[Neurocognition: Impact of radiotherapy].

Related Articles

[Neurocognition: Impact of radiotherapy].

Bull Cancer. 2017 Dec 26;:

Authors: Delphine A

Abstract
The cognitive evaluation is essential to arrest the impact of brain tumours on brain functions. Radiation therapy on the brain has side effects, which can impact on the cognitive functioning. The cognitive disorders constitute a predictive factor of the quality of life of the patients impacting on their autonomy, as well as on their social and professional life. This problem thus takes a more and more important place in the reflection on the cancer care. A better detection of these cognitive disorders requires a better cognitive evaluation from the diagnosis. What would allow the implementation of preventive actions upstream. This prospect of improvement of the coverage of the cognitive consequences of the irradiation should allow a better social reinstatement after the treatment, as well as a facilitation for the preservation of autonomy and functional independence. However, a complete cognitive evaluation is expensive in time and asks for a qualified personnel, which often slows down the exploration and the follow-up of the disorders.

PMID: 29287892 [PubMed - as supplied by publisher]

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Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario

Publication date: Available online 30 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Addeo Alfredo, Tabbò Fabrizio, Robinson Tim, Buffoni Lucio, Novello Silvia




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Loco-regional treatment for castration-resistant prostate cancer: is there any rationale?A critical review from the AFU-GETUG

Publication date: Available online 30 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jean-Baptiste Beauval, Yohann Loriot, Christophe Hennequin, François Rozet, Philippe Barthelemy, Delphine Borchiellini, Friederike Schlürmann Constans, Emmanuel Gross, Denis Maillet, Gilles Pasticier, Géraldine Pignot, Marc-Olivier Timsit, Sébastien Vincendeau, Guillaume Ploussard, Paul Sargos
Emerging evidence from population-based and retrospective series suggests a potential improvement of clinical outcomes in metastatic prostate cancer. Moreover, metastasis-directed treatment has shown encouraging results in this setting. There is an increasing interest in exploring the potential of local therapies in advanced prostate cancer, but this has rarely been specifically addressed in the castration-resistant state, whether non-metastatic or metastatic. A review of relevant articles was performed on the oncologic benefit of local treatment of the primary tumor or metastasis-targeted treatment in castration-resistant prostate cancer patients. The main goal of this strategy is to delay introduction of a new systemic agent to maintain quality of life and potentially to limit resistance. Further investigation is required to provide high-level evidence for the oncologic benefit of this treatment modality.



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Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario

Publication date: Available online 30 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Addeo Alfredo, Tabbò Fabrizio, Robinson Tim, Buffoni Lucio, Novello Silvia




http://ift.tt/2CtAk7P

Loco-regional treatment for castration-resistant prostate cancer: is there any rationale?A critical review from the AFU-GETUG

Publication date: Available online 30 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jean-Baptiste Beauval, Yohann Loriot, Christophe Hennequin, François Rozet, Philippe Barthelemy, Delphine Borchiellini, Friederike Schlürmann Constans, Emmanuel Gross, Denis Maillet, Gilles Pasticier, Géraldine Pignot, Marc-Olivier Timsit, Sébastien Vincendeau, Guillaume Ploussard, Paul Sargos
Emerging evidence from population-based and retrospective series suggests a potential improvement of clinical outcomes in metastatic prostate cancer. Moreover, metastasis-directed treatment has shown encouraging results in this setting. There is an increasing interest in exploring the potential of local therapies in advanced prostate cancer, but this has rarely been specifically addressed in the castration-resistant state, whether non-metastatic or metastatic. A review of relevant articles was performed on the oncologic benefit of local treatment of the primary tumor or metastasis-targeted treatment in castration-resistant prostate cancer patients. The main goal of this strategy is to delay introduction of a new systemic agent to maintain quality of life and potentially to limit resistance. Further investigation is required to provide high-level evidence for the oncologic benefit of this treatment modality.



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Comparison of detection methods for HPV status as a prognostic marker for loco-regional control after radiochemotherapy in patients with HNSCC

To compare six HPV detection methods in pre-treatment FFPE tumour samples from patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who received postoperative (N = 175) or primary (N = 90) radiochemotherapy.

http://ift.tt/2CoPZYi

In reply to recent letter to editor regarding: Towards consensus reporting of radiation induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints

Publication date: Available online 30 December 2017
Source:Practical Radiation Oncology
Author(s): Tobias R. Chapman, Stephen R. Bowen, Smith Apisarnthanarax




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Stereotactic radiosurgery for multiple brain metastases: Results of multi-centre benchmark planning studies

Publication date: Available online 30 December 2017
Source:Practical Radiation Oncology
Author(s): David J. Eaton, Jonathan Lee, Ian Paddick
PurposeStereotactic radiosurgery is indicated for treatment of multiple brain metastases. Various treatment platforms are available, but most comparisons are limited to single centre studies. As part of a national commissioning programme, benchmark planning cases were completed by 21 clinical centres, providing a unique dataset of current practice across a large number of providers and equipment platforms.Methods and MaterialsTwo brain metastases cases were provided, with images and structures pre-drawn, involving three and seven lesions. Centres produced plans according to their local practice, which were reviewed centrally using metrics for target coverage, selectivity, gradient fall-off and normal tissue sparing.Results50 plans were submitted, using 24 treatment platforms. 11 plans were revised following feedback, including two centres who acquired a new platform; and one other centre accepted a restriction of service. All centres prioritised coverage, with the prescription isodose covering ≥95% of 233/235 target volumes. Selectivity was much more variable, especially for smaller lesions, and when combined with poor gradient indices resulted in large volumes of normal tissue being irradiated. Tomotherapy submissions were outliers for either selectivity or gradient index, but other platforms could produce plans with relatively low gradient indices for larger lesion volumes. There was more variation among Varian and Elekta linac plans than for Gamma Knife and Cyberknife, and larger differences for smaller targets, both inter- and intra-treatment-platform. Doses to normal brain and brainstem were highest when margins were applied, but improvements were possible by re-planning alone.ConclusionsMulti-centre benchmarking exercises have highlighted some variation in clinical practice and priorities, with a few outliers. Most platforms are able to achieve comparable plans, except for the smallest volumes and when larger planning margins are used. The data will be used to progress standardisation and quality improvement of national services, and can provide useful guidance for centres worldwide.



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Regarding: “Towards consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints”

Publication date: Available online 29 December 2017
Source:Practical Radiation Oncology
Author(s): Naoko Sanuki




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Optimal imaging surveillance after stereotactic ablative radiation therapy for early-stage non-small cell lung cancer: Findings of an International Delphi Consensus Study

Publication date: Available online 30 December 2017
Source:Practical Radiation Oncology
Author(s): Timothy K. Nguyen, Suresh Senan, Jeffery D. Bradley, Kevin Franks, Meredith Giuliani, Matthias Guckenberger, Mark Landis, Billy W. Loo, Alexander V. Louie, Hiroshi Onishi, Heidi Schmidt, Robert Timmerman, Gregory M.M. Videtic, David A. Palma
PurposeImaging after stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer can detect recurrences and second primary lung cancers; however, the optimal follow-up practice of these patients remains unclear. We sought to establish consensus recommendations for surveillance after SABR.Methods and materialsInternational opinion leaders in thoracic radiation oncology and radiology were invited to participate (n = 31), with 11 accepting (9 radiation oncologists, 2 radiologists). Consensus-building was achieved using a 3-round Delphi process. Participants rated their agreement/disagreement with statements using a 5-point Likert scale. An a priori threshold of ≥75% agreement/disagreement was required for consensus.ResultsA 100% response rate was achieved and final consensus statements were approved by all participants. The consensus statements were: (1.1) thoracic computed tomography (CT) scans should be ordered routinely in follow-up; (1.2) if there is a suspicion for local recurrence (LR), fludeoxyglucose positron emission tomography/CT scans are strongly recommended. Otherwise, there is limited evidence to guide routine use of fludeoxyglucose positron emission tomography /CT; (1.3) CT imaging is not recommended at 6 weeks, but is recommended at months 3, 6, and 12 in year 1 and then every 6 months in year 2 and annually in years 3 through 5; (1.4) after 5 years, CT imaging should continue, although no consensus was reached regarding the frequency. (2.1) Response Evaluation Criteria in Solid Tumors 1.1 criteria are not sufficient for detecting LR; (2.2) a formal scoring system, informed by validated data, should be used to classify high-risk imaging features predictive of LR; (2.3) CT findings suspicious for LR include: infiltration into adjacent structures, bulging margins, sustained growth, mass-like growth, spherical growth, craniocaudal growth, and loss of air bronchograms. (3) Salvage therapy without pathologic confirmation of recurrence is acceptable if imaging findings are highly suspicious and a biopsy is not safe/feasible or if an attempted biopsy was nondiagnostic.ConclusionsThese guidelines provide international expert consensus on areas of uncertainty in the management of early-stage non-small cell lung cancer patients after SABR.



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In reply to recent letter to editor regarding: Towards consensus reporting of radiation induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints

Publication date: Available online 30 December 2017
Source:Practical Radiation Oncology
Author(s): Tobias R. Chapman, Stephen R. Bowen, Smith Apisarnthanarax




http://ift.tt/2lrHhiD

Stereotactic radiosurgery for multiple brain metastases: Results of multi-centre benchmark planning studies

Publication date: Available online 30 December 2017
Source:Practical Radiation Oncology
Author(s): David J. Eaton, Jonathan Lee, Ian Paddick
PurposeStereotactic radiosurgery is indicated for treatment of multiple brain metastases. Various treatment platforms are available, but most comparisons are limited to single centre studies. As part of a national commissioning programme, benchmark planning cases were completed by 21 clinical centres, providing a unique dataset of current practice across a large number of providers and equipment platforms.Methods and MaterialsTwo brain metastases cases were provided, with images and structures pre-drawn, involving three and seven lesions. Centres produced plans according to their local practice, which were reviewed centrally using metrics for target coverage, selectivity, gradient fall-off and normal tissue sparing.Results50 plans were submitted, using 24 treatment platforms. 11 plans were revised following feedback, including two centres who acquired a new platform; and one other centre accepted a restriction of service. All centres prioritised coverage, with the prescription isodose covering ≥95% of 233/235 target volumes. Selectivity was much more variable, especially for smaller lesions, and when combined with poor gradient indices resulted in large volumes of normal tissue being irradiated. Tomotherapy submissions were outliers for either selectivity or gradient index, but other platforms could produce plans with relatively low gradient indices for larger lesion volumes. There was more variation among Varian and Elekta linac plans than for Gamma Knife and Cyberknife, and larger differences for smaller targets, both inter- and intra-treatment-platform. Doses to normal brain and brainstem were highest when margins were applied, but improvements were possible by re-planning alone.ConclusionsMulti-centre benchmarking exercises have highlighted some variation in clinical practice and priorities, with a few outliers. Most platforms are able to achieve comparable plans, except for the smallest volumes and when larger planning margins are used. The data will be used to progress standardisation and quality improvement of national services, and can provide useful guidance for centres worldwide.



http://ift.tt/2lxJLLA

Regarding: “Towards consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints”

Publication date: Available online 29 December 2017
Source:Practical Radiation Oncology
Author(s): Naoko Sanuki




http://ift.tt/2lnSgJP

Optimal imaging surveillance after stereotactic ablative radiation therapy for early-stage non-small cell lung cancer: Findings of an International Delphi Consensus Study

Publication date: Available online 30 December 2017
Source:Practical Radiation Oncology
Author(s): Timothy K. Nguyen, Suresh Senan, Jeffery D. Bradley, Kevin Franks, Meredith Giuliani, Matthias Guckenberger, Mark Landis, Billy W. Loo, Alexander V. Louie, Hiroshi Onishi, Heidi Schmidt, Robert Timmerman, Gregory M.M. Videtic, David A. Palma
PurposeImaging after stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer can detect recurrences and second primary lung cancers; however, the optimal follow-up practice of these patients remains unclear. We sought to establish consensus recommendations for surveillance after SABR.Methods and materialsInternational opinion leaders in thoracic radiation oncology and radiology were invited to participate (n = 31), with 11 accepting (9 radiation oncologists, 2 radiologists). Consensus-building was achieved using a 3-round Delphi process. Participants rated their agreement/disagreement with statements using a 5-point Likert scale. An a priori threshold of ≥75% agreement/disagreement was required for consensus.ResultsA 100% response rate was achieved and final consensus statements were approved by all participants. The consensus statements were: (1.1) thoracic computed tomography (CT) scans should be ordered routinely in follow-up; (1.2) if there is a suspicion for local recurrence (LR), fludeoxyglucose positron emission tomography/CT scans are strongly recommended. Otherwise, there is limited evidence to guide routine use of fludeoxyglucose positron emission tomography /CT; (1.3) CT imaging is not recommended at 6 weeks, but is recommended at months 3, 6, and 12 in year 1 and then every 6 months in year 2 and annually in years 3 through 5; (1.4) after 5 years, CT imaging should continue, although no consensus was reached regarding the frequency. (2.1) Response Evaluation Criteria in Solid Tumors 1.1 criteria are not sufficient for detecting LR; (2.2) a formal scoring system, informed by validated data, should be used to classify high-risk imaging features predictive of LR; (2.3) CT findings suspicious for LR include: infiltration into adjacent structures, bulging margins, sustained growth, mass-like growth, spherical growth, craniocaudal growth, and loss of air bronchograms. (3) Salvage therapy without pathologic confirmation of recurrence is acceptable if imaging findings are highly suspicious and a biopsy is not safe/feasible or if an attempted biopsy was nondiagnostic.ConclusionsThese guidelines provide international expert consensus on areas of uncertainty in the management of early-stage non-small cell lung cancer patients after SABR.



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"Asian Pac J Cancer Prev"[jour]; +34 new citations

34 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Asian Pac J Cancer Prev"[jour]

These pubmed results were generated on 2017/12/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer

Abstract

Purpose

In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC).

Methods

In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant.

Results

Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%).

Conclusions

In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

http://ift.tt/2CrpgYL

Incidence, risk and prognostic role of anti-epidermal growth factor receptor-induced skin rash in biliary cancer: a meta-analysis

Abstract

Background

Anti-epidermal growth factor receptor (EGFR)-induced skin rash is a common adverse event and is considered a prognostic factor of various cancers. However, the role of rash is rarely known in biliary cancer, possibly owing to the low incidence of this frequently fatal malignancy. We thus performed a meta-analysis to investigate the incidence, risk and prognostic significance of skin rash related to anti-EGFR treatment for biliary cancer.

Methods

Eligible studies were enrolled after a systematic search of electronic databases. A fixed-effects or random-effects model was utilized according to the heterogeneity.

Results

Fourteen clinical trials published between 2006 and 2017 comprising 1,106 patients with advanced biliary cancer were included. The overall incidence of all-grade and high-grade (grade ≥3) rash was 78.2% [95% confidence interval (CI) 70.4–84.3] and 11.3% (7.6–16.5), respectively. Anti-EGFR treatment correlates with a significantly increased risk of all-grade [risk ratio (RR) 7.37, 95% CI 5.11–10.64, p < 0.0001] and high-grade (RR 6.94, 95% CI 1.89–25.45, p = 0.0035) rash compared with control medication. Higher grades of skin rash correlate with a higher objective response rate (RR 3.50, 95% CI 1.47–8.33, p = 0.0048), and a longer overall [hazard ratio (HR) 0.47, 95% CI 0.31–0.71, p = 0.0003) and progression-free survival (HR 0.51, 95% CI 0.36–0.72, p = 0.0001) compared with lower grades or no rash in patients who received anti-EGFR treatment.

Conclusions

Anti-EGFR treatment correlates with an increased risk of skin rash in advanced biliary cancer. Stratifying patients by the severity of rash may have major implications for survival benefit regarding anti-EGFR treatment for biliary cancer.

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Incidence, risk and prognostic role of anti-epidermal growth factor receptor-induced skin rash in biliary cancer: a meta-analysis

Abstract

Background

Anti-epidermal growth factor receptor (EGFR)-induced skin rash is a common adverse event and is considered a prognostic factor of various cancers. However, the role of rash is rarely known in biliary cancer, possibly owing to the low incidence of this frequently fatal malignancy. We thus performed a meta-analysis to investigate the incidence, risk and prognostic significance of skin rash related to anti-EGFR treatment for biliary cancer.

Methods

Eligible studies were enrolled after a systematic search of electronic databases. A fixed-effects or random-effects model was utilized according to the heterogeneity.

Results

Fourteen clinical trials published between 2006 and 2017 comprising 1,106 patients with advanced biliary cancer were included. The overall incidence of all-grade and high-grade (grade ≥3) rash was 78.2% [95% confidence interval (CI) 70.4–84.3] and 11.3% (7.6–16.5), respectively. Anti-EGFR treatment correlates with a significantly increased risk of all-grade [risk ratio (RR) 7.37, 95% CI 5.11–10.64, p < 0.0001] and high-grade (RR 6.94, 95% CI 1.89–25.45, p = 0.0035) rash compared with control medication. Higher grades of skin rash correlate with a higher objective response rate (RR 3.50, 95% CI 1.47–8.33, p = 0.0048), and a longer overall [hazard ratio (HR) 0.47, 95% CI 0.31–0.71, p = 0.0003) and progression-free survival (HR 0.51, 95% CI 0.36–0.72, p = 0.0001) compared with lower grades or no rash in patients who received anti-EGFR treatment.

Conclusions

Anti-EGFR treatment correlates with an increased risk of skin rash in advanced biliary cancer. Stratifying patients by the severity of rash may have major implications for survival benefit regarding anti-EGFR treatment for biliary cancer.

http://ift.tt/2CclN3E

Different applicabilities of the etch-bleach-seal technique for treating opacities on permanent incisor damage by molar incisor hypomineralisation in three young patients

Enamel opacity on anterior teeth can be prejudicial for the aesthetic appearance of affected patients. Patients with molar incisor hypomineralisation, for example, present opacities that can range from discrete white mottling to extensive yellow-brown discolourations. They can request a treatment to improve their aesthetic conditions. Many techniques have been considered to manage this condition. Wright developed a technique called etch–bleach–seal, which showed promising results for the management of anterior enamel opacities. The aims of this report are to present this technique and to analyse its benefits and inconveniences.

http://ift.tt/2pZMXVy

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

Summary

Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, where the majority of patients experienced no or minimum clinical benefits. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor-specific antigens, neoantigens, are generated by somatic mutations which are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity such as neoantigens, the likelihood of toxic effects is likely to be very limited. However, understanding the interaction between neoantigens and the host immune system has remained to be a big challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progresses of the different strategies in predicting, identifying and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Eir0nA

Pretreatment of Probiotic Bifico Ameliorates Colitis-Associated Cancer in Mice: Transcriptome and Gut Flora Profiling

Abstract

Individuals with inflammatory bowel disease (IBD) are at a high risk for developing colitis-associated cancer (CAC). Strategies to block the process from IBD to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane (AOM) and dextran sodium sulphate (DSS) induced colitis-associated cancer in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of thirty-five C57BL/6 mice were collected and examined for degree of inflammation and tumorigenesis. Methods of cDNA microarray, comparative 16S rRNA sequencing were performed to observe Bifico-target alterations in gene expression and microbiota structure. We found pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including chemokine C-X-C motif ligand 1 (CXCL1), CXCL2, CXCL3, and CXCL5, which were all ligands of C-X-C motif receptor 2 (CXCR2). 16S rRNA sequencing demonstrated that Bifico decreased the abundance of genus Desulfovibrio, Mucispirillum and Odoribacter, while a bloom of genus Lactobacillus was detected. Notably, we found abundance of these Bifico-target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies demonstrate that oral administration of Bifico can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus and CXCR2 signaling.

This article is protected by copyright. All rights reserved.

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Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway

Abstract

Cdc37 is an important partner for HSP90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulated cell survival remained unclear in colorectal carcinoma. Here, we investigated the expression of Cdc37 and its clinical significance in colorectal carcinoma, and systematically explored the role of Cdc37 in colorectal carcinoma cell survival both in vitro and in vivo and the underlying mechanism. Our results showed that Cdc37 was remarkably up-regulated in colorectal carcinoma, which facilitated cell survival mainly by promoting cell proliferation, G1-S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of CDK4 to activate the RB1 signaling pathway, followed by the increased expression of Bcl-2 and Bcl-xL, which ultimately promoted the cell survival in colorectal carcinoma. Moreover, knockdown of CDK4 reversed the Cdc37-mediated effect in promoting the progression of CRC. Our findings demonstrated that Cdc37 played a critical role in promoting colorectal carcinoma cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patient.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Eir1rE

Dietary acrylamide intake and risk of breast cancer: the Japan Public Health Center-based Prospective Study

Abstract

Acrylamide forms during cooking and is classified as a probable carcinogen in humans, mandating the need for epidemiological studies of dietary acrylamide and cancers. However, the risk of dietary acrylamide exposure to breast cancer in Japanese women has not been assessed. We investigated the association between dietary acrylamide intake and risk of breast cancer in the Japan Public Health Center-based Prospective Study. The present study included 48,910 women aged 45-74 years who responded to a 5-year follow-up survey questionnaire. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. During an average of 15.4 years of follow up, 792 breast cancers were diagnosed. Energy-adjusted dietary acrylamide intake was not associated with the risk of breast cancer (adjusted hazard ratio for highest versus lowest tertile=0.95, 95% confidence intervals: 0.79-1.14, p-trend=0.58). Further, no significant associations were observed when stratified analyses were conducted by smoking status, coffee consumption, alcohol consumption, body mass index, menopausal status, estrogen receptor status, and progesterone receptor status. In conclusion, dietary acrylamide intake was not associated with the risk of breast cancer in this population-based prospective cohort study of Japanese women.

This article is protected by copyright. All rights reserved.

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CCL5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment

Summary

Chemokines and their receptors have key roles in cancer progression. This study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when CCL5 neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling.

This article is protected by copyright. All rights reserved.

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IL-6/STAT3 promotes prostate cancer resistance to androgen deprivation therapy via regulating PTTG1 expression

Summary

Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration-resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen-independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen-dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen-deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44⁺CD24^- cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by IL-6 via activated STAT3 directly binding to the region -500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that IL-6/STAT3 activation can increase PTTG1 expression and consequently promote the resistance to ADT in CRPC via inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC.

This article is protected by copyright. All rights reserved.

http://ift.tt/2q1kZbW

A third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice

Summary

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.

This article is protected by copyright. All rights reserved.

http://ift.tt/2EfCR63

Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug

Summary

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in an MHC-unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

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Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

Summary

Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, where the majority of patients experienced no or minimum clinical benefits. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor-specific antigens, neoantigens, are generated by somatic mutations which are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity such as neoantigens, the likelihood of toxic effects is likely to be very limited. However, understanding the interaction between neoantigens and the host immune system has remained to be a big challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progresses of the different strategies in predicting, identifying and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

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Pretreatment of Probiotic Bifico Ameliorates Colitis-Associated Cancer in Mice: Transcriptome and Gut Flora Profiling

Abstract

Individuals with inflammatory bowel disease (IBD) are at a high risk for developing colitis-associated cancer (CAC). Strategies to block the process from IBD to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane (AOM) and dextran sodium sulphate (DSS) induced colitis-associated cancer in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of thirty-five C57BL/6 mice were collected and examined for degree of inflammation and tumorigenesis. Methods of cDNA microarray, comparative 16S rRNA sequencing were performed to observe Bifico-target alterations in gene expression and microbiota structure. We found pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including chemokine C-X-C motif ligand 1 (CXCL1), CXCL2, CXCL3, and CXCL5, which were all ligands of C-X-C motif receptor 2 (CXCR2). 16S rRNA sequencing demonstrated that Bifico decreased the abundance of genus Desulfovibrio, Mucispirillum and Odoribacter, while a bloom of genus Lactobacillus was detected. Notably, we found abundance of these Bifico-target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies demonstrate that oral administration of Bifico can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus and CXCR2 signaling.

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Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway

Abstract

Cdc37 is an important partner for HSP90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulated cell survival remained unclear in colorectal carcinoma. Here, we investigated the expression of Cdc37 and its clinical significance in colorectal carcinoma, and systematically explored the role of Cdc37 in colorectal carcinoma cell survival both in vitro and in vivo and the underlying mechanism. Our results showed that Cdc37 was remarkably up-regulated in colorectal carcinoma, which facilitated cell survival mainly by promoting cell proliferation, G1-S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of CDK4 to activate the RB1 signaling pathway, followed by the increased expression of Bcl-2 and Bcl-xL, which ultimately promoted the cell survival in colorectal carcinoma. Moreover, knockdown of CDK4 reversed the Cdc37-mediated effect in promoting the progression of CRC. Our findings demonstrated that Cdc37 played a critical role in promoting colorectal carcinoma cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patient.

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Dietary acrylamide intake and risk of breast cancer: the Japan Public Health Center-based Prospective Study

Abstract

Acrylamide forms during cooking and is classified as a probable carcinogen in humans, mandating the need for epidemiological studies of dietary acrylamide and cancers. However, the risk of dietary acrylamide exposure to breast cancer in Japanese women has not been assessed. We investigated the association between dietary acrylamide intake and risk of breast cancer in the Japan Public Health Center-based Prospective Study. The present study included 48,910 women aged 45-74 years who responded to a 5-year follow-up survey questionnaire. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. During an average of 15.4 years of follow up, 792 breast cancers were diagnosed. Energy-adjusted dietary acrylamide intake was not associated with the risk of breast cancer (adjusted hazard ratio for highest versus lowest tertile=0.95, 95% confidence intervals: 0.79-1.14, p-trend=0.58). Further, no significant associations were observed when stratified analyses were conducted by smoking status, coffee consumption, alcohol consumption, body mass index, menopausal status, estrogen receptor status, and progesterone receptor status. In conclusion, dietary acrylamide intake was not associated with the risk of breast cancer in this population-based prospective cohort study of Japanese women.

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CCL5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment

Summary

Chemokines and their receptors have key roles in cancer progression. This study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when CCL5 neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling.

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IL-6/STAT3 promotes prostate cancer resistance to androgen deprivation therapy via regulating PTTG1 expression

Summary

Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration-resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen-independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen-dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen-deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44⁺CD24^- cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by IL-6 via activated STAT3 directly binding to the region -500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that IL-6/STAT3 activation can increase PTTG1 expression and consequently promote the resistance to ADT in CRPC via inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC.

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A third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice

Summary

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.

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Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug

Summary

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in an MHC-unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

This article is protected by copyright. All rights reserved.

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Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

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Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

http://ift.tt/2lkucHJ

Melatonin and breast cancer: evidences from preclinical and human studies

Publication date: Available online 29 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Peter Kubatka, Pavol Zubor, Dietrich Büsselberg, Taeg Kyu Kwon, Mariusz Adamek, Daniel Petrovic, Radka Opatrilova, Katarina Gazdikova, Martin Caprnda, Luis Rodrigo, Jan Danko, Peter Kruzliak
The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women.The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed.



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Melatonin and breast cancer: evidences from preclinical and human studies

Publication date: Available online 29 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Peter Kubatka, Pavol Zubor, Dietrich Büsselberg, Taeg Kyu Kwon, Mariusz Adamek, Daniel Petrovic, Radka Opatrilova, Katarina Gazdikova, Martin Caprnda, Luis Rodrigo, Jan Danko, Peter Kruzliak
The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women.The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed.



http://ift.tt/2lq66dV

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

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Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

http://ift.tt/2lkucHJ

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

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Immunological hallmarks of cis -DDP-resistant Lewis lung carcinoma cells

Abstract

Purpose

Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.

Methods

Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.

Results

When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.

Conclusion

Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

http://ift.tt/2BWBtDO

Immunological hallmarks of cis -DDP-resistant Lewis lung carcinoma cells

Abstract

Purpose

Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.

Methods

Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.

Results

When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.

Conclusion

Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

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Progression to bone-marrow carcinomatosis and extraosseous legion during treatment with radium-223 for multiple bone metastases

Abstract

A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.

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Progression to bone-marrow carcinomatosis and extraosseous legion during treatment with radium-223 for multiple bone metastases

Abstract

A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.

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Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia

Abstract

Early death (ED) remains the most critical issue in the current care of patients with acute promyelocytic leukemia (APL). Very limited data are available regarding ED in patients with relapsed APL. In this retrospective study, 285 de novo and 79 relapsed patients were included. All patients received single-agent arsenic trioxide as induction therapy. The differences in baseline clinical features, incidence, causes, and prognostic factors of ED were compared between the two patient cohorts. The relapse cohort exhibited a better overall condition than the de novo cohort upon hospital admission. The ED rate in the relapsed patients (24.1%) was somewhat higher than that in the de novo patients (17.9%), although the difference was not significant (P = 0.219). For both cohorts, hemorrhage was the main cause of ED, followed by differentiation syndrome, infection, and other causes. Increased serum creatinine level, older age, male sex, white blood cell (WBC) count > 10 × 10⁹/L, and fibrinogen < 1 g/L were independently risk factors for ED in the de novo patients, whereas WBC count > 10 × 10⁹/L, elevated serum uric acid level, and D-dimer > 4 mg/L were independent risk factors for ED in the relapsed patients. These data furnish clinically relevant information that might be useful for designing more appropriate risk-adapted treatment protocols aimed at reducing ED rate in patients with relapsed APL.

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Pediatric radiology: practical imaging evaluation of infants and children (1st edn), by Edward Lee (ed)

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Pediatric radiology: practical imaging evaluation of infants and children (1st edn), by Edward Lee (ed)

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RING-finger protein 6 amplification activates JAK/STAT3 pathway by modifying SHP-1 ubiquitylation and associates with poor outcome in colorectal cancer

Objective The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer (CRC). We aimed to explore the mechanical, biological and clinical role of RNF6 in CRC initiation and progression. Design The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real time PCR, western blot and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and vitro. Role of RNF6 in modulating SHP-1 expression was examined by co-immunoprecipitation and confocal microscopy respectively. Results The copy number of RNF6 was significantly amplified in CRC and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with CRC patients with poor prognosis. GSEA analysis revealed cell proliferation and invasion-related genes were enriched in RNF6 high-expressed CRC cells as well as in patients from TCGA dataset. Down-regulation of RNF6 impaired the CRC cell proliferation and invasion in vitro and vivo. RNF6 may activate JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. Conclusions Genomic amplification drives RNF6 overexpression in CRC. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors.

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Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer - Early Results from the COMPASS Trial.

Purpose: To perform real time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.  Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results:Sixty three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared to those with the basal-like subtype (P=0.004). The best progression free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Conclusions:Prospective genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.

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CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by 1) depleting mouse macrophages in nude mice with liposomal clodronate injection, and 2) injecting tumor cells into nude vs. NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival. Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.

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RING-finger protein 6 amplification activates JAK/STAT3 pathway by modifying SHP-1 ubiquitylation and associates with poor outcome in colorectal cancer

Objective The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer (CRC). We aimed to explore the mechanical, biological and clinical role of RNF6 in CRC initiation and progression. Design The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real time PCR, western blot and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and vitro. Role of RNF6 in modulating SHP-1 expression was examined by co-immunoprecipitation and confocal microscopy respectively. Results The copy number of RNF6 was significantly amplified in CRC and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with CRC patients with poor prognosis. GSEA analysis revealed cell proliferation and invasion-related genes were enriched in RNF6 high-expressed CRC cells as well as in patients from TCGA dataset. Down-regulation of RNF6 impaired the CRC cell proliferation and invasion in vitro and vivo. RNF6 may activate JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. Conclusions Genomic amplification drives RNF6 overexpression in CRC. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors.

http://ift.tt/2zO6Z5d

Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer - Early Results from the COMPASS Trial.

Purpose: To perform real time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.  Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results:Sixty three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared to those with the basal-like subtype (P=0.004). The best progression free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Conclusions:Prospective genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.

http://ift.tt/2CbDGiT

CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by 1) depleting mouse macrophages in nude mice with liposomal clodronate injection, and 2) injecting tumor cells into nude vs. NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival. Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.

http://ift.tt/2zO8lN1

Trial design for brain metastases: The Lancet Oncology: Jan 2018

Ross Camidge discusses RANO's papers on clinical trial design for patients with brain metastases.

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[Clinical Picture] A rare location of palpebral rhabdomyosarcoma

We report the case of a 2-year-old child with a tumour of the left upper eyelid, which had been growing rapidly for the past 2 weeks before he presented at the paediatric emergency department in July, 2014. On examination, the child was in good general health, afebrile, and presented with a substantial chemosis of the left eye, which was complicated with ptosis and preseptal cellulitis. On admission to the emergency department, several potential diagnoses were discussed: cellulitis, insect sting, post-traumatic haematoma, vascular tumour, and rhabdomyosarcoma (figure, A).

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[Perspectives] Yale Cancer Center Precision Medicine Tumor Board: two patients, one targeted therapy, different outcomes

A 71-year-old male patient was diagnosed with localised prostate cancer with a Gleason score of 10 and was initially treated with radiotherapy and leuprolide. 2 years later, he developed oligometastatic recurrence in the scapula, which was irradiated, and he continued on leuprolide therapy. After another 3 years, he developed recurrence with widespread adenopathy, for which he received multiple lines of therapy including docetaxel, sipleucel-T, enzalutamide, and abiraterone over 5 years. He was then referred to the Yale Cancer Center and enrolled in two successive clinical trials, with disease progression.

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[Review] Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints.

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[Perspectives] Embracing the imperfect: new beginnings after cancer

If you had visited the Visual Arts Centre in Singapore in late May this year, you would have found yourself surrounded by a profusion of strange and beautiful spheroid objects, ranging in size from a grapefruit to a large pumpkin, but looking more like colossal pebbles washed up on a giant's cove. Made up of 174 unique sculptures, Beginnings represents the 174 lymph nodes removed from ceramicist Suan Ong's neck and chest after she was diagnosed with stage IV thyroid cancer. Using the bean-shaped lymph node as her inspiration, she spent 3 years creating the works, and through the process learned a lesson in accepting fallibility in her art that would allow her to accept it in herself.

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[Perspectives] A rare case of osteoblastoma from medieval Tuscany

In antiquity, tumours were less common conditions than nowadays, probably due to the shorter life expectancy of our ancestors, their different lifestyle and dietary habits, and their reduced exposure to risk factors such as environmental pollution. Additionally, it is not possible to obtain reliable cancer estimates through the analysis of ancient human remains. However, the field of paleopathology is inevitably biased because only bone lesions can be detected, limiting the evidence available to bone tumours, or metastasis to the bones originating from soft-tissue tumours.

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[Editorial] The NHS: failing to deliver on Beveridge's promise?

Just over 75 years have passed since Sir William Beveridge published his report outlining the parameters for a social welfare state for the UK, which crucially included "comprehensive health and rehabilitation services for prevention and cure of disease". Beveridge's report inspired Labour Minister of Health Aneurin Bevan to establish the National Health Service (NHS). Although the vision of Beveridge and Bevan—to provide free, adequate, and equally accessible health care for all—remains in high regard today, the execution and delivery of their goal is currently falling short.

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[Comment] Complications during minimal invasive thoracic surgery: are new surgeons prepared?

The approach to surgery of the thorax has substantially evolved in the past decade. Although open techniques (thoracotomy) are still used in lung cancer surgery today, most lung resections can be safely done by video-assisted thoracic surgery. In the past 5 years, robotic-assisted thoracic surgery has also used new technology to facilitate minimal invasive surgery. In 2017, it is already well established that minimal invasive surgery to resect lung tumours provides equivalent oncological benefits to, with less pain and more rapid recovery than, open surgery procedures.

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[Correspondence] Carfilzomib for relapsed or refractory multiple myeloma

In the second interim analysis of the randomised phase 3 ENDEAVOR study published in The Lancet Oncology, Meletios Dimopoulos and colleagues1 found that, with long-term follow-up, patients with relapsed or refractory multiple myeloma treated with carfilzomib and dexamethasone (median 47·6 months [95% CI 42·5-not evaluable]) had significantly longer overall survival than those who were treated with bortezomib and dexamethasone (40·0 months [32·6–42·3]; hazard ratio 0·791 [95% CI 0·648–0·964]). Although the study was done as an open-label study because of the different dosing schedules for the two proteasome inhibitors, baseline clinical and treatment characteristics, including various prognostic factors and subsequent antimyeloma therapies, were generally balanced between groups.

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[Comment] Perspectives: call for papers

Since its launch in 2000, The Lancet Oncology has been committed to publishing content that advances clinical practice, challenges the status quo, and advocates change in health policy. During these years, the Cancer and Society section has explored the intersection between clinical practice, the portrayal of cancer in the wider world or mainstream media, and the perception of oncology with patients and an informed lay audience. In 2018, we refresh this section of the journal to focus articles on the views and experiences of clinicians in practice and the art of medicine.

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[Review] Systematic review of health-related quality of life and patient-reported outcome measures in gestational trophoblastic disease: a parallel synthesis approach

Gestational trophoblastic disease is a rare complication of pregnancy that can develop into cancer. Medical outcomes of gestational trophoblastic disease are well researched, but the effect of the disease on health-related quality of life (HRQOL) requires attention if care is to be improved. This systematic review was designed to establish the effect of gestational trophoblastic disease and its treatment on HRQOL and to identify the appropriateness of HRQOL measures. Quantitative studies found HRQOL in long-term survivors of gestational trophoblastic disease to be at or above population norms.

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[Review] Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs.

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[Review] Leptomeningeal metastases in non-small-cell lung cancer

Leptomeningeal metastasis is a complication of advanced non-small-cell lung cancer (NSCLC). Diagnosis and monitoring of leptomeningeal metastasis are challenging, and are based on neurological, radiographic, and cerebrospinal fluid findings. Substantial progress has been made in several key aspects of management of leptomeningeal metastasis, including improved characterisation of the genetic profiles, generation of clinically relevant animal models, advances in cerebrospinal fluid liquid biopsy with improved cytology and genotyping analysis, and the development of therapeutic agents with greater CNS penetration.

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[Comment] Introduction to the Yale Precision Medicine Tumor Board

The Precision Medicine Tumor Board (PMTB) at the Yale Cancer Center (New Haven, CT, USA) was established to integrate tumour molecular profiling data with clinical care. The PMTB exists alongside disease-specific tumour boards at the Yale Cancer Center, and primarily serves patients with refractory disease and those with actionable somatic alterations.

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[Correspondence] Carfilzomib for relapsed or refractory multiple myeloma – Authors' reply

In the randomised, phase 3 ENDEAVOR trial in patients with relapsed or refractory multiple myeloma, we showed that treatment with carfilzomib and dexamethasone compared with bortezomib and dexamethasone significantly improved progression-free survival (18·7 months with carfilzomib vs 9·4 months with bortezomib; hazard ratio [HR] 0·53 [95% CI 0·44–0·65]; p<0·0001) and overall survival (47·6 vs 40·0 months; HR 0·79 [0·65–0·96], p=0·010).1,2 ENDEAVOR was the first head-to-head study of two different proteasome inhibitors in relapsed or refractory multiple myeloma, and these results established the combination of carfilzomib administered at 56 mg/m2 twice weekly with dexamethasone as a new standard of care in this disease setting.

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[Correspondence] Dacomitinib in NSCLC: a positive trial with little clinical impact

I have read with great interest the report of the ARCHER 1050 trial by Li-Yong Wu and colleagues.1 The findings showed the superiority of dacomitinib over gefitinib in terms of progression-free survival in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) with the common EGFR mutation. The results were initially presented at the 2017 ASCO Annual Meeting and, at that time, it was the first time that a second-generation EGFR tyrosine kinase inhibitor (TKI) showed a clear and clinically significant improvement in terms of progression-free survival (14·7 months [95% CI 11·1–16·6] with dacomitinib vs 9·2 months [9·1–11·0] with gefitinib).

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[Correspondence] Implementation of a community-based breast cancer management programme

In their Series paper, Catherine Duggan and colleagues1 state that a community-based programme for breast health is a successful example of an intervention to increase breast health-care capacity in a country like Peru. The authors indicate that 75% of breast cancers detected are in advanced stages;1 a situation that can be improved through effective and early community detection.

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[Correspondence] Dacomitinib in NSCLC: a positive trial with little clinical impact – Authors' reply

Alfredo Addeo has noted two issues in our trial1 of dacomitinib versus gefitinib in patients with non-small-cell lung cancer (NSCLC): the fact that we did not discuss central nervous system (CNS) penetration by dacomitinib and the similar progression-free survival in the Asian and non-Asian intention-to-treat (ITT) subpopulations.

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[Correspondence] PD-1 inhibition in sarcoma still needs investigation

In their Article, Hussein Tawbi and colleagues1 suggest that pembrolizumab might have clinical activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. However, the SARC028 trial was not designed to specifically assess the activity of pembrolizumab in undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma, and this study was negative for its primary endpoint.

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[Correspondence] PD-1 inhibition in sarcoma still needs investigation – Authors’ reply

We appreciate the opportunity to respond to Maud Toulmonde and Antoine Italiano's letter. SARC028 was a phase 2 study evaluating the safety and activity of PD-1 inhibition in advanced bone and soft tissue sarcomas and emphasised collection of biospecimens to explore immune-related biomarkers.1 We used objective response as our primary endpoint because this was a signal-finding study. We limited the soft tissue sarcoma cohort to ten patients in each of four common soft tissue sarcoma subtypes to obtain pilot data.

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[Corrections] Correction to Lancet Oncol 2017; 18: 1493–501

Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 2017; 18: 1493–501—The appendix of this Article has been updated. This correction has been made to the online version as of Dec 29, 2017.

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Hypofractionated radiation therapy (HFRT) versus conventional fractionated radiation therapy (CRT) for newly diagnosed glioblastoma patients. A propensity score matched analysis

The current treatment for newly diagnosed glioblastoma consists of surgery followed by conventional radiotherapy (CRT) with concomitant and adjuvant chemotherapy. Hypofractionated radiation therapy (HFRT) has been investigated and it resulted feasible and safe. The aim of this study was to evaluate whether HFRT can be comparable to CRT.

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Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Radhe Mohan, Kathryn D. Held, Michael D. Story, David Grosshans, Jacek Capala
In April 2016, the National Cancer Institute (NCI) hosted a multidisciplinary workshop to discuss current knowledge of the radiobiological aspects of charged particles used in cancer therapy, to identify gaps in that knowledge that may hinder the effective clinical use of charged particles and to propose research that may help fill those gaps. The workshop was organized into ten topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness (RBE) of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, omics, hypoxia and particle-induced second malignancies. Given that the most commonly used charged particle in the clinic currently is protons, much of the discussion revolved around evaluating the state of knowledge and current practice of using an RBE of 1.1 for protons. Discussion also included the potential advantages of heavier ions, notably carbon ions, due to their increased biological effectiveness, particularly for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells and potential for differentially altering immune responses. The participants identified a large number of research areas in which information is needed to inform the most effective use of charged particles in the future in clinical radiotherapy. This unique form of radiation therapy holds great promise for improving cancer treatment.



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via IFTTT

Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Radhe Mohan, Kathryn D. Held, Michael D. Story, David Grosshans, Jacek Capala
In April 2016, the National Cancer Institute (NCI) hosted a multidisciplinary workshop to discuss current knowledge of the radiobiological aspects of charged particles used in cancer therapy, to identify gaps in that knowledge that may hinder the effective clinical use of charged particles and to propose research that may help fill those gaps. The workshop was organized into ten topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness (RBE) of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, omics, hypoxia and particle-induced second malignancies. Given that the most commonly used charged particle in the clinic currently is protons, much of the discussion revolved around evaluating the state of knowledge and current practice of using an RBE of 1.1 for protons. Discussion also included the potential advantages of heavier ions, notably carbon ions, due to their increased biological effectiveness, particularly for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells and potential for differentially altering immune responses. The participants identified a large number of research areas in which information is needed to inform the most effective use of charged particles in the future in clinical radiotherapy. This unique form of radiation therapy holds great promise for improving cancer treatment.



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Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region s...

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Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the i...

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