Watch-and-Wait as a Therapeutic Strategy in Rectal Cancer

Abstract

Purpose of Review

Pathological complete response is seen in approximately one fifth of rectal cancer patients following neoadjuvant chemoradiation. Since these patients have excellent oncological outcomes, there has been a rapidly growing interest in organ preservation for those who develop a clinical complete response. We review the watch-and-wait strategy and focus on all aspects of this hot topic, including who should be considered for this approach, how should we identify treatment response and what are the expected outcomes.

Recent Findings

The major challenges in interpreting the data on watch-and-wait are the significant heterogeneity of patients selected for this approach and of methods employed to identify them. The evidence available comes mostly from retrospective cohort studies, but has shown good oncological outcomes, including the rate of successful salvage surgery, locoregional control and overall survival.

Summary

There is currently not enough and not robust enough evidence to support watch-and-wait as a standard approach, outside a clinical trial, for patients achieving clinical complete response following neoadjuvant chemoradiation. Furthermore, there is a lack of data on long-term outcomes. However, the results we have so far are promising, and there is therefore an urgent need for randomised control studies such as the TRIGGER trial to confirm the safety of this strategy.

http://ift.tt/2oZrVCW

Update on the Treatment of Anaplastic Large Cell Lymphoma

Abstract

Purpose of Review

Given the rarity of anaplastic large cell lymphoma (ALCL), studies evaluating new therapies have typically grouped ALCL together with other peripheral T cell lymphomas (PTCL). Thus, the treatment paradigm for ALCL largely mirrors that of PTCL in general. In this review, we discuss the current standard of care as well as emerging therapies, including antibody-based drugs, in systemic ALCL as well as primary cutaneous and breast implant-associated ALCL.

Recent Findings

High CD30 expression in ALCL has allowed the use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in both systemic and primary cutaneous ALCL. Recent clinical trials with brentuximab have shown substantial activity in the relapsed/refractory setting. A randomized phase III study is ongoing comparing brentuximab plus CHP (cyclophosphamide, doxorubicin, prednisone) with standard CHOP in the front-line setting.

Summary

The use of targeted therapies and other novel agents have improved outcomes for ALCL patients and in the future can complement or even replace the current standard of care and front-line treatment options.

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Update on the Treatment of Anaplastic Large Cell Lymphoma

Abstract

Purpose of Review

Given the rarity of anaplastic large cell lymphoma (ALCL), studies evaluating new therapies have typically grouped ALCL together with other peripheral T cell lymphomas (PTCL). Thus, the treatment paradigm for ALCL largely mirrors that of PTCL in general. In this review, we discuss the current standard of care as well as emerging therapies, including antibody-based drugs, in systemic ALCL as well as primary cutaneous and breast implant-associated ALCL.

Recent Findings

High CD30 expression in ALCL has allowed the use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in both systemic and primary cutaneous ALCL. Recent clinical trials with brentuximab have shown substantial activity in the relapsed/refractory setting. A randomized phase III study is ongoing comparing brentuximab plus CHP (cyclophosphamide, doxorubicin, prednisone) with standard CHOP in the front-line setting.

Summary

The use of targeted therapies and other novel agents have improved outcomes for ALCL patients and in the future can complement or even replace the current standard of care and front-line treatment options.

http://ift.tt/2G3qKtW

Retrospective analysis on the clinical outcomes of recombinant human soluble thrombomodulin for disseminated intravascular coagulation syndrome associated with solid tumors

Abstract

Background

Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs.

Methods

Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration.

Results

The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS.

Conclusions

rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible.

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Retrospective analysis on the clinical outcomes of recombinant human soluble thrombomodulin for disseminated intravascular coagulation syndrome associated with solid tumors

Abstract

Background

Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs.

Methods

Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration.

Results

The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS.

Conclusions

rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible.

http://ift.tt/2oOC7yD

Nomograms forecasting long-term overall and cancer-specific survival of patients with oral squamous cell carcinoma

Abstract

Our aim was to establish a "nomogram" model to forecast the overall survival (OS) and cancer-specific survival (CSS) of oral squamous cell carcinoma (OSCC) patients. The clinicopathological data for the 10,533 OSCC patients were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used a credible random split-sample method to divide 10,533 patients into two cohorts: 7046 patients in the modeling cohort and 3487 patients in the external validation cohort (split-ratio = 2:1). The median follow-up period was 32 months (1–119 months). We developed nomograms to predict 5- and 8-year OS and CSS of OSCC patients with a Cox proportional hazards model. The precision of the nomograms was assessed by the concordance index (C-index) and calibration curves through internal and external validation. The C-indexes of internal validation regarding 5- and 8-year OS and CSS were 0.762 and 0.783, respectively. In addition, the external validation's C-indexes were 0.772 and 0.800. Based on a large-sample analysis targeting the SEER database, we established two nomograms to predict long-term OS and CSS for OSCC patients successfully, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.

We successfully established two nomograms predicting overall survival(OS) and cancer-specific survival(CSS) of OSCC patients collected from SEER database. The validation results of the nomograms through the concordance index (C-index) and calibration curves showed that the model were credible, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.

http://ift.tt/2D7aGV3

Nomograms forecasting long-term overall and cancer-specific survival of patients with oral squamous cell carcinoma

Abstract

Our aim was to establish a "nomogram" model to forecast the overall survival (OS) and cancer-specific survival (CSS) of oral squamous cell carcinoma (OSCC) patients. The clinicopathological data for the 10,533 OSCC patients were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used a credible random split-sample method to divide 10,533 patients into two cohorts: 7046 patients in the modeling cohort and 3487 patients in the external validation cohort (split-ratio = 2:1). The median follow-up period was 32 months (1–119 months). We developed nomograms to predict 5- and 8-year OS and CSS of OSCC patients with a Cox proportional hazards model. The precision of the nomograms was assessed by the concordance index (C-index) and calibration curves through internal and external validation. The C-indexes of internal validation regarding 5- and 8-year OS and CSS were 0.762 and 0.783, respectively. In addition, the external validation's C-indexes were 0.772 and 0.800. Based on a large-sample analysis targeting the SEER database, we established two nomograms to predict long-term OS and CSS for OSCC patients successfully, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.

We successfully established two nomograms predicting overall survival(OS) and cancer-specific survival(CSS) of OSCC patients collected from SEER database. The validation results of the nomograms through the concordance index (C-index) and calibration curves showed that the model were credible, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.

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PAK4 pathway as a potential therapeutic target in pancreatic cancer

Future Oncology, Ahead of Print.


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Background and rationale of the eXalt3 trial investigating X-396 in the treatment of ALK+ non-small-cell lung cancer

Future Oncology, Ahead of Print.


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PAK4 pathway as a potential therapeutic target in pancreatic cancer

Future Oncology, Ahead of Print.


http://ift.tt/2D5Frd3

Background and rationale of the eXalt3 trial investigating X-396 in the treatment of ALK+ non-small-cell lung cancer

Future Oncology, Ahead of Print.


http://ift.tt/2FYvCR7

Safety and Efficacy of Autologous Tissue-derived Mesenchymal Stem Cells for Radiation-Induced Xerostomia: A Randomized, Placebo-Controlled Phase I/II Trial (MESRIX)

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Christian Grønhøj, David H. Jensen, Peter Vester-Glowinski, Siri Beier Jensen, Allan Bardow, Roberto S. Oliveri, Lea Munthe Fog, Lena Specht, Carsten Thomsen, Sune Darkner, Michael Jensen, Vera Müller, Katalin Kiss, Tina Agander, Elo Andersen, Anne Fischer-Nielsen, Christian von Buchwald
BackgroundSalivary gland hypofunction and xerostomia are major complications to head and neck radiotherapy. This trial assessed the safety and efficacy of adipose tissue-derived mesenchymal stem cell (ASC) therapy for radiation-induced xerostomia.Patient and MethodsThis randomized, placebo-controlled phase I/II trial included 30 patients, randomized in a 1:1 ratio to receive ultrasound-guided transplantation of ASCs or placebo to the submandibular glands. Patients had previously received radiotherapy for a T1-2, N0-2A, human papillomavirus-positive, oropharyngeal squamous cell carcinoma. The primary outcome was the change in unstimulated whole salivary flow rate, measured before and after the intervention. All assessments were performed one month prior (baseline) and one and four months following ASC or placebo administration.ResultsNo adverse events were detected. Unstimulated whole salivary flow rates significantly increased in the ASC-arm at one (33%; p=0.048) and four months (50%; p=0.003), but not in the placebo-arm (p=0.6 and p=0.8), compared to baseline. The ASC-arm symptom scores significantly decreased on the xerostomia and VAS questionnaires, in the domains of thirst (-22%, p=0.035) and difficulties in eating solid foods (-2%, p=0.008) after four months compared to baseline. The ASC-arm showed significantly improved salivary gland functions of inorganic element secretion and absorption, at baseline and four months, compared to the placebo-arm. Core-needle biopsies showed increases in serous gland tissue and decreases in adipose and connective tissues in the ASC-arm compared to the placebo-arm (p=0.04 and p=0.02, respectively). MRIs showed no significant differences between groups in gland size or intensity (p < 0.05).ConclusionsASC therapy for radiation-induced hypofunction and xerostomia was safe and significantly improved salivary gland functions and patient-reported outcomes. These results should encourage further exploratory and confirmatory trials.



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The Biology of SBRT: LQ or Something New?

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): J Martin Brown




http://ift.tt/2D6e6Hy

The Resident Individual Development Plan as a Guide for Radiation Oncology Mentorship

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Huaising C. Ko, Randall J. Kimple




http://ift.tt/2FkQ3qn

Total Mesorectal Excision versus Local Excision Following Preoperative Chemoradiotherapy in Rectal Cancer with Lymph Node Metastasis: A Propensity Score-Matched Analysis

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Young Seob Shin, Jin-hong Park, Sang Min Yoon, Jin Cheon Kim, Chang Sik Yu, Seok-Byung Lim, In Ja Park, Tae Won Kim, Yong Sang Hong, Kyu-pyo Kim, Eun Kyung Choi, Seung Do Ahn, Sang-Wook Lee, Jong Hoon Kim
BackgroundLocal excision (LE) in good responders to preoperative chemoradiotherapy (PCRT), which is considered as a good alternative to total mesorectal excision (TME) in early-stage rectal cancer, is not commonly recommended for node-positive (cN+) cases. This study aimed to determine whether LE outcomes were comparable to TME outcomes in cN+ rectal cancer patients who were good responders.Materials and MethodsThis retrospective study included clinical T2-3 and cN+ low rectal cancer patient who received PCRT followed by TME or LE. Clinical stage T1 or T4 tumors, upper-to-middle rectal tumors (>7 cm from anal verge), and synchronous distant metastases were excluded. Lymph nodes ≥5 mm in size were defined as tumor-positive, and patients with metastatic lymph nodes >20 mm in size were excluded. Preoperative chemoradiotherapy comprised radiation (50–50.4 Gy/25–28 fractions over 5 weeks) with two cycles of 5-fluorouracil or oral capecitabine. Propensity scores were computed from tumor and patient variables and used for one-to-one matched analysis. Local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were compared between the two matched groups.ResultsBetween January 2007 and December 2013, 563 and 55 patients underwent TME and LE, respectively. Median follow-up period was 54 months. In propensity score-matched analysis, 48 patients were included in each group. No statistical differences were observed in 3-year LRFS (97.9% vs. 97.9%, p = 0.994), 3-year DFS (91.5% vs. 91.4%, p = 0.968), or 3-year OS (93.7% vs. 97.9%, p = 0.809) between TME and LE groups.ConclusionsIn clinical N+ rectal cancer patients, oncological outcomes of PCRT followed by LE were comparable to those of TME; this finding might be applicable only to those patients with good response in the primary tumor and small lymph node metastases.



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Contemporary statewide practice pattern assessment of the palliative treatment of bone metastasis

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daniel E. Spratt, Brandon Mancini, James A. Hayman, Thomas Boike, Lori Pierce, Jean M. Moran, Michael M. Dominello, Mark Fireman, Kent Griffith, Shruti Jolly
PurposePalliative radiotherapy for bone metastases is often viewed as a single entity, despite national guidelines providing input principally only for painful uncomplicated bone metastases. Data surrounding the treatment of bone metastases is often gleaned from questionnaires of what providers would theoretically do in practice or population-based data lacking critical granular information. Herein, we investigate the real-world treatment of bone metastases with radiotherapy.Methods and MaterialsTwenty diverse institutions across the state of XXXXX had data extracted on their 10 most recent cases of radiotherapy delivered for the treatment of bone metastases at their institution between January and February of 2017. Uni- and multivariable binary logistic regression was used to assess use of single fraction (8 Gy x 1) radiotherapy.ResultsA total of 196 cases were eligible for inclusion. Twenty-eight different fractionation schedules were identified. The most common schedule was 3 Gy x 10 fractions (n=100, 51.0%), 4 Gy x 5 fractions (n=32, 16.3%), and 8 Gy x 1 (n=15, 7.7%). Significant predictors for use of single fraction radiotherapy were presence of oligometastatic disease (p=0.008), prior overlapping radiotherapy (p=0.050), and academic practice type (p=0.039). Twenty-nine cases (14.8%) received >10 fractions (median 15, range 11-20 fractions). Intensity modulated radiotherapy was used in 14 cases (7.1%), stereotactic body radiotherapy in 11 cases (5.6%), and image guidance with cone beam CT in 11 cases (5.6%). Amongst simple painful bone metastases (no prior surgery, cord compression, fracture, soft tissue extension, or overlapping prior radiotherapy; n=70), only 12.9% were treated with 8 Gy x 1.ConclusionsBone metastases represent a heterogeneous disease, and the radiotherapeutic treatment of bone metastases is similarly diverse. Future work is needed to understand barrier to single fraction use, and clinical trials are necessary to establish appropriate guidelines for the breadth of this complex disease.



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Scholarly Impact of Student Participation in Radiation Oncology Research

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M. Paracha, K.N. Kim, M.M. Qureshi, A. Shah, A. Agarwal, T. Sachs, S. Sarfaty, A.E. Hirsch
IntroductionLiterature evaluating student authorship has used the H-index (Hi), a measure of scholarly impact. However, student authorship over time is less well defined. In this study, we evaluated the rate of non-doctoral student authors publishing in an academic journal over time. Additionally, we analyzed the effects student authors have on the scholarly impact of corresponding authors (CA) by comparing their respective Hi.MethodsWe created a database of authors that published articles in the International Journal of Radiation Oncology Biology Physics (IJROBP) in 2006, 2010, and 2014 that included CA, degree and student author designations. CAs' Hi were obtained from Scopus (scopus.com). Student authorship rates were compared between the sampled years. The data was divided into two groups, CA publishing with student authors (SA) and those without (nSA). CAs' median and mean Hi with standard deviation (sd) and a 95% confidence interval (CI) were compared between SA and nSA.ResultsA total of 1,728 published articles were identified with 1,477 unique CA. Percentage of published articles with student authors increased from 44.4% in 2006, 52.9% in 2010 to 55.9% in 2014, p=0.0003. In overall analysis, mean Hi was higher for SA as compared to nSA (24.3 vs. 22.9), although this did not achieve statistical significance (p=0.094). Mean Hi (sd) in 2006, 2010 and 2014 were 27.9 (16.6), 23.6 (16.7) and 18.5 (14.6), respectively. Mean Hi was significantly higher for SA compared to nSA in years 2006 (29.5 vs. 26.6, p=0.048) and 2010 (24.9 vs. 21.9, p=0.038) but not in 2014 (18.5 vs. 18.4, p=0.963).ConclusionStudent authorship rates in IJROBP are increasing. The data suggest that student participation in research may benefit both corresponding and student authors. Creating and expanding research programs to integrate research into medical education may enhance students' experience and encourage interest in radiation oncology.

Teaser

Student authorship rates over time are ill defined. This is an analysis of the effects of student authorship on scholarly impact in radiation oncology by comparing the H-indices of corresponding authors in IJROBP that published with and without student authors in 2006-2014. Students are not a detriment to scholarly productivity; student authorship rates increased and corresponding authors publishing with student authors had higher H-indices compared to those that did not publish with student authors.


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Safety and Efficacy of Autologous Tissue-derived Mesenchymal Stem Cells for Radiation-Induced Xerostomia: A Randomized, Placebo-Controlled Phase I/II Trial (MESRIX)

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Christian Grønhøj, David H. Jensen, Peter Vester-Glowinski, Siri Beier Jensen, Allan Bardow, Roberto S. Oliveri, Lea Munthe Fog, Lena Specht, Carsten Thomsen, Sune Darkner, Michael Jensen, Vera Müller, Katalin Kiss, Tina Agander, Elo Andersen, Anne Fischer-Nielsen, Christian von Buchwald
BackgroundSalivary gland hypofunction and xerostomia are major complications to head and neck radiotherapy. This trial assessed the safety and efficacy of adipose tissue-derived mesenchymal stem cell (ASC) therapy for radiation-induced xerostomia.Patient and MethodsThis randomized, placebo-controlled phase I/II trial included 30 patients, randomized in a 1:1 ratio to receive ultrasound-guided transplantation of ASCs or placebo to the submandibular glands. Patients had previously received radiotherapy for a T1-2, N0-2A, human papillomavirus-positive, oropharyngeal squamous cell carcinoma. The primary outcome was the change in unstimulated whole salivary flow rate, measured before and after the intervention. All assessments were performed one month prior (baseline) and one and four months following ASC or placebo administration.ResultsNo adverse events were detected. Unstimulated whole salivary flow rates significantly increased in the ASC-arm at one (33%; p=0.048) and four months (50%; p=0.003), but not in the placebo-arm (p=0.6 and p=0.8), compared to baseline. The ASC-arm symptom scores significantly decreased on the xerostomia and VAS questionnaires, in the domains of thirst (-22%, p=0.035) and difficulties in eating solid foods (-2%, p=0.008) after four months compared to baseline. The ASC-arm showed significantly improved salivary gland functions of inorganic element secretion and absorption, at baseline and four months, compared to the placebo-arm. Core-needle biopsies showed increases in serous gland tissue and decreases in adipose and connective tissues in the ASC-arm compared to the placebo-arm (p=0.04 and p=0.02, respectively). MRIs showed no significant differences between groups in gland size or intensity (p < 0.05).ConclusionsASC therapy for radiation-induced hypofunction and xerostomia was safe and significantly improved salivary gland functions and patient-reported outcomes. These results should encourage further exploratory and confirmatory trials.



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The Biology of SBRT: LQ or Something New?

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): J Martin Brown




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A method for automatic selection of parameters in NTCP modelling

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Damianos Christophides, Ane L. Appelt, Arief Gusnanto, John Lilley, David Sebag-Montefiore
PurposeIn this study we present a fully automatic method to generate multiparameter normal tissue complication probability (NTCP) models and compare its results with a published model of the same patient cohort.Methods and MaterialsData were analysed from 345 rectal cancer patients treated with external radiotherapy to predict the risk of patients developing grade 1 or ≥2 cystitis. In total 23 clinical factors were included in the analysis as candidate predictors of cystitis.Principal component analysis (PCA) was used to decompose the bladder dose volume histogram (DVHs) into 8 principal components (PCs), explaining more than 95% of the variance. The dataset of clinical factors and PCs was divided into training (70%) and test (30%) datasets, with the training dataset used by the algorithm to compute an NTCP model. The first step of the algorithm was to obtain a bootstrap sample, followed by multicollinearity reduction using the variance inflation factor (VIF) and genetic algorithm optimisation to determine an ordinal logistic regression model that minimises the Bayesian information criterion (BIC). The process was repeated 100 times and the model with the minimum BIC was recorded on each iteration. The most frequent model was selected as the final 'automatically generated model' (AGM). The published model and AGM were fitted on the training datasets and the risk of cystitis was calculated.ResultsThe two models had no significant differences in predictive performance both for the training and test datasets (p-value>0.05), and found similar clinical and dosimetric factors as predictors. Both models exhibited good explanatory performance on the training dataset (p-values>0.44) which was reduced on the test datasets (p-values<0.05).ConclusionsThe predictive value of the AGM is equivalent to the expert-derived published model. It demonstrates potential in saving time, tackling problems with a large number of parameters and standardising variable selection in NTCP modelling.



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The Resident Individual Development Plan as a Guide for Radiation Oncology Mentorship

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Huaising C. Ko, Randall J. Kimple




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Total Mesorectal Excision versus Local Excision Following Preoperative Chemoradiotherapy in Rectal Cancer with Lymph Node Metastasis: A Propensity Score-Matched Analysis

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Young Seob Shin, Jin-hong Park, Sang Min Yoon, Jin Cheon Kim, Chang Sik Yu, Seok-Byung Lim, In Ja Park, Tae Won Kim, Yong Sang Hong, Kyu-pyo Kim, Eun Kyung Choi, Seung Do Ahn, Sang-Wook Lee, Jong Hoon Kim
BackgroundLocal excision (LE) in good responders to preoperative chemoradiotherapy (PCRT), which is considered as a good alternative to total mesorectal excision (TME) in early-stage rectal cancer, is not commonly recommended for node-positive (cN+) cases. This study aimed to determine whether LE outcomes were comparable to TME outcomes in cN+ rectal cancer patients who were good responders.Materials and MethodsThis retrospective study included clinical T2-3 and cN+ low rectal cancer patient who received PCRT followed by TME or LE. Clinical stage T1 or T4 tumors, upper-to-middle rectal tumors (>7 cm from anal verge), and synchronous distant metastases were excluded. Lymph nodes ≥5 mm in size were defined as tumor-positive, and patients with metastatic lymph nodes >20 mm in size were excluded. Preoperative chemoradiotherapy comprised radiation (50–50.4 Gy/25–28 fractions over 5 weeks) with two cycles of 5-fluorouracil or oral capecitabine. Propensity scores were computed from tumor and patient variables and used for one-to-one matched analysis. Local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were compared between the two matched groups.ResultsBetween January 2007 and December 2013, 563 and 55 patients underwent TME and LE, respectively. Median follow-up period was 54 months. In propensity score-matched analysis, 48 patients were included in each group. No statistical differences were observed in 3-year LRFS (97.9% vs. 97.9%, p = 0.994), 3-year DFS (91.5% vs. 91.4%, p = 0.968), or 3-year OS (93.7% vs. 97.9%, p = 0.809) between TME and LE groups.ConclusionsIn clinical N+ rectal cancer patients, oncological outcomes of PCRT followed by LE were comparable to those of TME; this finding might be applicable only to those patients with good response in the primary tumor and small lymph node metastases.



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Contemporary statewide practice pattern assessment of the palliative treatment of bone metastasis

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daniel E. Spratt, Brandon Mancini, James A. Hayman, Thomas Boike, Lori Pierce, Jean M. Moran, Michael M. Dominello, Mark Fireman, Kent Griffith, Shruti Jolly
PurposePalliative radiotherapy for bone metastases is often viewed as a single entity, despite national guidelines providing input principally only for painful uncomplicated bone metastases. Data surrounding the treatment of bone metastases is often gleaned from questionnaires of what providers would theoretically do in practice or population-based data lacking critical granular information. Herein, we investigate the real-world treatment of bone metastases with radiotherapy.Methods and MaterialsTwenty diverse institutions across the state of XXXXX had data extracted on their 10 most recent cases of radiotherapy delivered for the treatment of bone metastases at their institution between January and February of 2017. Uni- and multivariable binary logistic regression was used to assess use of single fraction (8 Gy x 1) radiotherapy.ResultsA total of 196 cases were eligible for inclusion. Twenty-eight different fractionation schedules were identified. The most common schedule was 3 Gy x 10 fractions (n=100, 51.0%), 4 Gy x 5 fractions (n=32, 16.3%), and 8 Gy x 1 (n=15, 7.7%). Significant predictors for use of single fraction radiotherapy were presence of oligometastatic disease (p=0.008), prior overlapping radiotherapy (p=0.050), and academic practice type (p=0.039). Twenty-nine cases (14.8%) received >10 fractions (median 15, range 11-20 fractions). Intensity modulated radiotherapy was used in 14 cases (7.1%), stereotactic body radiotherapy in 11 cases (5.6%), and image guidance with cone beam CT in 11 cases (5.6%). Amongst simple painful bone metastases (no prior surgery, cord compression, fracture, soft tissue extension, or overlapping prior radiotherapy; n=70), only 12.9% were treated with 8 Gy x 1.ConclusionsBone metastases represent a heterogeneous disease, and the radiotherapeutic treatment of bone metastases is similarly diverse. Future work is needed to understand barrier to single fraction use, and clinical trials are necessary to establish appropriate guidelines for the breadth of this complex disease.



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Scholarly Impact of Student Participation in Radiation Oncology Research

Publication date: Available online 6 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M. Paracha, K.N. Kim, M.M. Qureshi, A. Shah, A. Agarwal, T. Sachs, S. Sarfaty, A.E. Hirsch
IntroductionLiterature evaluating student authorship has used the H-index (Hi), a measure of scholarly impact. However, student authorship over time is less well defined. In this study, we evaluated the rate of non-doctoral student authors publishing in an academic journal over time. Additionally, we analyzed the effects student authors have on the scholarly impact of corresponding authors (CA) by comparing their respective Hi.MethodsWe created a database of authors that published articles in the International Journal of Radiation Oncology Biology Physics (IJROBP) in 2006, 2010, and 2014 that included CA, degree and student author designations. CAs' Hi were obtained from Scopus (scopus.com). Student authorship rates were compared between the sampled years. The data was divided into two groups, CA publishing with student authors (SA) and those without (nSA). CAs' median and mean Hi with standard deviation (sd) and a 95% confidence interval (CI) were compared between SA and nSA.ResultsA total of 1,728 published articles were identified with 1,477 unique CA. Percentage of published articles with student authors increased from 44.4% in 2006, 52.9% in 2010 to 55.9% in 2014, p=0.0003. In overall analysis, mean Hi was higher for SA as compared to nSA (24.3 vs. 22.9), although this did not achieve statistical significance (p=0.094). Mean Hi (sd) in 2006, 2010 and 2014 were 27.9 (16.6), 23.6 (16.7) and 18.5 (14.6), respectively. Mean Hi was significantly higher for SA compared to nSA in years 2006 (29.5 vs. 26.6, p=0.048) and 2010 (24.9 vs. 21.9, p=0.038) but not in 2014 (18.5 vs. 18.4, p=0.963).ConclusionStudent authorship rates in IJROBP are increasing. The data suggest that student participation in research may benefit both corresponding and student authors. Creating and expanding research programs to integrate research into medical education may enhance students' experience and encourage interest in radiation oncology.

Teaser

Student authorship rates over time are ill defined. This is an analysis of the effects of student authorship on scholarly impact in radiation oncology by comparing the H-indices of corresponding authors in IJROBP that published with and without student authors in 2006-2014. Students are not a detriment to scholarly productivity; student authorship rates increased and corresponding authors publishing with student authors had higher H-indices compared to those that did not publish with student authors.


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Effect of perioperative opioids on cancer-relevant circulating parameters: mu opioid receptor and TLR4 activation potential, and proteolytic profile

Purpose: To investigate the potential interplay between opioid analgesia and tumour metastasis through modulation of μ opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement pre-operatively and at 3, 6 and 24 h after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen^TM cyclic AMP (cAMP) assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue™ hTLR4 were utilised to measure TLR4 activation. Circulating matrix metalloprotease (MMP) and Tissue Inhibitor of Matrix Protease (TIMP) activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Post-operative plasma samples displayed the ability to activate MOR and to inhibit LPS-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was neither correlated to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point.

http://ift.tt/2FhcOQ1

Telatinib is an effective targeted therapy for pseudomyogenic hemangioendothelioma

Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1-FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1-FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib. Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells. Results: Truncated FOSB significantly affected tumor growth in 3D on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (4-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1 and FLT4 signaling and down-regulated SERPINE1, thereby affecting the self-regulation of the fusion gene. Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor, could be a highly specific treatment option for patients with multifocal unresectable PHE.

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Toxicity and efficacy of a novel GADD34-expressing oncolytic HSV-1 for the treatment of experimental glioblastoma.

Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives. Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in non-dividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neuro-toxicity evaluation of NG34 was tested by intracerebral inoculation. Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose-response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared to rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model. Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM.

http://ift.tt/2Fh9DI8

Tissue transglutaminase regulates interactions between ovarian cancer stem cells and the tumor niche

Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin β1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/β-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.

http://ift.tt/2FkYJNj

Extracellular citrate affects critical elements of cancer cell metabolism and supports cancer development in vivo

Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.

http://ift.tt/2FiGvjR

Tight junction protein claudin-2 promotes self-renewal of human colorectal cancer stem-like cells

Post-treatment recurrence of colorectal cancer (CRC), the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSCs). The tight junction (TJ) protein claudin-2 is overexpressed in human CRC where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-FU-based chemotherapy, an outcome in which CSC play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted CRC self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSC and increased their proportion in CRC cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSC towards the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine microRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within CRC stem-like cells, suggesting a potential role for this protein as a therapeutic target in CRC.

http://ift.tt/2D5rV9l

Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program

CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two-thirds of ErbB2+ and triple-negative breast cancers and in one-third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and triple-negative breast cancer cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or down-regulated by CHIP. We characterized Myeloid Zinc Finger 1 (MZF1) as a CHIP target given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression.

http://ift.tt/2Fh9ggG

Effect of perioperative opioids on cancer-relevant circulating parameters: mu opioid receptor and TLR4 activation potential, and proteolytic profile

Purpose: To investigate the potential interplay between opioid analgesia and tumour metastasis through modulation of μ opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement pre-operatively and at 3, 6 and 24 h after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen^TM cyclic AMP (cAMP) assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue™ hTLR4 were utilised to measure TLR4 activation. Circulating matrix metalloprotease (MMP) and Tissue Inhibitor of Matrix Protease (TIMP) activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Post-operative plasma samples displayed the ability to activate MOR and to inhibit LPS-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was neither correlated to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point.

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Telatinib is an effective targeted therapy for pseudomyogenic hemangioendothelioma

Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1-FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1-FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib. Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells. Results: Truncated FOSB significantly affected tumor growth in 3D on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (4-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1 and FLT4 signaling and down-regulated SERPINE1, thereby affecting the self-regulation of the fusion gene. Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor, could be a highly specific treatment option for patients with multifocal unresectable PHE.

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Toxicity and efficacy of a novel GADD34-expressing oncolytic HSV-1 for the treatment of experimental glioblastoma.

Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives. Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in non-dividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neuro-toxicity evaluation of NG34 was tested by intracerebral inoculation. Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose-response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared to rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model. Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM.

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Tissue transglutaminase regulates interactions between ovarian cancer stem cells and the tumor niche

Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin β1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/β-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.

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Extracellular citrate affects critical elements of cancer cell metabolism and supports cancer development in vivo

Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.

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Tight junction protein claudin-2 promotes self-renewal of human colorectal cancer stem-like cells

Post-treatment recurrence of colorectal cancer (CRC), the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSCs). The tight junction (TJ) protein claudin-2 is overexpressed in human CRC where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-FU-based chemotherapy, an outcome in which CSC play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted CRC self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSC and increased their proportion in CRC cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSC towards the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine microRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within CRC stem-like cells, suggesting a potential role for this protein as a therapeutic target in CRC.

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Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program

CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two-thirds of ErbB2+ and triple-negative breast cancers and in one-third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and triple-negative breast cancer cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or down-regulated by CHIP. We characterized Myeloid Zinc Finger 1 (MZF1) as a CHIP target given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression.

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Kite, Sangamo Partner on Gene-Edited Cell Therapies [News in Brief]

Firms will use zinc finger nuclease technology to make autologous and allogeneic CAR T-cell and other cellular treatments.

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Cross-cohort analysis identifies a TEAD4 {leftrightarrow} MYCN positive-feedback loop as the core regulatory element of high-risk neuroblastoma [Research Articles]

High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10 protein transcriptional module - centered around a TEAD4 MYCN positive-feedback loop - emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.

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Genetic mechanisms of immune evasion in colorectal cancer [Research Articles]

To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration, and furthermore, that CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.

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High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression

Publication date: Available online 6 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Riccardo Sgarra, Silvia Pegoraro, Gloria Ros, Carlotta Penzo, Eusebio Chiefari, Daniela Foti, Antonio Brunetti, Guidalberto Manfioletti
Cancer heterogeneity is one of the factors that constitute an obstacle towards an efficient targeting of this multifaceted disease. Molecular information can help in classifying cancer subtypes and in providing clinicians with novel targeted therapeutic opportunities. In this regard, classification of breast cancer into intrinsic subtypes based on molecular profiling represents a valuable prototype.The High Mobility Group A (HMGA) chromatin architectural factors (HMGA1a, HMGA1b, and HMGA2) have a relevant and causal role in breast cancer onset and development, by influencing virtually all cancer hallmarks. The regulation of HMGA expression is under the control of major pathways involved in cell proliferation and survival, as well as in other cancer-related processes, thereby suggesting, for the HMGA members, a high degree of homology and overlapping activities. Despite of this evidence, HMGA proteins display also specific functions.In this review, we provide an overview of (i) the pathways involved in HMGA transcriptional and post-transcriptional regulation, (ii) the utilization of HMGA as molecular markers, and (iii) the biological role of HMGA in the context of breast cancer. We focus on the potential significance of HMGA in governing the onset and development of this tumour, as well as on the potential of these factors as novel specific targets for preventing and treating strategies. The emerging picture is a highly interconnected triad of proteins that could mutually influence each other, either in a competitive or cooperative manner, and that, in our opinion, should be considered as a unified and integrated protein system.



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Pharmacokinetics of intravenous mycophenolate mofetil in allogeneic hematopoietic stem cell-transplanted Japanese patients

Abstract

Purpose

Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation.

Methods

Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow-transplanted patients, and every 12 h in cord blood-transplanted patients. MMF was administered orally at the same dose from day 11. Plasma concentrations of mycophenolic acid (MPA) were measured by high-performance liquid chromatography.

Results

The MPA AUC_{0 − tau} was 31.9 ± 3.4, 26.2 ± 2.4, and 21.0 ± 2.2 µg*h/mL, the mean C_trough was 0.25, 0.35, and 0.37 µg/mL, and the C_max was 10.8, 9.2, and 5.5 µg/mL on days 2, 9, and 16, respectively. The AUC_{0 − tau} and C_max were significantly higher after intravenous MMF dosing than after oral MMF dosing. All patients exhibited successful neutrophil engraftments in a median time of 18 days. Grade II acute graft-versus-host disease (GvHD) of the skin was observed in two patients, and one patient developed limited chronic GvHD. Individual cases of transient and curable grade III oral mucositis and diarrhea were observed; however, MMF was not discontinued. No other severe complications or infections were observed.

Conclusions

Intravenously administered MMF was safe and possibly effective in achieving higher MPA plasma concentrations for GvHD prophylaxis after allo-SCT in Japanese patients.

http://ift.tt/2Fl8boc

Pharmacokinetics of intravenous mycophenolate mofetil in allogeneic hematopoietic stem cell-transplanted Japanese patients

Abstract

Purpose

Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation.

Methods

Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow-transplanted patients, and every 12 h in cord blood-transplanted patients. MMF was administered orally at the same dose from day 11. Plasma concentrations of mycophenolic acid (MPA) were measured by high-performance liquid chromatography.

Results

The MPA AUC_{0 − tau} was 31.9 ± 3.4, 26.2 ± 2.4, and 21.0 ± 2.2 µg*h/mL, the mean C_trough was 0.25, 0.35, and 0.37 µg/mL, and the C_max was 10.8, 9.2, and 5.5 µg/mL on days 2, 9, and 16, respectively. The AUC_{0 − tau} and C_max were significantly higher after intravenous MMF dosing than after oral MMF dosing. All patients exhibited successful neutrophil engraftments in a median time of 18 days. Grade II acute graft-versus-host disease (GvHD) of the skin was observed in two patients, and one patient developed limited chronic GvHD. Individual cases of transient and curable grade III oral mucositis and diarrhea were observed; however, MMF was not discontinued. No other severe complications or infections were observed.

Conclusions

Intravenously administered MMF was safe and possibly effective in achieving higher MPA plasma concentrations for GvHD prophylaxis after allo-SCT in Japanese patients.

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PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC, Published online: 06 March 2018; doi:10.1038/bjc.2018.9

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition, Published online: 06 March 2018; doi:10.1038/bjc.2018.11

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

http://ift.tt/2Fj8yzL

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC, Published online: 06 March 2018; doi:10.1038/bjc.2018.9

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition, Published online: 06 March 2018; doi:10.1038/bjc.2018.11

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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An atlas to aid delineation of para-aortic lymph node region in cervical cancer: Design and validation of contouring guidelines

Previous studies have investigated the anatomical distribution of para-aortic lymph nodes (PAN) in patients with cervical cancer. However, an atlas for accurate clinical target volume (CTV) delineation has yet to be defined. The purpose of this study was to design and verify a computerized tomography (CT) atlas to provide guidance for contouring the PAN CTV in patients with cervical cancer.

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Applying Lean-Six-Sigma Methodology in radiotherapy: Lessons learned by the breast daily repositioning case

Lean Six Sigma Methodology (LSSM) was introduced in industry to provide near-perfect services to large processes, by reducing improbable occurrence. LSSM has been applied to redesign the 2D-2D breast repositioning process (Lean) by the retrospective analysis of the database (Six Sigma).

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DAHANCA 10 – Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group

To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC).

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

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PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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Testing an Interactive Approach to Promote Exercise in Young Cancer Survivors

An interactive website designed to promote physical activity among children and adolescents who have completed treatment for cancer may indeed help encourage them to get regular exercise, according to preliminary results from a pilot study.

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Testing an Interactive Approach to Promote Exercise in Young Cancer Survivors

An interactive website designed to promote physical activity among children and adolescents who have completed treatment for cancer may indeed help encourage them to get regular exercise, according to preliminary results from a pilot study.

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Management of thin melanoma

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Relapse in dermatofibrosarcoma protuberans: A histological and molecular analysis

Background

Dermatofibrosarcoma protuberans (DFSP) is a rare low grade tumor with a locally aggressive behavior and low metastatic potential.

Objectives

To evaluate the factors that are associated with relapse in DFSP.

Methods Retrospective analysis of medical records from 61 patients with dermatofibrosarcoma. Fluorescence in situ hybridization was used to detect translocations.

Results

Of 61 patients, 6 experienced a relapse. No patient with resection margins greater than 3 cm had a recurrence. One relapse was observed in a patient treated with at least 2 cm margins and 4 relapses occurred in 16 patients whose margins were below 2 cm (P = 0.018). The frequency of translocations was 77.8%. The recurrence rate was lower in patients with translocation, but this difference was not significant. Immunohistochemical markers did not correlate with recurrence rates, but greater FasL expression was associated with recurrence in patients with margins smaller than 3 cm.

Conclusions

Surgical margins smaller than than 2 cm are related to higher recurrences in dermatofibrosarcomas. In this analysis a 2 cm margin was acceptable for treatment. Between all the immunohistochemical markers analyzed, only FasL was associated with a higher recurrence rate in patients with margins smaller than 3 cm.

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Role of staging laparoscopy in the management of Pancreatic Duct Carcinoma (PDAC): Single-center experience from a tertiary hospital in Brazil

Background

Proper staging is critical to the management of pancreatic ductal carcinoma (PDAC). Laparoscopy has been used to stage patients without gross metastatic disease with variable success.

Objectives

We aimed to identify the frequency of patients diagnosed by laparoscopy with occult metastatic disease. Also, we looked for variables related to a higher chance of occult metastasis.

Methods

Patients with PDAC submitted to staging laparoscopy either immediately before pancreatectomy or as a separate procedure between January 2010 and December 2016 were included. None presented gross metastatic disease at initial staging. We used logistic regression to search for variables associated with metastatic disease.

Results

The study population consisted of 63 patients. Among all patients, nine (16.7%) had occult metastases at laparoscopy. Unresectable tumor (Odds ratio = 18.0, P = 0.03), increasing tumor size (Odds ratio = 1.36, P = 0.01), and abdominal pain (Odds ratio = 5.6, P = 0.04) significantly predicted the risk of occult metastases in univariate analysis. In multivariate analysis, only tumor size predicted the risk of occult metastases.

Conclusion

Laparoscopy remains a valuable tool in PDAC staging. Patients with either large or unresectable tumors, or presenting with abdominal pain present the highest risk for occult intra-abdominal metastases.

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Neutrophil-lymphocyte ratio is associated with prognosis in patients who underwent potentially curative resection for gastric cancer

Background and Objectives

The role of inflammation in cancer development is a well-known phenomenon that may be represented by the neutrophil-lymphocyte ratio (NLR). The present research intends to determine the impact of NLR on the survival outcome of patients with gastric cancer (GC), and to evaluate its use as a stratification factor for the staging groups.

Methods

Data regarding clinical characteristics, surgery, pathology, and follow-up were retrospectively collected from our single-center prospective database. Blood samples were obtained before surgery.

Results

A total of 383 patients (231 males) who underwent gastrectomy with lymphadenectomy were evaluated between 2009 and 2016. NLR established cutoff was 2.44, and patients were divided in NLR ≥2.44 (hNLR) and <2.44 (lNLR). hNLR patients (38.4% of the cases) had lower disease-free survival and overall survival (OS) compared to lNLR patients (P = 0.047 and P = 0.045, respectively). Risk stratification according to NLR value was done in same tumor depth (T4 and <T4), stage (III and <III) and lymph node status (N+ and N−) group of patients. The OS was significantly lower when NLR was high in same tumor depth (P = 0.032) and stage (P = 0.020), but not in same lymph node status patients (P = 0.184). In a multivariate analysis, NLR was an independent factor of worse OS (HR 1.50 95%CI 1.27-4.21, P = 0.048).

Conclusion

A high NLR was an independent risk factor for reduced survival in GC patients submitted to potentially curative resection. Calculating NLR is easily reproducible and may be incorporated in pre-operative evaluation.

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Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers

Abstract

Purpose

It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy.

Experimental design

Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients' primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor-specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration.

Results

There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005).

Conclusions

Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy.

http://ift.tt/2Flq81L

Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers

Abstract

Purpose

It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy.

Experimental design

Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients' primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor-specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration.

Results

There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005).

Conclusions

Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy.

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Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers

Abstract

Purpose

It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy.

Experimental design

Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients' primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor-specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration.

Results

There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005).

Conclusions

Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy.

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Dialysis Increases the Risk of Bladder Recurrence in Patients with Upper Tract Urothelial Cancer: A Population-Based Study

Abstract

Background

The relation of dialysis to tumor recurrence in patients with upper tract urothelial cancer (UTUC) is unknown; however, a limited number of small-scale studies suggest that patients with renal diseases prior to UTUC are more likely to exhibit bladder recurrence. We performed a population-based analysis to determine the effect of dialysis on bladder recurrence for patients with UTUC.

Methods

This retrospective cohort study included patients diagnosed with UTUC (2002–2007) from the Taiwan National Cancer Registry and divided them into two groups—dialysis and non-dialysis groups. These patients were followed up until bladder recurrence, death, or the end of 2010. Competing risk analyses adjusting covariates and death were applied to determine the relation of dialysis and bladder recurrence.

Results

Of the 5141 eligible patients, 548 (10.7%) were undergoing dialysis. The cumulative bladder recurrence was significantly higher in the dialysis group than in the non-dialysis group (29% vs. 21%, modified log-rank p < 0.001). In the multivariable analysis, the dialysis group exhibited a 64% increased bladder recurrence risk (cause-specific hazard ratio 1.64, 95% confidence interval 1.34–2.01, p < 0.001), which was confirmed using stratification and propensity score weighting methods. The other prognostic factors for bladder recurrence were sex, diabetes, cardiac disorder, Charlson Comorbidity Index, and tumor grade.

Conclusions

Despite unknown reasons, approximately one-tenth of patients with UTUC have experienced dialysis treatment. Patients undergoing dialysis have a higher risk of bladder recurrence. Various treatment and screening strategies should be developed for dialysis and non-dialysis patients.

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Desmoplastic Small Round Cell Tumor Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Results of a Phase 2 Trial

Abstract

Background

Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that primarily affects adolescents and young adults. Patients can present with many peritoneal implants. We conducted a phase 2 clinical trial utilizing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with cisplatin for DSRCT and pediatric-type abdominal sarcomas.

Patients and Methods

A prospective cohort study was performed on 20 patients, who underwent CRS-HIPEC procedures, with cisplatin from 2012 to 2013. All patients were enrolled in the phase 2 clinical trial. Patients with extraabdominal disease and in whom complete cytoreduction (CCR0–1) could not be achieved were excluded. All outcomes were recorded.

Results

Fourteen patients had DSRCT, while five patients had other sarcomas. One patient had repeat HIPEC. Patients with DSRCT had significantly longer median overall survival after surgery than patients with other tumors (44.3 vs. 12.5 months, p = 0.0013). The 3-year overall survival from time of diagnosis for DSRCT patients was 79 %. Estimated median recurrence-free survival (RFS) was 14.0 months. However, RFS for patients with DSRCT was significantly longer than for non-DSRCT patients (14.9 vs. 4.5 months, p = 0.0012). Among DSRCT patients, those without hepatic or portal metastases had longer median RFS than those with tumors at these sites (37.9 vs. 14.3 months, p = 0.02). In 100 % of patients without hepatic or portal metastasis, there was no peritoneal disease recurrence after CRS-HIPEC.

Conclusions

Complete CRS-HIPEC with cisplatin is effective in select DSRCT patients. DSRCT patients with hepatic or portal metastasis have poorer outcomes.

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Neoadjuvant Chemotherapy for Hypopharyngeal Squamous Cell Carcinoma and Personalized Medicine in Head and Neck Cancer

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Predictors for Use of Sentinel Node Biopsy and the Association with Improved Survival in Melanoma Patients Who Have Nodal Staging

Abstract

Background

It is unknown how many patients with localized melanoma undergo sentinel lymph node biopsy (SLNB) or if there is a therapeutic effect from performing nodal staging. We evaluated predictors for SLNB use and assessed if there was an association with improved survival in melanoma patients who had SLNB.

Methods

The Surveillance, Epidemiology, and End Results database was queried for clinically node-negative melanoma cases ≥ 0.75 mm in thickness treated from 2010 to 2012. Clinicopathologic factors were correlated with SLNB use, overall survival (OS), and melanoma-specific survival (MSS).

Results

Overall, 13,703 cases were included. SLNB was performed in 1479 of 3439 thin cases (43.0%), 5810 of 8522 intermediate-thickness cases (68.2%), and 916 of 1742 thick cases (52.6%). On multivariable analysis, age ≥ 70 years, thickness < 1 or > 4 mm, head/neck or trunk tumor location, being unmarried, African American race, and residing in a county with a lower level of education were significantly associated with a lower likelihood of performing SLNB (p < 0.05). Patients with intermediate-thickness or thick melanoma who had a SLNB had significantly improved OS and MSS compared with patients who did not have a SLNB (p < 0.05). On multivariable analysis, SLNB use significantly predicted for improved OS and MSS (p < 0.01).

Conclusions

Only 68.2% of intermediate-thickness and 52.6% of thick melanomas are treated with SLNB. Age, thickness, tumor location, race, marital status, and socioeconomic factors appear to influence the performance of SLNB. This data becomes more relevant with the finding that SLNB use is potentially associated with improved survival.

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Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas

Abstract

Background

The optimal treatment of high-risk soft tissue sarcomas (STS) of the extremities remains controversial. We report follow-up from a phase II study of dose-intense chemotherapy with preoperative hypofractionated radiation in this population supplemented with subsequent data from an extensive institutional experience using this regimen.

Methods

Patients with localized, intermediate- or high-grade STS of the extremity or body wall measuring > 5 cm were treated with epirubicin 30 mg/m²/day and ifosfamide 2.5 g/m²/day on days 1–4 every 21 days for 3 preoperative and 3 postoperative cycles. During cycle 2 of preoperative therapy, epirubicin was omitted, and a total of 28 Gy of radiation (8 fractions) was delivered. Twenty-five patients were treated on the phase II study (2002–2005). Fifty-one additional patients were identified from a retrospective chart review (2005–2014).

Results

The 5-year rates for overall survival, distant disease-free survival, and freedom from local regional failure were 70.4% (95% CI 59.2–83.7%), 55.9% (95% CI 44.5–70.2%), and 87.2% (95% CI 77.9–96.5%) respectively. Thirty-eight percent of tumors (29/76) demonstrated ≥ 90% pathologic response. Wound complications occurred in 32% (24/76) of patients.

Discussion

Treatment with preoperative radiation and pre- and post-operative epirubicin and ifosfamide was associated with favorable clinical outcomes. Survival and recurrence rates were comparable to those reported with other preoperative chemotherapy regimens in high-risk extremity sarcomas. Use of trimodality therapy should be considered for appropriate high-risk STS patients.

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Laparoscopic-Assisted Modified Intersphincter Resection for Ultralow Rectal Cancer

Abstract

Background

Intersphincter resection (ISR) is considered to be a superior technique offering sphincter preservation in patients with ultralow rectal cancer.1 Because high-definition laparoscopy offers wider and clearer vision into the narrow pelvic cavity and intersphincteric space, ISR has been further refined.2 However, functional outcome after ISR has not been optimal. More than half of patients receiving ISR suffer partial or even complete anal incontinence.3 We therefore propose a laparoscopic-assisted modified ISR, with the aim of improving sphincter function following ISR.

Methods

The video describes the technique for performing such laparoscopic-assisted modified ISR in a 62-year-old woman with ultralow rectal cancer (3 cm from anal verge). Preoperative staging by endorectal ultrasound and pelvic magnetic resonance imaging revealed stage I rectal cancer (cT₂N₀M₀). The operation consisted of an abdominal and a perineal phase. The abdominal phase routinely involved colonic mobilization with high ligation of inferior mesenteric vessels, total mesorectal excision (TME), as well as transabdominal intersphincteric dissection. The procedure for laparoscopic TME was performed according to our published method.4 Along the TME dissection plane, the puborectalis could be reached and the intersphincteric space was entered posterolaterally. The hiatal ligament at the posterior side of the rectum was transected afterwards. The dissection of the intersphincteric space was continued caudally at the anterior side of the rectum. The distal bowel wall was mobilized for 2 cm from the lower edge of the tumor to obtain adequate distal margin. At this point, circular dissection of the intersphincteric space was completed. After the abdominal phase, perineal dissection was performed with wide exposure by use of a hooked self-retaining retractor. The lower margin of the tumor was identified under direct vision. We developed a modified ISR technique. Resection of the mucosa and internal sphincter was initiated 2 cm distal to the lower edge of the tumor at the tumor side to obtain the necessary distal margin. Meanwhile, at the opposite side of the tumor, the resection line was just above the dentate line so that partial dentate line could be preserved. After removal of the specimen en bloc per anus, the pelvic cavity was generously irrigated with diluted povidone iodine solutions. The distal margin of the specimen was then examined by frozen section for presence of cancer. If clear, coloanal anastomosis was performed using a handsewn technique. The colon was rotated 90° and anastomosed to the anal canal with interrupted absorbable 3–0 sutures. Finally, a pelvic suction drain was placed, and a temporary diverting stoma made in the terminal ileum.

Results

There were no intraoperative complications. The operating time was 180 min. Blood loss was 50 mL. The distal margin was clear, and the final pathology was pT₂N₀M₀. The patient underwent an uneventful recovery. She began sphincter-strengthening exercises 2 weeks after surgery. The stoma was closed after examinations 3 months later. No local recurrence or distant metastasis was found. At 12-month follow-up, in terms of sphincteric function, the patient was continent to solids, liquids, and flatus.

Conclusions

Laparoscopic-assisted modified intersphincter resection for ultralow rectal cancer is safe and feasible. This technique should be considered whenever possible as a means to offer sphincter preservation and improve sphincter function in patients with ultralow rectal cancer.

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Chemotherapy with or Without Definitive Radiation Therapy in Inoperable Pancreatic Cancer

Abstract

Background

The LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC.

Methods

Using the NCDB, patients with American Joint Committee on Cancer (AJCC) clinical stage T2–4, N0–1, M0 adenocarcinoma of the pancreas from 2004 to 2014 were analyzed. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions or ≥ 5 Gy per fraction [i.e., stereotactic body radiation therapy (SBRT)] were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively.

Results

13,004 patients met inclusion criteria, of whom 7034 (54%) received CT and 5970 (46%) received CRT. After PSM, 5215 patients remained in each cohort. The CRT cohort demonstrated better overall survival (OS) compared with CT alone, with median and 1-year OS of 12 versus 10 months, and 50% and 41%, respectively (p < 0.001). On multivariable analysis, CRT was associated with superior OS with hazard ratio of 0.79 (95% confidence interval 0.76–0.83) compared with CT alone.

Conclusions

In our series, addition of definitive radiotherapy to CT was associated with better OS when compared with CT alone in LAPC. Definitive radiotherapy should remain a treatment option for LAPC, but optimal selection criteria remain unclear.

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Robot-Assisted Technique for Total Gastrectomy and D2 Lymphadenectomy with Anomalous Vasculature

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Detection of Parathyroid Autofluorescence Using Near-Infrared Imaging: A Multicenter Analysis of Concordance Between Different Surgeons

Abstract

Background

Parathyroid glands (PGs) exhibit autofluorescence (AF) when excited by near-infrared laser. This multicenter study aims to analyze how this imaging could facilitate the detection of PGs during thyroidectomy and parathyroidectomy procedures.

Methods

This was a retrospective Institutional Review Board-approved analysis of prospectively collected data at three centers. Near-infrared fluorescence imaging (NIFI) was used to detect AF from PGs during thyroidectomy and parathyroidectomy procedures. Logistic regression analysis was performed to assess the utility of NIFI to identify PGs and concordance at these centers.

Results

Overall, 210 patients underwent total thyroidectomy (n = 95), thyroid lobectomy (n = 41), and parathyroidectomy (n = 74) (n = 70 per center). Using NIFI, AF was detected from 98% of visually identified PGs. Upon initial exploration, 46% of PGs were not visible to the naked eye due to coverage by soft tissue, but AF from these glands could be detected by NIFI without any further dissection. Overall, a median of one PG per patient was detected by NIFI in this fashion before being identified visually (p = nonsignificant between centers). On logistic regression, smaller PGs were more likely to be missed visually, but localized by AF on NIFI (odds ratio with increasing size, 0.91; p = 0.02).

Conclusions

In our experience, NIFI facilitated PG identification by detecting their AF, before conventional recognition by the surgeon, in 37–67% of the time. Despite the variability in this rate across centers, there was a concordance in detecting AF from 97 to 99% of the PGs using NIFI. We suggest the incorporation of AF on NIFI alongside conventional visual cues to aid identification of PGs during neck operations.

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