, including ENE, in PTC patients.

Methods

This study enrolled 2071 consecutive patients with treatment-naïve PTC who underwent thyroidectomy between 2006 and 2010. Microscopic/macroscopic ENE was determined by pathological and operative findings. Univariate and multivariate analyses were used to identify the relationship of factors with recurrence and survival in all study patients and in the node-positive subset.

Results

Of 2071 patients, 975 (47.1%) had positive lymph nodes, and 271 (13.1%) and 70 (3.4%) had microscopic and macroscopic ENE, respectively. During a median follow-up of 96 months, 114 (5.5%) patients had post-treatment recurrence. Multivariate analyses showed that, in all patients, the number of positive nodes, lymph node ratio, ENE status, and ATA risk group were independent variables affecting recurrence (P < 0.05). T4 and macroscopic ENE were independent variables associated with shorter overall survival (P < 0.05). Macroscopic ENE was significantly associated with macroscopic extrathyroidal extension.

Conclusion

Macroscopic ENE has a significant adverse impact on recurrence and survival after treatment for PTC. ENE is considered a high risk factor for recurrence.

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A Comparison of Yttrium-90 Microsphere Radioembolization to Hepatic Arterial Infusional Chemotherapy for Patients with Chemo-refractory Hepatic Colorectal Metastases

Opinion statement

Patients with unresectable hepatic colorectal metastases who become chemo-refractory have limited treatment options. Systemic chemotherapies such as TAS102 and regorafenib have been used in the refractory setting, but with only modest improvement in overall survival compared to best supportive care. In patients with liver-only or liver-dominant disease, direct chemotherapy to the liver such as hepatic artery infusional (HAI) chemotherapy and radioembolization (yttrium-90 (Y90)) should be considered. Due to the difficulty of HAI therapy post Y90 for technical reasons, we recommend HAI therapy prior to Y90.

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Correction: Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer [Correction]

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Detection of Driver and Resistance Mutations in Leptomeningeal Metastases of NSCLC by Next-Generation Sequencing of Cerebrospinal Fluid Circulating Tumor Cells

Purpose: <p>Leptomeningeal metastases (LM) are more common in non-small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of LM.</p> <br />Experimental Design: <p>We compared the CellSearch Assay™, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected LM. Next-Generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTCs) of 19 patients.</p> <br />Results: <p>Twenty-one patients were diagnosed with LM, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/ 7.5 mL; range, 27-14,888). CellSearch had a sensitivity of 95.2% for LM diagnosis, which was higher than that of TCT(12/21, 57.1%), MRI(10/21, 47.6%), and MRI plus TCT(19/21, 90.5%), respectively. CTCs were found in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2-4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was only detected in 1 of 14 CSFCTC samples. Other potential resistant mutations such as MET amplification and ERBB2 mutation were also identified in CSFCTCs.</p> <br />Conclusions: <p>CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose LM, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with LM.

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Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.<br /><br />Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.<br /><br />Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P<0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P =0.002), lymph node metastasis (P =0.004) and advanced clinical stage (P =0.001). LUAD patients with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for LUAD patients. Moreover, forced expression of RCC2 promoted intra-pulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion and proliferation in vitro. Further study found that RCC2 induced epithelial-mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP -9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT and the expression of MMP-2 and MMP-9.<br /><br />Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK-JNK signaling.

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In situ vaccination after accelerated hypofractionated radiation and surgery in a mesothelioma mouse model

Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated non-ablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade.<br /><br />Experimental Design: We therefore assessed the impact of non-ablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short term impact and radical surgery (R0 resection) was used to analyze the long-term impact of this radiation protocol before surgery. <br /><br />Results: Non-ablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8+ T cells limiting the negative impact of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long term antitumor immune protection that was primarily driven by CD4+ T cells. Radical surgery alone or radical surgery with a short course of non-ablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.     <br /><br />Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Non-ablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting.

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Age and gender associations of virus positivity in Merkel cell carcinoma characterized using a novel RNA in situ hybridization assay

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection. <p>Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMAs) and whole tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, quantitative PCR (qPCR) was performed on 57 cases of MCC from 52 patients.   </p> <p>Results: RNA-ISH demonstrated the presence of MCPyV in 37/75 (49.3%) cases. Notably, tumors from younger patients (< 73 years) had a significantly higher virus positivity than those from elderly patients (≥ 73 years) (64.9% vs. 34.2%, P =0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P =0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman's correlation coefficient R² = 0.932, P < 0.0001).  </p> <p>Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. 

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Single-cell dynamics determines response to CDK4/6 inhibition in triple negative breast cancer

Purpose: Triple negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes, and investigated mechanisms of sensitivity. <p>Experimental design: A panel of cell lines representative of TNBC were tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single cell analysis in conjunction with time-lapse imaging.</p> <p>Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro [p<0.001 LAR vs. basal-like] and in vivo in MDAMB453 LAR cell line xenografts. Single cell analysis of CDK2 activity demonstrated differences in cell cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell cycle re-entry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity post-mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes.</p> <p>Conclusion: Cell cycle dynamics determine the response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitors, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC.

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Expression and Therapeutic Potential of SOX9 in Chordoma

Purpose: Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma. <br /><br />Experimental Design: <p>SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescence assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound healing assay and a transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell cycle arrest as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by a MTT assay.</p> <br /><br />Results: <p>Tissue microarray (TMA) and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells.</p> <br /><br />Conclusions: <p>Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma.

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Evaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early stage non-small-cell lung cancer using next-generation sequencing

Purpose: <br />To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma (AC) and squamous cell carcinoma (SCC) as a non-invasive method in the early diagnosis of non-small-cell lung cancer (NSCLC). <br /><br />Experimental Design: <br />Tumor-derived exosomes from the plasma of early stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate AC- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.<br /><br />Results: <br />There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in AC and SCC patients, respectively, compared to healthy volunteers. Distinct AC- and SCC-specific  exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24 and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p were AC-specific, and miR-10b-5p, miR-15b-5p and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, AC and SCC, respectively.<br /><br />Conclusions:<br /> <p> Tumor-derived exosomal miRNAs, AC-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p and miR-320b, were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, non-invasive biomarkers for early NSCLC diagnosis.

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The Role of Cold-inducible RNA binding protein (CIRP) in Cell Stress Response

Abstract

Cold-inducible RNA binding protein (CIRP) was discovered after the cells were exposed to a moderate cold shock because its production was induced. Other cellular stresses such as UV radiation and hypoxia also could increase its expression. Under stress conditions, CIRP could up regulate its own expression by self-transcriptional activation of alternative promoters. After relocating into cytoplasm from nucleus, CIRP assists cells in adapting to novel environmental conditions via stabilizing specific mRNAs and facilitating their translation. It not only participates in anti-apoptosis processes under mild hypothermia condition, but also protects cells from ultraviolet radiation and hypoxia induced senescence process. This article focuses on the possible mechanisms of its inducible expression, cytoprotective functions and carcinogenesis. In addition, extracellular CIRP has been shown to be a novel danger-associated molecular patter (DAMP) member and is able to induce inflammatory response. Finally, based on the distinct roles of CIRP in intracellular and extracellular conditions, a possible model of CIRP-mediated cell fate has been proposed. This article is protected by copyright. All rights reserved.

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Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling

Abstract

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies. This article is protected by copyright. All rights reserved.

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Examining the role of attachment styles and self-control in suicide ideation and death anxiety for patients receiving chemotherapy in Iran

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JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin

Abstract

Purpose

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.

Methods

The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species.

Results

We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production.

Conclusions

JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

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JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin

Abstract

Purpose

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.

Methods

The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species.

Results

We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production.

Conclusions

JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

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Low levels of physiological interstitial flow eliminate morphogen gradients and guide angiogenesis

Abstract

Convective transport can significantly distort spatial concentration gradients. Interstitial flow is ubiquitous throughout living tissue, but our understanding of how interstitial flow affects concentration gradients in biological processes is limited. Interstitial flow is of particular interest for angiogenesis because pathological and physiological angiogenesis is associated with altered interstitial flow, and both interstitial flow and morphogen gradients (e.g., vascular endothelial growth factor, VEGF) can potentially stimulate and guide new blood vessel growth. We designed an in vitro microfluidic platform to simulate 3D angiogenesis in a tissue microenvironment that precisely controls interstitial flow and spatial morphogen gradients. The microvascular tissue was developed from endothelial colony forming cell-derived endothelial cells extracted from cord blood and stromal fibroblasts in a fibrin extracellular matrix. Pressure in the microfluidic lines was manipulated to control the interstitial flow. A mathematical model of mass and momentum transport, and experimental studies with fluorescently labeled dextran were performed to validate the platform. Our data demonstrate that at physiological interstitial flow (0.1–10 μm/s), morphogen gradients were eliminated within hours, and angiogenesis demonstrated a striking bias in the opposite direction of interstitial flow. The interstitial flow-directed angiogenesis was dependent on the presence of VEGF, and the effect was mediated by αvβ3 integrin. We conclude that under physiological conditions, growth factors such as VEGF and fluid forces work together to initiate and spatially guide angiogenesis.

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JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin

Abstract

Purpose

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.

Methods

The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species.

Results

We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production.

Conclusions

JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

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Limited nucleotide pools restrict Epstein–Barr virus-mediated B-cell immortalization

Limited nucleotide pools restrict Epstein–Barr virus-mediated B-cell immortalization

Oncogenesis 6, e349 (June 2017). doi:10.1038/oncsis.2017.46

Authors: A Y Hafez, J E Messinger, K McFadden, G Fenyofalvi, C N Shepard, G M Lenzi, B Kim & M A Luftig

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MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells

MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells

Oncogenesis 6, e345 (June 2017). doi:10.1038/oncsis.2017.44

Authors: C Rattanasinchai, B J Llewellyn, S E Conrad & K A Gallo

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The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function

The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function

Oncogenesis 6, e348 (June 2017). doi:10.1038/oncsis.2017.45

Authors: M Mehić, V K de Sa, S Hebestreit, C-H Heldin & P Heldin

http://ift.tt/2rTrgp6

Proline-Rich Homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth

Proline-Rich Homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth

Oncogenesis 6, e346 (June 2017). doi:10.1038/oncsis.2017.42

Authors: R M Kershaw, D Roberts, J Wragg, A M Shaaban, E Humphreys, J Halsall, L Price, R Bicknell, K Gaston & P-S Jayaraman

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TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

Oncogenesis 6, e347 (June 2017). doi:10.1038/oncsis.2017.49

Authors: F Yin, G Sharen, F Yuan, Y Peng, R Chen, X Zhou, H Wei, B Li, W Jing & J Zhao

http://ift.tt/2rTCGJl

Limited nucleotide pools restrict Epstein–Barr virus-mediated B-cell immortalization

Limited nucleotide pools restrict Epstein–Barr virus-mediated B-cell immortalization

Oncogenesis 6, e349 (June 2017). doi:10.1038/oncsis.2017.46

Authors: A Y Hafez, J E Messinger, K McFadden, G Fenyofalvi, C N Shepard, G M Lenzi, B Kim & M A Luftig

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MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells

MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells

Oncogenesis 6, e345 (June 2017). doi:10.1038/oncsis.2017.44

Authors: C Rattanasinchai, B J Llewellyn, S E Conrad & K A Gallo

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The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function

The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function

Oncogenesis 6, e348 (June 2017). doi:10.1038/oncsis.2017.45

Authors: M Mehić, V K de Sa, S Hebestreit, C-H Heldin & P Heldin

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Proline-Rich Homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth

Proline-Rich Homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth

Oncogenesis 6, e346 (June 2017). doi:10.1038/oncsis.2017.42

Authors: R M Kershaw, D Roberts, J Wragg, A M Shaaban, E Humphreys, J Halsall, L Price, R Bicknell, K Gaston & P-S Jayaraman

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TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway

Oncogenesis 6, e347 (June 2017). doi:10.1038/oncsis.2017.49

Authors: F Yin, G Sharen, F Yuan, Y Peng, R Chen, X Zhou, H Wei, B Li, W Jing & J Zhao

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Prognostic value of programmed cell death ligand 1 expression in patients with head and neck cancer: A systematic review and meta-analysis

by Ji Li, Ping Wang, Youliang Xu

Background

Programmed cell death ligand 1 (PD-L1) expression was reported to be correlated with poor prognosis in various cancers. However, the relationship between PD-L1 expression and the survival of patients with head and neck cancer (HNC) remains inconclusive. In the present study, we aimed to clarify the prognostic value of PD-L1 in HNC patients using meta-analysis techniques.

Methods

A comprehensive database searching was conducted in the PubMed, EMBASE, Web of Science and Cochrane Library from inception to August 2016. Studies meeting the inclusion criteria were included. The methodological quality of included studies was assessed by the Newcastle-Ottawa quality assessment scale. Hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were pooled by STATA 11.0 for the outcome of overall survival (OS) and disease-free survival (DFS).

Results

A total of 17 studies with 2,869 HNC patients were included in the meta-analysis. The results of meta-analysis showed that there was no significant correlation between PD-L1 expression and OS (HR, 1.23; 95% CI, 0.99–1.53; P = 0.065) or DFS (HR, 1.42; 95% CI, 1.00–2.03; P = 0.052) of HNC patients. However, the subgroup analysis suggested that positive expression of PD-L1 was associated with poor OS (HR, 1.38; 95% CI, 1.12, 1.70; P = 0.003) and DFS (HR, 1.99; 95% CI, 1.59, 2.48; P = 0.001) in HNC patients from Asian countries/regions. The subgroup analysis also showed that the correlations between PD-L1 and prognosis are variant among different subtypes of HNC. When performing sensitive analyses, we found that the results of meta-analyses were not robust.

Conclusion

The meta-analysis indicated that positive expression of PD-L1 could serve as a good predictor for poor prognosis of Asian patients with HNC. However, the findings still need to be confirmed by large-scale, prospective studies.

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Prognostic value of programmed cell death ligand 1 expression in patients with head and neck cancer: A systematic review and meta-analysis

by Ji Li, Ping Wang, Youliang Xu

Background

Programmed cell death ligand 1 (PD-L1) expression was reported to be correlated with poor prognosis in various cancers. However, the relationship between PD-L1 expression and the survival of patients with head and neck cancer (HNC) remains inconclusive. In the present study, we aimed to clarify the prognostic value of PD-L1 in HNC patients using meta-analysis techniques.

Methods

A comprehensive database searching was conducted in the PubMed, EMBASE, Web of Science and Cochrane Library from inception to August 2016. Studies meeting the inclusion criteria were included. The methodological quality of included studies was assessed by the Newcastle-Ottawa quality assessment scale. Hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were pooled by STATA 11.0 for the outcome of overall survival (OS) and disease-free survival (DFS).

Results

A total of 17 studies with 2,869 HNC patients were included in the meta-analysis. The results of meta-analysis showed that there was no significant correlation between PD-L1 expression and OS (HR, 1.23; 95% CI, 0.99–1.53; P = 0.065) or DFS (HR, 1.42; 95% CI, 1.00–2.03; P = 0.052) of HNC patients. However, the subgroup analysis suggested that positive expression of PD-L1 was associated with poor OS (HR, 1.38; 95% CI, 1.12, 1.70; P = 0.003) and DFS (HR, 1.99; 95% CI, 1.59, 2.48; P = 0.001) in HNC patients from Asian countries/regions. The subgroup analysis also showed that the correlations between PD-L1 and prognosis are variant among different subtypes of HNC. When performing sensitive analyses, we found that the results of meta-analyses were not robust.

Conclusion

The meta-analysis indicated that positive expression of PD-L1 could serve as a good predictor for poor prognosis of Asian patients with HNC. However, the findings still need to be confirmed by large-scale, prospective studies.

http://ift.tt/2rjhXjt

ANGPTL1 attenuates colorectal cancer metastasis by up-regulating microRNA-138

Angiopoietin-like protein 1 (ANGPTL1) has been reported to suppress migration and invasion in lung and breast cancer, acting as a novel tumor suppressor candidate. Nevertheless, its effects on colorectal cance...

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Thymic large cell neuroendocrine carcinoma – a rare and aggressive tumor: a case report

Neuroendocrine tumors are a large group of tumors with a wide spectrum of behavior, affecting mainly the digestive system and the lung. The thymus is very rarely affected.

http://ift.tt/2rjT2fR

Survival of melanoma patients treated with novel drugs: retrospective analysis of real-world data

Abstract

Purpose

Recently, several new drugs have been licensed for advanced melanoma therapy, significantly changing the therapeutic landscape. Ipilimumab and vemurafenib were the first drugs that demonstrated a survival benefit over the long-standing standard therapy with dacarbazine. However, the comparative efficacy of these novel drugs has not been properly assessed yet.

Patients and methods

We conducted a retrospective analysis of all the Polish population treated between January 2012 and October 2016 with one of the following agents: ipilimumab (IPI), vemurafenib (VEM), dabrafenib (DAB), and classic chemotherapy (CTH). The main objective was to assess the overall survival of melanoma patients treated in real-world conditions, taking into account sequences of treatment.

Results

We identified 3397 patients with malignant melanoma treated for the first line and the second line. Patients receiving CTH were significantly older than those treated with the novel drugs. At the same time, the population treated with immunotherapy and targeted therapy was well balanced. Overall survival was significantly better for the novel drugs compared to classic chemotherapy in both lines (for the first line, VEM vs CTH HR = 0.72, 95% CI 0.65–0.81; p < .01, and for the second line, VEM vs CTH HR = 0.78, 95% CI 0.62–0.98; p = .03; IPI vs CTH HR = 0.72, 95% CI 0.62–0.86; p < .01). There was no statistically significant difference for IPI vs VEM; however, subgroup analysis revealed superior results in the case of the CTH–IPI over BRAFi–IPI sequence.

Conclusion

Novel drugs for melanoma provide a significant advantage in survival over classic chemotherapy. Comparative assessment of IPI and VEM indicated no difference, but only immunotherapy-treated patients achieved long-lasting results. Our data on sequential treatment indicate that immunotherapy might be a better option for the first line rather than targeted therapy, but that conclusion requires further studies of the best way to manage the treatment of melanoma patients.

http://ift.tt/2rTjJqp

Survival of melanoma patients treated with novel drugs: retrospective analysis of real-world data

Abstract

Purpose

Recently, several new drugs have been licensed for advanced melanoma therapy, significantly changing the therapeutic landscape. Ipilimumab and vemurafenib were the first drugs that demonstrated a survival benefit over the long-standing standard therapy with dacarbazine. However, the comparative efficacy of these novel drugs has not been properly assessed yet.

Patients and methods

We conducted a retrospective analysis of all the Polish population treated between January 2012 and October 2016 with one of the following agents: ipilimumab (IPI), vemurafenib (VEM), dabrafenib (DAB), and classic chemotherapy (CTH). The main objective was to assess the overall survival of melanoma patients treated in real-world conditions, taking into account sequences of treatment.

Results

We identified 3397 patients with malignant melanoma treated for the first line and the second line. Patients receiving CTH were significantly older than those treated with the novel drugs. At the same time, the population treated with immunotherapy and targeted therapy was well balanced. Overall survival was significantly better for the novel drugs compared to classic chemotherapy in both lines (for the first line, VEM vs CTH HR = 0.72, 95% CI 0.65–0.81; p < .01, and for the second line, VEM vs CTH HR = 0.78, 95% CI 0.62–0.98; p = .03; IPI vs CTH HR = 0.72, 95% CI 0.62–0.86; p < .01). There was no statistically significant difference for IPI vs VEM; however, subgroup analysis revealed superior results in the case of the CTH–IPI over BRAFi–IPI sequence.

Conclusion

Novel drugs for melanoma provide a significant advantage in survival over classic chemotherapy. Comparative assessment of IPI and VEM indicated no difference, but only immunotherapy-treated patients achieved long-lasting results. Our data on sequential treatment indicate that immunotherapy might be a better option for the first line rather than targeted therapy, but that conclusion requires further studies of the best way to manage the treatment of melanoma patients.

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Quality assurance of the PREOPANC trial (2012-003181-40) for preoperative radiochemotherapy in pancreatic cancer

Abstract

Background

The Dutch Pancreatic Cancer Group initiated the national, multicentre, controlled PREOPANC trial, randomising between preoperative radiochemotherapy and direct explorative laparotomy for patients with (borderline) resectable pancreatic cancer. The aim of this dummy run is to evaluate compliance with the radiotherapy protocol of this trial, and the quality of delineation and radiation plans.

Methods

Eleven radiation oncology departments open for accrual of patients in the PREOPANC trial were provided with all necessary information of a selected 'dummy' patient. Each institute was asked to delineate the target volumes, including gross tumour volume, internal gross tumour volume (iGTV), internal clinical target volume, and planning target volume. The institutions were also asked to provide a radiation treatment plan in accordance with the PREOPANC trial protocol.

Results

The range of the iGTV was 19.3–77.2 cm³ with a mean iGTV of 41.5 cm³ (standard deviation 14.8 cm³). Nine institutions made a treatment plan using an arc technique for treatment delivery, one an intensity modulated technique and one a 3-field conformal technique. All institutions reached the prescribed target coverage, without exceeding the organs at risk constraints. The institution with the 3‑field conformal technique was advised to use a more sophisticated technique (e. g. volumetric modulated arc therapy) to reduce the dose to the spinal cord.

Conclusion

All institutions showed acceptable deviations from the PREOPANC trial protocol and achieved an acceptable quality of delineation and radiation technique. All institutions were allowed to continue participation in the PREOPANC trial.

http://ift.tt/2tdvBBt

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

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via IFTTT

Quality assurance of the PREOPANC trial (2012-003181-40) for preoperative radiochemotherapy in pancreatic cancer

Abstract

Background

The Dutch Pancreatic Cancer Group initiated the national, multicentre, controlled PREOPANC trial, randomising between preoperative radiochemotherapy and direct explorative laparotomy for patients with (borderline) resectable pancreatic cancer. The aim of this dummy run is to evaluate compliance with the radiotherapy protocol of this trial, and the quality of delineation and radiation plans.

Methods

Eleven radiation oncology departments open for accrual of patients in the PREOPANC trial were provided with all necessary information of a selected 'dummy' patient. Each institute was asked to delineate the target volumes, including gross tumour volume, internal gross tumour volume (iGTV), internal clinical target volume, and planning target volume. The institutions were also asked to provide a radiation treatment plan in accordance with the PREOPANC trial protocol.

Results

The range of the iGTV was 19.3–77.2 cm³ with a mean iGTV of 41.5 cm³ (standard deviation 14.8 cm³). Nine institutions made a treatment plan using an arc technique for treatment delivery, one an intensity modulated technique and one a 3-field conformal technique. All institutions reached the prescribed target coverage, without exceeding the organs at risk constraints. The institution with the 3‑field conformal technique was advised to use a more sophisticated technique (e. g. volumetric modulated arc therapy) to reduce the dose to the spinal cord.

Conclusion

All institutions showed acceptable deviations from the PREOPANC trial protocol and achieved an acceptable quality of delineation and radiation technique. All institutions were allowed to continue participation in the PREOPANC trial.

http://ift.tt/2tdvBBt

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

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Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC

Abstract

Background

The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear.

Methods

We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials. Severe adverse events (AEs) (grade ≥ 3) based on the ALK-TKI type were analysed.

Results

Seventeen trials published between 2011 and 2016, including a total of 1826 patients, were eligible for analysis. Patients in 10 trials (n = 1000) received crizotinib, patients in 5 trials (n = 601) received ceritinib and patients in 2 trials (n = 225) received alectinib. The overall frequencies of treatment-related death and AEs due to treatment withdrawal were 0.9% (12/1365) and 5.5% (85/1543), respectively. Moreover, the frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib or alectinib, especially for hepatotoxicity, fatigue and some of gastrointestinal symptoms. Additionally, significant difference in the elevated lipase and amylase levels (grade ≥ 3) were detected between ceritinib and crizotinib/alectinib, whereas neutropenia was less frequent.

Conclusions

ALK-TKIs were safe for ALK-positive patients. Moreover, statistically significant differences in some severe AEs among ceritinib, crizotinib and alectinib were detected in present study.

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Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

Abstract

Background

Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors.

Methods

R-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker.

Results

Properdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors.

Conclusions

Properdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.

from Cancer via ola Kala on Inoreader http://ift.tt/2riP9YG
via IFTTT

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

http://ift.tt/2su9QjW

Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC

Abstract

Background

The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been administered to patients with ALK-positive non-small cell lung cancer for a long period of time and show a promising response. However, the differences in the toxicity profiles among these drugs are still unclear.

Methods

We performed a comprehensive search of the MEDLINE, EMBASE, WEB OF SCIENCE and COCHRANE databases from the drugs' inception to May 2016 to identify clinical trials. Severe adverse events (AEs) (grade ≥ 3) based on the ALK-TKI type were analysed.

Results

Seventeen trials published between 2011 and 2016, including a total of 1826 patients, were eligible for analysis. Patients in 10 trials (n = 1000) received crizotinib, patients in 5 trials (n = 601) received ceritinib and patients in 2 trials (n = 225) received alectinib. The overall frequencies of treatment-related death and AEs due to treatment withdrawal were 0.9% (12/1365) and 5.5% (85/1543), respectively. Moreover, the frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib or alectinib, especially for hepatotoxicity, fatigue and some of gastrointestinal symptoms. Additionally, significant difference in the elevated lipase and amylase levels (grade ≥ 3) were detected between ceritinib and crizotinib/alectinib, whereas neutropenia was less frequent.

Conclusions

ALK-TKIs were safe for ALK-positive patients. Moreover, statistically significant differences in some severe AEs among ceritinib, crizotinib and alectinib were detected in present study.

http://ift.tt/2sl5zzP

Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

Abstract

Background

Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors.

Methods

R-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker.

Results

Properdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors.

Conclusions

Properdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.

http://ift.tt/2riP9YG

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

http://ift.tt/2su9QjW

Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

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via IFTTT

MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

Abstract

Background

Increasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.

Methods

The levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.

Results

We found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.

Conclusions

Underexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.

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Erratum to: Effective treatment of intractable cutaneous metastases of breast cancer with electrochemotherapy: a useful contributor to cutaneous disease control

http://ift.tt/2rb71Av

MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

Abstract

Background

Increasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.

Methods

The levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.

Results

We found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.

Conclusions

Underexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.

http://ift.tt/2tdwkm9